Journal:

Sorted by: date / impact
Abstract

Four versus six cycles of CHOP chemotherapy in combination with six applications of rituximab in patients with aggressive B-cell lymphoma with favourable prognosis (FLYER): a randomised, phase 3, non-inferiority trial.

Poeschel V, Held G, Ziepert M, Witzens-Harig M, ... ,
Background
Six cycles of R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) are the standard treatment for aggressive B-cell non-Hodgkin lymphoma. In the FLYER trial, we assessed whether four cycles of CHOP plus six applications of rituximab are non-inferior to six cycles of R-CHOP in a population of patients with B-cell non-Hodgkin lymphoma with favourable prognosis.
Methods
This two-arm, open-label, international, multicentre, prospective, randomised phase 3 non-inferiority trial was done at 138 clinical sites in Denmark, Israel, Italy, Norway, and Germany. We enrolled patients aged 18-60 years, with stage I-II disease, normal serum lactate dehydrogenase concentration, ECOG performance status 0-1, and without bulky disease (maximal tumour diameter <7·5 cm). Randomisation was computer-based and done centrally in a 1:1 ratio using the Pocock minimisation algorithm after stratification for centres, stage (I vs II), and extralymphatic sites (no vs yes). Patients were assigned to receive either six cycles of R-CHOP or four cycles of R-CHOP plus two doses of rituximab. CHOP comprised cyclophosphamide (750 mg/m), doxorubicin (50 mg/m), and vincristine (1·4 mg/m, with a maximum total dose of 2 mg), all administered intravenously on day 1, plus oral prednisone or prednisolone at the discretion of the investigator (100 mg) administered on days 1-5. Rituximab was given at a dose of 375 mg/m of body surface area. Cycles were repeated every 21 days. No radiotherapy was planned except for testicular lymphoma treatment. The primary endpoint was progression-free survival after 3 years. The primary analysis was done in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of assigned treatment. A non-inferiority margin of -5·5% was chosen. The trial, which is completed, was prospectively registered at ClinicalTrials.gov, NCT00278421.
Findings
Between Dec 2, 2005, and Oct 7, 2016, 592 patients were enrolled, of whom 295 patients were randomly assigned to receive six cycles of R-CHOP and 297 were assigned to receive four cycles of R-CHOP plus two doses of rituximab. Four patients in the four-cycles group withdrew informed consent before the start of treatment, so 588 patients were included in the intention-to-treat analysis. After a median follow-up of 66 months (IQR 42-100), 3-year progression-free survival of patients who had four cycles of R-CHOP plus two doses of rituximab was 96% (95% CI 94-99), which was 3% better (lower limit of the one-sided 95% CI for the difference was 0%) than six cycles of R-CHOP, demonstrating the non-inferiority of the four-cycles regimen. 294 haematological and 1036 non-haematological adverse events were documented in the four-cycles group compared with 426 haematological and 1280 non-haematological adverse events in the six-cycles group. Two patients, both in the six-cycles group, died during study therapy.
Interpretation
In young patients with aggressive B-cell non-Hodgkin lymphoma and favourable prognosis, four cycles of R-CHOP is non-inferior to six cycles of R-CHOP, with relevant reduction of toxic effects. Thus, chemotherapy can be reduced without compromising outcomes in this population.
Funding
Deutsche Krebshilfe.

Copyright © 2019 Elsevier Ltd. All rights reserved.

Lancet: 20 Dec 2020; 394:2271-2281
Poeschel V, Held G, Ziepert M, Witzens-Harig M, ... ,
Lancet: 20 Dec 2020; 394:2271-2281 | PMID: 31868632
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

A Population-Based Registry of Patients With Inherited Cardiac Conditions and Resuscitated Cardiac Arrest.

Rucinski C, Winbo A, Marcondes L, Earle N, ... Martin A, Skinner JR
Background
The relative proportion of each cardiac inherited disease (CID) causing resuscitated sudden cardiac arrest (RSCA) on a population basis is unknown.
Objectives
This study describes the profile of patients with CIDs presenting with RSCA; their data were collected by the national Cardiac Inherited Diseases Registry New Zealand (CIDRNZ).
Methods
Data were collated from CIDRNZ probands presenting with RSCA (2002 to 2018).
Results
CID was identified in 115 (51%) of 225 RSCA cases: long QT syndrome (LQTS) (n = 48 [42%]), hypertrophic cardiomyopathy (HCM) (n = 28 [24%]), Brugada syndrome (BrS) (n = 16 [14%]), catecholaminergic polymorphic ventricular tachycardia (CPVT) (n = 9 [8%]), arrhythmogenic right ventricular cardiomyopathy (ARVC) (n = 9 [8%]), and dilated cardiomyopathy (n = 5 [4%]). Seventy-one (62%) of 115 were male. Of 725 probands from the CIDRNZ with CID, the proportion presenting with RSCA was: CPVT, 9 (53%) of 17; BrS, 16 (33%) of 49; ARVC, 9 (25%) of 36; LQTS, 48 (20%) of 238; dilated cardiomyopathy, 5 (9%) of 58; and HCM, 28 (8%) of 354. Incident activity was: normal everyday activities, 44 (40%); exercising, 33 (30%); concurrent illness, 13 (12%); sleeping, 10 (9%); drugs/medication, 9 (8%); and emotion, 2 (2%). LQTS and CPVT predominated in those <24 years of age, 30 (77%) of 39; cardiomyopathies and BrS predominated in those >24 years of age, 49 (64%) of 76. For those >40 years of age, HCM was the most common (33%) CID. A genetic diagnosis in patients with CID was made in 48 (49%) of 98 tested. Diagnosis by age range was as follows: age 1 to 14 years, 78%; age 15 to 24 years, 53%; age 25 to 39 years, 54%; and age >40 years, 26%.
Conclusions
The commonest CID identified after RSCA was LQTS; the most common CID cause of RSCA for those >40 years of age was HCM. CPVT was the CID most likely to present with RSCA and HCM the least. Genetic yield decreases with age. Only one-third of RSCA cases due to CID occurred while exercising.

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 01 Jul 2020; 75:2698-2707
Rucinski C, Winbo A, Marcondes L, Earle N, ... Martin A, Skinner JR
J Am Coll Cardiol: 01 Jul 2020; 75:2698-2707 | PMID: 32466885
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Drug-Coated Balloon Angioplasty Versus Drug-Eluting Stent Implantation in Patients With Coronary Stent Restenosis.

Giacoppo D, Alfonso F, Xu B, Claessen BEPM, ... Kastrati A, Byrne RA
Background
In patients with coronary in-stent restenosis (ISR) requiring reintervention, it is unclear if the choice of treatment should depend on whether the restenotic stent was a bare-metal stent (BMS) or a drug-eluting stent (DES).
Objectives
This study aimed to assess the comparative efficacy and safety of the 2 most frequently used treatments - angioplasty with drug-coated balloon (DCB) and repeat stenting DES - in patients with BMS-and DES-ISR.
Methods
The DAEDALUS (Difference in Antirestenotic Effectiveness of Drug-Eluting Stent and Drug-Coated Balloon Angioplasty for the Occurrence of Coronary In-Stent Restenosis) study was a pooled analysis of individual patient data from all 10 existing randomized clinical trials comparing DCB angioplasty with repeat DES implantation for the treatment of coronary ISR. In this pre-specified analysis, patients were stratified according to BMS- versus DES-ISR and treatment assigned. The primary efficacy endpoint was target lesion revascularization (TLR) at 3 years. The primary safety endpoint was a composite of all-cause death, myocardial infarction, or target lesion thrombosis at 3 years. Primary analysis was performed by mixed-effects Cox models accounting for the trial of origin. Secondary analyses included nonparsimonious multivariable adjustment accounting also for multiple lesions per patient and 2-stage analyses.
Results
A total of 710 patients with BMS-ISR (722 lesions) and 1,248 with DES-ISR (1,377 lesions) were included. In patients with BMS-ISR, no significant difference between treatments was observed in terms of primary efficacy (9.2% vs. 10.2%; hazard ratio [HR]: 0.83; 95% confidence interval [CI]: 0.51 to 1.37) and safety endpoints (8.7% vs. 7.5%; HR: 1.13; 95% CI: 0.65 to 1.96); results of secondary analyses were consistent. In patients with DES-ISR, the risk of the primary efficacy endpoint was higher with DCB angioplasty than with repeat DES implantation (20.3% vs. 13.4%; HR: 1.58; 95% CI: 1.16 to 2.13), whereas the risk of the primary safety endpoint was numerically lower (9.5% vs. 13.3%; HR: 0.69; 95% CI: 0.47 to 1.00); results of secondary analyses were consistent. Regardless of the treatment used, the risk of TLR was lower in BMS- versus DES-ISR (9.7% vs. 17.0%; HR: 0.56; 95% CI: 0.42 to 0.74), whereas safety was not significantly different between ISR types.
Conclusions
At 3-year follow-up, DCB angioplasty and repeat stenting with DES are similarly effective and safe in the treatment of BMS-ISR, whereas DCB angioplasty is significantly less effective than repeat DES implantation in the treatment DES-ISR, and associated with a nonsignificant reduction in the primary composite safety endpoint. Overall, DES-ISR is associated with higher rates of treatment failure and similar safety compared with BMS-ISR.

Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 01 Jul 2020; 75:2664-2678
Giacoppo D, Alfonso F, Xu B, Claessen BEPM, ... Kastrati A, Byrne RA
J Am Coll Cardiol: 01 Jul 2020; 75:2664-2678 | PMID: 32466881
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Validation of the Academic Research Consortium High Bleeding Risk Definition in Contemporary PCI Patients.

Cao D, Mehran R, Dangas G, Baber U, ... Sharma SK, Kini A
Background
Bleeding following percutaneous coronary intervention has important prognostic implications. The Academic Research Consortium (ARC) recently proposed a list of clinical criteria to define patients at high bleeding risk (HBR).
Objectives
This study sought to validate the ARC definition for HBR patients in a contemporary real-world cohort.
Methods
Patients undergoing coronary stenting between 2014 and 2017 at a tertiary-care center were defined as HBR if they met at least 1 major or 2 minor ARC-HBR criteria. To account for the presence of multiple criteria, patients were further stratified by the number of times they fulfilled the ARC-HBR definition. The primary endpoint was a composite of peri-procedural in-hospital or post-discharge bleeding at 1 year. Secondary endpoints included individual components of the primary bleeding endpoint, myocardial infarction, and all-cause mortality.
Results
Among 9,623 patients, 4,278 (44.4%) qualified as HBR. Moderate or severe anemia was the most common major criterion (33.2%); age ≥75 years was the most frequent minor criterion and the most common overall (46.8%). The rate of the primary bleeding endpoint at 1 year was 9.1% in HBR patients compared with 3.2% in non-HBR patients (p < 0.001), with a stepwise increase in bleeding risk corresponding to the number of times the ARC-HBR definition was fulfilled. HBR patients also experienced significantly higher rates of all secondary endpoints.
Conclusions
This study validates the ARC-HBR definition in a contemporary group of patients who underwent percutaneous coronary intervention. The ARC-HBR definition identified patients at increased risk not only for bleeding but also for thrombotic events, including all-cause mortality. Coexistence of multiple ARC-HBR criteria showed additive prognostic value.

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 01 Jul 2020; 75:2711-2722
Cao D, Mehran R, Dangas G, Baber U, ... Sharma SK, Kini A
J Am Coll Cardiol: 01 Jul 2020; 75:2711-2722 | PMID: 32466887
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Mechanistic Biomarkers Informative of Both Cancer and Cardiovascular Disease: JACC State-of-the-Art Review.

Narayan V, Thompson EW, Demissei B, Ho JE, Januzzi JL, Ky B

Cardiovascular disease (CVD) and cancer are leading causes of morbidity and mortality worldwide. Although conventionally managed as separate disease processes, recent research has lent insight into compelling commonalities between CVD and cancer, including shared mechanisms for disease development and progression. In this review, the authors discuss several pathophysiological processes common to both CVD and cancer, such as inflammation, resistance to cell death, cellular proliferation, neurohormonal stress, angiogenesis, and genomic instability, in an effort to understand common mechanisms of both disease states. In particular, the authors highlight key circulating and genomic biomarkers associated with each of these processes, as well as their associations with risk and prognosis in both cancer and CVD. The purpose of this state-of-the-art review is to further our understanding of the potential mechanisms underlying cancer and CVD by contextualizing pathways and biomarkers common to both diseases.

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 01 Jul 2020; 75:2726-2737
Narayan V, Thompson EW, Demissei B, Ho JE, Januzzi JL, Ky B
J Am Coll Cardiol: 01 Jul 2020; 75:2726-2737 | PMID: 32466889
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Evaluation of Mavacamten in Symptomatic Patients With Nonobstructive Hypertrophic Cardiomyopathy.

Ho CY, Mealiffe ME, Bach RG, Bhattacharya M, ... Wong TC, Heitner SB
Background
Patients with nonobstructive hypertrophic cardiomyopathy (nHCM) often experience a high burden of symptoms; however, there are no proven pharmacological therapies. By altering the contractile mechanics of the cardiomyocyte, myosin inhibitors have the potential to modify pathophysiology and improve symptoms associated with HCM.
Objectives
MAVERICK-HCM (Mavacamten in Adults With Symptomatic Non-Obstructive Hypertrophic Cardiomyopathy) explored the safety and efficacy of mavacamten, a first-in-class reversible inhibitor of cardiac-specific myosin, in nHCM.
Methods
The MAVERICK-HCM trial was a multicenter, double-blind, placebo-controlled, dose-ranging phase II study in adults with symptomatic nHCM (New York Heart Association functional class II/III), left ventricular ejection fraction (LVEF) ≥55%, and N-terminal pro-B-type natriuretic peptide (NT-proBNP) ≥300 pg/ml. Participants were randomized 1:1:1 to mavacamten at a pharmacokinetic-adjusted dose (targeting plasma levels of 200 or 500 ng/ml), or placebo for 16 weeks, followed by an 8-week washout. Initial dose was 5 mg daily with 1 dose titration at week 6.
Results
Fifty-nine participants were randomized (19, 21, 19 patients to 200 ng/ml, 500 ng/ml, placebo, respectively). Their mean age was 54 years, and 58% were women. Serious adverse events occurred in 10% of participants on mavacamten and in 21% participants on placebo. Five participants on mavacamten had reversible reduction in LVEF ≤45%. NT-proBNP geometric mean decreased by 53% in the pooled mavacamten group versus 1% in the placebo group, with geometric mean differences of -435 and -6 pg/ml, respectively (p = 0.0005). Cardiac troponin I (cTnI) geometric mean decreased by 34% in the pooled mavacamten group versus a 4% increase in the placebo group, with geometric mean differences of -0.008 and 0.001 ng/ml, respectively (p = 0.009).
Conclusions
Mavacamten, a novel myosin inhibitor, was well tolerated in most subjects with symptomatic nHCM. Furthermore, treatment was associated with a significant reduction in NT-proBNP and cTnI, suggesting improvement in myocardial wall stress. These results set the stage for future studies of mavacamten in this patient population using clinical parameters, including LVEF, to guide dosing. (A Phase 2 Study of Mavacamten in Adults With Symptomatic Non-Obstructive Hypertrophic Cardiomyopathy [MAVERICK-HCM]; NCT03442764).

Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 01 Jul 2020; 75:2649-2660
Ho CY, Mealiffe ME, Bach RG, Bhattacharya M, ... Wong TC, Heitner SB
J Am Coll Cardiol: 01 Jul 2020; 75:2649-2660 | PMID: 32466879
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Ascertainment Bias in the Association Between Elevated Lipoprotein(a) and Familial Hypercholesterolemia.

Trinder M, DeCastro ML, Azizi H, Cermakova L, ... Francis GA, Brunham LR
Background
Lipoprotein(a) is an atherogenic low-density lipoprotein-like particle and circulating levels are largely determined by genetics. Patients with familial hypercholesterolemia (FH) have elevated lipoprotein(a); however, it remains unclear why.
Objectives
This study compared the levels of lipoprotein(a) and associated genetic factors between individuals that were ascertained for FH clinically versus genetically.
Methods
We investigated causes of elevated lipoprotein(a) in individuals with clinically diagnosed FH (FH cohort, n = 391) and in individuals with genetically diagnosed FH from the general population (UK Biobank; n = 37,486).
Results
Patients in the FH cohort had significantly greater lipoprotein(a) levels than either the general population or non-FH dyslipidemic patients. This was accounted for by increased frequency of the rs10455872-G LPA risk allele (15.1% vs. 8.8%; p < 0.05). However, within the FH cohort, lipoprotein(a) levels did not differ based on the presence or absence of an FH-causing variant (means = 1.43 log mg/dl vs. 1.42 log mg/dl; p = 0.97). Lipoprotein(a) levels were also not statistically different between individuals with and without an FH-causing variant in the UK Biobank cohort, which represents a population sample not biased to cardiovascular ascertainment (n = 221 vs. 37,486). We performed a phenome-wide association study between LPA genotypes and 19,202 phenotypes to demonstrate that elevated lipoprotein(a) is associated with increased low-density lipoprotein cholesterol, a family history of cardiovascular disease, premature coronary artery disease, and a diagnosis of FH.
Conclusions
These results suggest that FH does not cause elevated lipoprotein(a), but that elevated lipoprotein(a) increases the likelihood that an individual with genetic FH will be clinically recognized.

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 01 Jul 2020; 75:2682-2693
Trinder M, DeCastro ML, Azizi H, Cermakova L, ... Francis GA, Brunham LR
J Am Coll Cardiol: 01 Jul 2020; 75:2682-2693 | PMID: 32466883
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Summary of Updated Recommendations for Primary Prevention of Cardiovascular Disease in Women: JACC State-of-the-Art Review.

Cho L, Davis M, Elgendy I, Epps K, ... Volgman AS,

Cardiovascular disease (CVD) remains the leading cause of morbidity and mortality for women in the United States and worldwide. There has been no American College of Cardiology (ACC)/American Heart Association guideline update specifically for the prevention of CVD in women since 2011. Since then, the body of sex-specific data has grown, in addition to updated hypertension, cholesterol, diabetes, atrial fibrillation, and primary prevention guidelines. The ACC CVD in Women Committee undertook a review of the recent guidelines and major studies to summarize recommendations pertinent to women. In this update, the authors address special topics, particularly the risk factors and treatments that have led to some controversies and confusion. Specifically, sex-related risk factors, hypertension, diabetes, hyperlipidemia, anticoagulation for atrial fibrillation, use of aspirin, perimenopausal hormone therapy, and psychosocial issues are highlighted.

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 25 May 2020; 75:2602-2618
Cho L, Davis M, Elgendy I, Epps K, ... Volgman AS,
J Am Coll Cardiol: 25 May 2020; 75:2602-2618 | PMID: 32439010
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Challenges and Special Aspects of Pulmonary Hypertension in Middle- to Low-Income Regions: JACC State-of-the-Art Review.

Hasan B, Hansmann G, Budts W, Heath A, ... Kumar RK,

Challenges and special aspects related to the management and prognosis of pulmonary hypertension (PH) in middle- to low-income regions (MLIRs) range from late presentation to comorbidities, lack of resources and expertise, cost, and rare options of lung transplantation. Expert consensus recommendations addressing the specific challenges for prevention and therapy of PH in MLIRs with limited resources have been lacking. To date, 6 MLIR-PH registries containing mostly adult patients with PH exist. Importantly, the global prevalence of PH is much higher in MLIRs compared with high-income regions: group 2 PH (left heart disease), pulmonary arterial hypertension associated with unrepaired congenital heart disease, human immunodeficiency virus, or schistosomiasis are highly prevalent. This consensus statement provides selective, tailored modifications to the current PH guidelines to address the specific challenges faced in MLIRs, resulting in the first pragmatic and cost-effective consensus recommendations for PH care providers, patients, and their families.

Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 18 May 2020; 75:2463-2477
Hasan B, Hansmann G, Budts W, Heath A, ... Kumar RK,
J Am Coll Cardiol: 18 May 2020; 75:2463-2477 | PMID: 32408981
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Worldwide Prevalence of Familial Hypercholesterolemia: Meta-Analyses of 11 Million Subjects.

Beheshti SO, Madsen CM, Varbo A, Nordestgaard BG
Background
Despite the greater prevalence of familial hypercholesterolemia (FH) in subjects with ischemic heart disease (IHD), premature IHD, and severe hypercholesterolemia (low-density lipoprotein ≥190 mg/dl), overall prevalence estimates are not available.
Objectives
The aim of this study was to provide worldwide estimates of FH prevalence in subjects with IHD, premature IHD, and severe hypercholesterolemia compared with those in the general population.
Methods
In this systematic review and meta-analyses, Embase, PubMed, and the Web of Science were searched until June 3, 2019, for peer-reviewed papers and conference abstracts reporting heterozygous FH prevalence in nonfounder populations, revealing 104 studies eligible for inclusion.
Results
Estimates of FH prevalence were pooled using random-effects meta-analyses and were 0.32% (95% confidence interval [CI]: 0.26% to 0.39% [corresponding to 1:313]) among 10,921,310 unique subjects in the general population (33,036 patients with FH) on the basis of 44 studies, 3.2% (95% CI: 2.2% to 4.3% [1:31]) among 84,479 unique subjects with IHD (2,103 patients with FH) on the basis of 28 studies, 6.7% (95% CI: 4.9% to 8.7% [1:15]) among 31,316 unique subjects with premature IHD (1,471 patients with FH) on the basis of 32 studies, and 7.2% (95% CI: 4.6% to 10.8% [1:14]) among 17,728 unique subjects with severe hypercholesterolemia (920 patients with FH) on the basis of 7 studies. FH prevalence in the general population was similar using genetic versus clinical diagnoses. Seventeen of 195 countries (9%) in the world have reported FH prevalence for the general population, leaving 178 (91%) countries in the world with unknown prevalence.
Conclusions
Compared with 1:313 among subjects in the general population, FH prevalence is 10-fold higher among those with IHD, 20-fold higher among those with premature IHD, and 23-fold higher among those with severe hypercholesterolemia. The prevalence of FH is unknown in 90% of countries in the world.

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 25 May 2020; 75:2553-2566
Beheshti SO, Madsen CM, Varbo A, Nordestgaard BG
J Am Coll Cardiol: 25 May 2020; 75:2553-2566 | PMID: 32439005
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Associations Between Cardiovascular Risk, Structural Brain Changes, and Cognitive Decline.

Song R, Xu H, Dintica CS, Pan KY, ... Bennett DA, Xu W
Background
The impact of cardiovascular risk burden on cognitive trajectories and brain structure changes remains unclear.
Objectives
This study aimed to examine whether cardiovascular risk burden assessed by the Framingham General Cardiovascular Risk Score (FGCRS) is associated with cognitive decline and structural brain differences.
Methods
Within the Rush Memory and Aging Project, 1,588 dementia-free participants (mean age: 79.5 years) were followed for up to 21 years. FGCRS was assessed at baseline and categorized into tertiles (lowest, middle, and highest). Episodic memory, semantic memory, working memory, visuospatial ability, and perceptual speed were assessed annually with a battery of 19 tests, from which composite scores were derived. A subsample (n = 378) of participants underwent magnetic resonance imaging. Structural total and regional brain volumes were estimated. Data were analyzed using linear mixed-effects models and linear regression models.
Results
In all participants, FGCRS ranged from 4 to 28 (mean score: 15.6 ± 3.7). Compared with the lowest tertile of FGCRS, the highest tertile was associated with faster decline in global cognition (β = -0.019; 95% confidence interval [CI]: -0.035 to -0.003), episodic memory (β = -0.023; 95% CI: -0.041 to -0.004), working memory (β = -0.021; 95% CI: -0.035 to -0.007), and perceptual speed (β = -0.027; 95% CI: -0.042 to -0.011) over the follow-up. In magnetic resonance imaging data analyses, higher FGCRS was related to smaller volumes of the hippocampus (β = -0.021; 95% CI: -0.042 to -0.000), gray matter (β = -1.569; 95% CI: -2.757 to -0.382), and total brain (β = -1.588; 95% CI: -2.832 to -0.344), and greater volume of white matter hyperintensities (β = 0.035; 95% CI: 0.001 to 0.069).
Conclusions
Higher cardiovascular risk burden may predict decline in episodic memory, working memory, and perceptual speed and is associated with neurodegeneration and vascular lesions in the brain.

Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 25 May 2020; 75:2525-2534
Song R, Xu H, Dintica CS, Pan KY, ... Bennett DA, Xu W
J Am Coll Cardiol: 25 May 2020; 75:2525-2534 | PMID: 32439001
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Regression of Left Ventricular Mass After Transcatheter Aortic Valve Replacement: The PARTNER Trials and Registries.

Chau KH, Douglas PS, Pibarot P, Hahn RT, ... Leon MB, Lindman BR
Background
Greater early left ventricular mass index (LVMi) regression is associated with fewer hospitalizations 1 year after transcatheter aortic valve replacement (TAVR). The association between LVMi regression and longer-term post-TAVR outcomes is unclear.
Objectives
The purpose of this study was to determine the association between LVMi regression at 1-year post-TAVR and clinical outcomes between 1 and 5 years.
Methods
Among intermediate- and high-risk patients who received TAVR in the PARTNER (Placement of Aortic Transcatheter Valves) I, II, and S3 trials or registries and were alive at 1 year, we included patients with baseline moderate or severe left ventricular hypertrophy (LVH) and paired measurements of LVMi at baseline and 1 year. The associations between LVMi regression (percent change between baseline and 1 year) and death or rehospitalization from 1 to 5 years were examined.
Results
Among 1,434 patients, LVMi was 146 g/m (interquartile range [IQR]: 133 to 168 g/m) at baseline and decreased 14.5% (IQR: 4.2% to 26.1%) to 126 g/m (IQR: 106 to 148 g/m) at 1 year. After adjustment, greater LVMi regression at 1 year was associated with lower all-cause death (adjusted hazard ratio [aHR]: 0.95 per 10% decrease in LVMi; 95% confidence interval [CI]: 0.91 to 0.98; p = 0.004; aHR of the quartile with greatest vs. least LVMi regression: 0.61; 95% CI: 0.43 to 0.86; p = 0.005). Severe LVH at 1 year was observed in 39%, which was independently associated with increased all-cause death (aHR of severe LVH vs. no LVH: 1.71; 95% CI: 1.20 to 2.44; p = 0.003). Similar associations were found for rates of cardiovascular mortality and rehospitalization.
Conclusions
Among patients with moderate or severe LVH treated with TAVR who are alive at 1 year, greater LVMi regression at 1 year is associated with lower death and hospitalization rates to 5 years. These findings may have implications for the timing of valve replacement and the role of adjunctive medical therapy after TAVR.

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 18 May 2020; 75:2446-2458
Chau KH, Douglas PS, Pibarot P, Hahn RT, ... Leon MB, Lindman BR
J Am Coll Cardiol: 18 May 2020; 75:2446-2458 | PMID: 32408979
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Blood Pressure Variation and Subclinical Brain Disease.

Ma Y, Yilmaz P, Bos D, Blacker D, ... Vernooij MW, Ikram MK
Background
Large blood pressure (BP) variability may contribute to stroke and dementia, but the mechanisms are largely unknown.
Objectives
This study investigated the association of BP variation, considering its magnitude and direction, with the presence and progression of subclinical brain disease in the general population.
Methods
This study included 2,348 participants age ≥55 years from a prospective cohort study. BP was measured at each visit every 3 to 4 years from 1990 onward. Brain magnetic resonance imaging (MRI) was performed at all visits from 2005 onward. The authors primarily assessed variation as the absolute difference in BP divided by the mean over 2 sequential visits for both systolic BP (SBP) and diastolic BP (DBP), and further assessed the direction of the variation. The authors investigated the multivariate-adjusted associations of BP variation with subsequent measurements of MRI markers of cerebral small vessel disease, brain tissue volumes, and white matter microstructural integrity. Longitudinal changes in these markers also were assessed.
Results
A large SBP variation (top vs. bottom tertiles), measured on average 7 years preceding brain MRI, was associated with higher odds of having severe white matter hyperintensities (WMH) (odds ratio [OR]: 1.32; 95% confidence interval [CI]: 1.21 to 1.43), lacunes (OR: 1.25; 95% CI: 1.04 to 1.48), and microbleeds (OR: 1.16; 95% CI: 1.03 to 1.31). Similarly, this variation was associated with smaller total brain volume and worse white matter microstructural integrity (all p < 0.001). A large SBP variation was also associated with the progression of WMH (rate ratio [RR]: 1.14; 95% CI: 1.02 to 1.27). Higher burdens of these brain imaging markers were observed with both large rises and falls in SBP. Similar findings were observed for DBP variation.
Conclusions
Elevated BP variation was associated with a wide range of subclinical brain structural changes, including MRI markers of cerebral small vessel disease, smaller brain tissue volumes, and worse white matter microstructural integrity. These subclinical brain changes could be the underlying mechanisms linking BP variation to dementia and stroke.

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 18 May 2020; 75:2387-2399
Ma Y, Yilmaz P, Bos D, Blacker D, ... Vernooij MW, Ikram MK
J Am Coll Cardiol: 18 May 2020; 75:2387-2399 | PMID: 32408975
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Physiological Stratification of Patients With Angina Due to Coronary Microvascular Dysfunction.

Rahman H, Demir OM, Khan F, Ryan M, ... Webb A, Perera D
Background
Coronary microvascular dysfunction (CMD) is defined by diminished flow reserve. Functional and structural CMD endotypes have recently been described, with normal and elevated minimal microvascular resistance, respectively.
Objectives
This study determined the mechanism of altered resting and maximal flow in CMD endotypes.
Methods
A total of 86 patients with angina but no obstructive coronary disease underwent coronary pressure and flow measurement during rest, exercise, and adenosine-mediated hyperemia and were classified as the reference group or as patients with CMD by a coronary flow reserve threshold of 2.5; functional or structural endotypes were distinguished by a hyperemic microvascular resistance threshold of 2.5 mm Hg/cm/s. Endothelial function was assessed by forearm blood flow (FBF) response to acetylcholine, and nitric oxide synthase (NOS) activity was defined as the inverse of FBF reserve to N-monomethyl-L-arginine.
Results
Of the 86 patients, 46 had CMD (28 functional, 18 structural), and 40 patients formed the reference group. Resting coronary blood flow (CBF) (24.6 ± 2.0 cm/s vs. 16.6 ± 3.9 cm/s vs. 15.1 ± 4.7 cm/s; p < 0.001) and NOS activity (2.27 ± 0.96 vs. 1.77 ± 0.59 vs. 1.30 ± 0.16; p < 0.001) were higher in the functional group compared with the structural CMD and reference groups, respectively. The structural group had lower acetylcholine FBF augmentation than the functional or reference group (2.1 ± 1.8 vs. 4.1 ± 1.7 vs. 4.5 ± 2.0; p < 0.001). On exercise, oxygen demand was highest (rate-pressure product: 22,157 ± 5,497 beats/min/mm Hg vs. 19,519 ± 4,653 beats/min/mm Hg vs. 17,530 ± 4,678 beats/min/mm Hg; p = 0.004), but peak CBF was lowest in patients with structural CMD compared with the functional and reference groups.
Conclusions
Functional CMD is characterized by elevated resting flow that is linked to enhanced NOS activity. Patients with structural CMD have endothelial dysfunction, which leads to diminished peak CBF augmentation and increased demand during exercise. The value of pathophysiologically stratified therapy warrants investigation.

Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 25 May 2020; 75:2538-2549
Rahman H, Demir OM, Khan F, Ryan M, ... Webb A, Perera D
J Am Coll Cardiol: 25 May 2020; 75:2538-2549 | PMID: 32439003
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Longevity genes, cardiac ageing, and the pathogenesis of cardiomyopathy: implications for understanding the effects of current and future treatments for heart failure.

Packer M

The two primary molecular regulators of lifespan are sirtuin-1 (SIRT1) and mammalian target of rapamycin complex 1 (mTORC1). Each plays a central role in two highly interconnected pathways that modulate the balance between cellular growth and survival. The activation of SIRT1 [along with peroxisome proliferator-activated receptor-gamma coactivator (PGC-1α) and adenosine monophosphate-activated protein kinase (AMPK)] and the suppression of mTORC1 (along with its upstream regulator, Akt) act to prolong organismal longevity and retard cardiac ageing. Both activation of SIRT1/PGC-1α and inhibition of mTORC1 shifts the balance of cellular priorities so as to promote cardiomyocyte survival over growth, leading to cardioprotective effects in experimental models. These benefits may be related to direct actions to modulate oxidative stress, organellar function, proinflammatory pathways, and maladaptive hypertrophy. In addition, a primary shared benefit of both SIRT1/PGC-1α/AMPK activation and Akt/mTORC1 inhibition is the enhancement of autophagy, a lysosome-dependent degradative pathway, which clears the cytosol of dysfunctional organelles and misfolded proteins that drive the ageing process by increasing oxidative and endoplasmic reticulum stress. Autophagy underlies the ability of SIRT1/PGC-1α/AMPK activation and Akt/mTORC1 suppression to extend lifespan, mitigate cardiac ageing, alleviate cellular stress, and ameliorate the development and progression of cardiomyopathy; silencing of autophagy genes abolishes these benefits. Loss of SIRT1/PGC-1α/AMPK function or hyperactivation of Akt/mTORC1 is a consistent feature of experimental cardiomyopathy, and reversal of these abnormalities mitigates the development of heart failure. Interestingly, most treatments that have been shown to be clinically effective in the treatment of chronic heart failure with a reduced ejection fraction have been reported experimentally to exert favourable effects to activate SIRT1/PGC-1α/AMPK and/or suppress Akt/mTORC1, and thereby, to promote autophagic flux. Therefore, the impairment of autophagy resulting from derangements in longevity gene signalling is likely to represent a seminal event in the evolution and progression of cardiomyopathy.

© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.

Eur Heart J: 26 May 2020; epub ahead of print
Packer M
Eur Heart J: 26 May 2020; epub ahead of print | PMID: 32460327
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Subcutaneous Selatogrel Inhibits Platelet Aggregation in Patients With Acute Myocardial Infarction.

Sinnaeve P, Fahrni G, Schelfaut D, Spirito A, ... Atar S, Valgimigli M
Background
Oral P2Y receptor antagonists exhibit delayed onset of platelet inhibition in patients with acute myocardial infarction (AMI). Selatogrel is a potent, highly selective, and reversible P2Y receptor antagonist with a rapid onset and short duration of action.
Objectives
This study sought to assess inhibition of platelet aggregation following subcutaneous administration of selatogrel in patients with AMI.
Methods
Patients with AMI were randomized to a single subcutaneous dose of selatogrel of 8 or 16 mg. The primary endpoint was response to treatment (P2Y reaction units <100; measured by VerifyNow) at 30 min post-dose. Safety was assessed up to 48 h post-injection.
Results
Forty-seven patients received selatogrel 8 mg (n = 24) or 16 mg (n = 23) followed by ticagrelor (n = 43) or clopidogrel (n = 1). The proportion of responders 30 min post-dose was 91% (one-sided 97.5% confidence interval [CI]: 80% to 100%) and 96% (97.5% CI: 87% to 100%) with 8 and 16 mg, respectively (p values for responders >85% target; p = 0.142 and p = 0.009, respectively). Response rates were independent from type of AMI presentation, age, or sex. A similar response rate was observed at 15 min (8 mg: 75% [97.5% CI: 58% to 100%]; 16 mg: 91% [97.5% CI: 80% to 100%]), which was sustained at 60 min post-dose (8 mg: 75% [97.5% CI: 58% to 100%]; 16 mg: 96% [97.5% CI: 87% to 100%]). At 15 min, median P2Y reaction units was 51 (range: 4 to 208) for 8 mg and 9 (range: 2 to 175) for 16 mg. Selatogrel was well tolerated, without major bleeding complications.
Conclusions
Single-dose subcutaneous administration of selatogrel in patients with AMI was safe and induced a profound, rapid, and dose-related antiplatelet response. (A Medical Research Study to Evaluate the Effects of ACT-246475 in Adults With Heart Attack; NCT03487445, 2018-000765-36 [EudraCT]).

Copyright © 2020. Published by Elsevier Inc.

J Am Coll Cardiol: 25 May 2020; 75:2588-2597
Sinnaeve P, Fahrni G, Schelfaut D, Spirito A, ... Atar S, Valgimigli M
J Am Coll Cardiol: 25 May 2020; 75:2588-2597 | PMID: 32439008
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Cardiac Scintigraphy With Technetium-99m-Labeled Bone-Seeking Tracers for Suspected Amyloidosis: JACC Review Topic of the Week.

Hanna M, Ruberg FL, Maurer MS, Dispenzieri A, ... Witteles RM, Grogan M

Technetium-labeled cardiac scintigraphy (i.e., Tc-PYP scan) has been repurposed for the diagnosis of transthyretin amyloid cardiomyopathy (ATTR-CM). Validated in cohorts of patients with heart failure and echocardiographic and/or cardiac magnetic resonance imaging findings suggestive of cardiac amyloidosis, cardiac scintigraphy can confirm the diagnosis of ATTR-CM only when combined with blood and urine testing to exclude a monoclonal protein. Multisocietal guidelines support the nonbiopsy diagnosis of ATTR-CM using cardiac scintigraphy, yet emphasize its use in the appropriate clinical context and the crucial need to rule out light chain amyloid cardiomyopathy. Although increased awareness of ATTR-CM and the advent of effective therapy have led to rapid adoption of diagnostic scintigraphy, there is heterogeneity in adherence to consensus guidelines. This perspective outlines clinical scenarios wherein findings on technetium-labeled cardiac scintigraphy have been misinterpreted, reviews causes of false-negative and false-positive results, and provides strategies to avoid costly and potentially fatal misdiagnoses.

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 08 Jun 2020; 75:2851-2862
Hanna M, Ruberg FL, Maurer MS, Dispenzieri A, ... Witteles RM, Grogan M
J Am Coll Cardiol: 08 Jun 2020; 75:2851-2862 | PMID: 32498813
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Prevention of aortic dissection and aneurysm via an ALDH2-mediated switch in vascular smooth muscle cell phenotype.

Yang K, Ren J, Li X, Wang Z, ... Chen Y, Xu F
Aims
Aortic aneurysm/dissection (AAD) is a life-threatening disorder lacking effective pharmacotherapeutic remedies. Aldehyde dehydrogenase 2 (ALDH2) polymorphism is tied with various risk factors for AAD including hypertension, atherosclerosis, and hypercholesterolaemia although direct correlation between the two remains elusive.
Methods and results
Two independent case-control studies were conducted involving 307 AAD patients and 399 healthy controls in two geographically distinct areas in China. Our data revealed that subjects carrying mutant ALDH2 gene possessed a ∼50% reduced risk of AAD compared with wild-type (WT) alleles. Using 3-aminopropionitrile fumarate (BAPN)- and angiotensin II (Ang II)-induced AAD animal models, inhibition of ALDH2 was found to retard development of AAD. Mechanistically, ALDH2 inhibition ablated pathological vascular smooth muscle cell (VSMC) phenotypical switch through interaction with myocardin, a determinant of VSMC contractile phenotype. Using microarray and bioinformatics analyses, ALDH2 deficiency was found to down-regulate miR-31-5p, which further altered myocardin mRNA level. Gain-of-function and loss-of-function studies verified that miR-31-5p significantly repressed myocardin level and aggravated pathological VSMC phenotypical switch and AAD, an effect that was blunted by ALDH2 inhibition. We next noted that ALDH2 deficiency increased Max expression and decreased miR-31-5p level. Moreover, ALDH2 mutation or inhibition down-regulated levels of miR-31-5p while promoting myocardin downstream contractile genes in the face of Ang II in primary human VSMCs.
Conclusions
ALDH2 deficiency is associated with a lower risk of AAD in patients and mice, possibly via suppressing VSMC phenotypical switch in a miR-31-5p-myocardin-dependent manner. These findings favour a role for ALDH2 and miR-31-5p as novel targets for AAD therapy.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: [email protected]

Eur Heart J: 17 May 2020; epub ahead of print
Yang K, Ren J, Li X, Wang Z, ... Chen Y, Xu F
Eur Heart J: 17 May 2020; epub ahead of print | PMID: 32428930
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

The thrombotic risk of spaceflight: has a serious problem been overlooked for more than half of a century?

Limper U, Tank J, Ahnert T, Maegele M, ... Hein M, Jordan J

The first ever venous thrombotic condition associated with spaceflight, an internal jugular vein thrombus requiring anticoagulation, has recently been reported. Systematic investigation of space travel-associated thrombotic risk has not been conducted. Cellular, animal, and human studies performed in ground-based models and in actual weightlessness revealed influences of weightlessness and gravity on the blood coagulation system. However, human study populations were small and limited to highly selected participants. Evidence in individuals with medical conditions and older persons is lacking. Evidence for thrombotic risk in spaceflight is unsatisfactory. This issue deserves further study in heterogeneous, high risk populations to find prevention strategies and to enable safe governmental and touristic human spaceflight.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: [email protected]

Eur Heart J: 17 May 2020; epub ahead of print
Limper U, Tank J, Ahnert T, Maegele M, ... Hein M, Jordan J
Eur Heart J: 17 May 2020; epub ahead of print | PMID: 32428936
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Reduction of hospitalizations for myocardial infarction in Italy in the COVID-19 era.

De Rosa S, Spaccarotella C, Basso C, Calabrò MP, ... Indolfi C,
Aims
To evaluate the impact of the COVID-19 pandemic on patient admissions to Italian cardiac care units (CCUs).
Methods and results
We conducted a multicentre, observational, nationwide survey to collect data on admissions for acute myocardial infarction (AMI) at Italian CCUs throughout a 1 week period during the COVID-19 outbreak, compared with the equivalent week in 2019. We observed a 48.4% reduction in admissions for AMI compared with the equivalent week in 2019 (P < 0.001). The reduction was significant for both ST-segment elevation myocardial infarction [STEMI; 26.5%, 95% confidence interval (CI) 21.7-32.3; P = 0.009] and non-STEMI (NSTEMI; 65.1%, 95% CI 60.3-70.3; P < 0.001). Among STEMIs, the reduction was higher for women (41.2%; P = 0.011) than men (17.8%; P = 0.191). A similar reduction in AMI admissions was registered in North Italy (52.1%), Central Italy (59.3%), and South Italy (52.1%). The STEMI case fatality rate during the pandemic was substantially increased compared with 2019 [risk ratio (RR) = 3.3, 95% CI 1.7-6.6; P < 0.001]. A parallel increase in complications was also registered (RR = 1.8, 95% CI 1.1-2.8; P = 0.009).
Conclusion
Admissions for AMI were significantly reduced during the COVID-19 pandemic across Italy, with a parallel increase in fatality and complication rates. This constitutes a serious social issue, demanding attention by the scientific and healthcare communities and public regulatory agencies.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: [email protected]

Eur Heart J: 14 May 2020; epub ahead of print
De Rosa S, Spaccarotella C, Basso C, Calabrò MP, ... Indolfi C,
Eur Heart J: 14 May 2020; epub ahead of print | PMID: 32412631
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Pulmonary Vascular Endothelialitis, Thrombosis, and Angiogenesis in Covid-19.

Ackermann M, Verleden SE, Kuehnel M, Haverich A, ... Mentzer SJ, Jonigk D
Background
Progressive respiratory failure is the primary cause of death in the coronavirus disease 2019 (Covid-19) pandemic. Despite widespread interest in the pathophysiology of the disease, relatively little is known about the associated morphologic and molecular changes in the peripheral lung of patients who die from Covid-19.
Methods
We examined 7 lungs obtained during autopsy from patients who died from Covid-19 and compared them with 7 lungs obtained during autopsy from patients who died from acute respiratory distress syndrome (ARDS) secondary to influenza A(H1N1) infection and 10 age-matched, uninfected control lungs. The lungs were studied with the use of seven-color immunohistochemical analysis, micro-computed tomographic imaging, scanning electron microscopy, corrosion casting, and direct multiplexed measurement of gene expression.
Results
In patients who died from Covid-19-associated or influenza-associated respiratory failure, the histologic pattern in the peripheral lung was diffuse alveolar damage with perivascular T-cell infiltration. The lungs from patients with Covid-19 also showed distinctive vascular features, consisting of severe endothelial injury associated with the presence of intracellular virus and disrupted cell membranes. Histologic analysis of pulmonary vessels in patients with Covid-19 showed widespread thrombosis with microangiopathy. Alveolar capillary microthrombi were 9 times as prevalent in patients with Covid-19 as in patients with influenza (P<0.001). In lungs from patients with Covid-19, the amount of new vessel growth - predominantly through a mechanism of intussusceptive angiogenesis - was 2.7 times as high as that in the lungs from patients with influenza (P<0.001).
Conclusions
In our small series, vascular angiogenesis distinguished the pulmonary pathobiology of Covid-19 from that of equally severe influenza virus infection. The universality and clinical implications of our observations require further research to define. (Funded by the National Institutes of Health and others.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 20 May 2020; epub ahead of print
Ackermann M, Verleden SE, Kuehnel M, Haverich A, ... Mentzer SJ, Jonigk D
N Engl J Med: 20 May 2020; epub ahead of print | PMID: 32437596
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Remdesivir for the Treatment of Covid-19 - Preliminary Report.

Beigel JH, Tomashek KM, Dodd LE, Mehta AK, ... Lane HC,
Background
Although several therapeutic agents have been evaluated for the treatment of coronavirus disease 2019 (Covid-19), none have yet been shown to be efficacious.
Methods
We conducted a double-blind, randomized, placebo-controlled trial of intravenous remdesivir in adults hospitalized with Covid-19 with evidence of lower respiratory tract involvement. Patients were randomly assigned to receive either remdesivir (200 mg loading dose on day 1, followed by 100 mg daily for up to 9 additional days) or placebo for up to 10 days. The primary outcome was the time to recovery, defined by either discharge from the hospital or hospitalization for infection-control purposes only.
Results
A total of 1063 patients underwent randomization. The data and safety monitoring board recommended early unblinding of the results on the basis of findings from an analysis that showed shortened time to recovery in the remdesivir group. Preliminary results from the 1059 patients (538 assigned to remdesivir and 521 to placebo) with data available after randomization indicated that those who received remdesivir had a median recovery time of 11 days (95% confidence interval [CI], 9 to 12), as compared with 15 days (95% CI, 13 to 19) in those who received placebo (rate ratio for recovery, 1.32; 95% CI, 1.12 to 1.55; P<0.001). The Kaplan-Meier estimates of mortality by 14 days were 7.1% with remdesivir and 11.9% with placebo (hazard ratio for death, 0.70; 95% CI, 0.47 to 1.04). Serious adverse events were reported for 114 of the 541 patients in the remdesivir group who underwent randomization (21.1%) and 141 of the 522 patients in the placebo group who underwent randomization (27.0%).
Conclusions
Remdesivir was superior to placebo in shortening the time to recovery in adults hospitalized with Covid-19 and evidence of lower respiratory tract infection. (Funded by the National Institute of Allergy and Infectious Diseases and others; ACCT-1 ClinicalTrials.gov number, NCT04280705.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 21 May 2020; epub ahead of print
Beigel JH, Tomashek KM, Dodd LE, Mehta AK, ... Lane HC,
N Engl J Med: 21 May 2020; epub ahead of print | PMID: 32445440
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Prognostic Value of Magnetic Resonance Phenotype in Patients With Arrhythmogenic Right Ventricular Cardiomyopathy.

Aquaro GD, De Luca A, Cappelletto C, Raimondi F, ... Di Bella G, Sinagra G
Background
Cardiac magnetic resonance (CMR) is widely used to assess tissue and functional abnormalities in arrhythmogenic right ventricular cardiomyopathy (ARVC). Recently, a ARVC risk score was proposed to predict the 5-year risk of malignant ventricular arrhythmias in patients with ARVC. However, CMR features such as fibrosis, fat infiltration, and left ventricular (LV) involvement were not considered.
Objectives
The authors sought to evaluate the prognostic role of CMR phenotype in patients with definite ARVC and to evaluate the effectiveness of the novel 5-year ARVC risk score to predict cardiac events in different CMR presentations.
Methods
A total of 140 patients with definite ARVC were enrolled (mean age 42 ± 17 years, 97 males) in this multicenter prospective registry. As per study design, CMR was performed in all the patients at enrollment. The novel 5-year ARVC risk score was retrospectively calculated using the patient\'s characteristics at the time of enrollment. During a median follow-up of 5 years (2 to 8 years), the combined endpoint of sudden cardiac death, appropriate implantable cardioverter-defibrillator intervention, and aborted cardiac arrest was considered.
Results
CMR was completely negative in 14 patients (10%), isolated right ventricular (RV) involvement was found in 58 (41%), biventricular in 52 (37%), and LV dominant in 16 (12%). During the follow-up, 48 patients (34%) had major events, but none occurred in patients with negative CMR. At Kaplan-Meier analysis, patients with LV involvement (LV dominant and biventricular) had a worse prognosis than those with lone RV (p < 0.0001). At multivariate analysis, the LV involvement, a LV-dominant phenotype, and the 5-year ARVC risk score were independent predictors of major events. The estimated 5-year risk was able to predict the observed risk in patients with lone RV but underestimated the risk in those with LV involvement.
Conclusions
Different CMR presentations of ARVC are associated with different prognoses. The 5-year ARVC risk score is valid for the estimation of risk in patients with lone-RV presentation but underestimated the risk when LV is involved.

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 08 Jun 2020; 75:2753-2765
Aquaro GD, De Luca A, Cappelletto C, Raimondi F, ... Di Bella G, Sinagra G
J Am Coll Cardiol: 08 Jun 2020; 75:2753-2765 | PMID: 32498802
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Comparison of in-hospital outcomes and readmissions for valve-in-valve transcatheter aortic valve replacement vs. reoperative surgical aortic valve replacement: a contemporary assessment of real-world outcomes.

Hirji SA, Percy ED, Zogg CK, Malarczyk A, ... Yazdchi F, Kaneko T
Aims
We sought to perform a head-to-head comparison of contemporary 30-day outcomes and readmissions between valve-in-valve transcatheter aortic valve replacement (VIV-TAVR) patients and a matched cohort of high-risk reoperative surgical aortic valve replacement (re-SAVR) patients using a large, multicentre, national database.
Methods and results
We utilized the nationally weighted 2012-16 National Readmission Database claims to identify all US adult patients with degenerated bioprosthetic aortic valves who underwent either VIV-TAVR (n = 3443) or isolated re-SAVR (n = 3372). Thirty-day outcomes were compared using multivariate analysis and propensity score matching (1:1). Unadjusted, VIV-TAVR patients had significantly lower 30-day mortality (2.7% vs. 5.0%), 30-day morbidity (66.4% vs. 79%), and rates of major bleeding (35.8% vs. 50%). On multivariable analysis, re-SAVR was a significant risk factor for both 30-day mortality [adjusted odds ratio (aOR) of VIV-SAVR (vs. re-SAVR) 0.48, 95% confidence interval (CI) 0.28-0.81] and 30-day morbidity [aOR for VIV-TAVR (vs. re-SAVR) 0.54, 95% CI 0.43-0.68]. After matching (n = 2181 matched pairs), VIV-TAVR was associated with lower odds of 30-day mortality (OR 0.41, 95% CI 0.23-0.74), 30-day morbidity (OR 0.53, 95% CI 0.43-0.72), and major bleeding (OR 0.66, 95% CI 0.51-0.85). Valve-in-valve TAVR was also associated with shorter length of stay (median savings of 2 days, 95% CI 1.3-2.7) and higher odds of routine home discharges (OR 2.11, 95% CI 1.61-2.78) compared to re-SAVR.
Conclusion
In this large, nationwide study of matched high-risk patients with degenerated bioprosthetic aortic valves, VIV-TAVR appears to confer an advantage over re-SAVR in terms of 30-day mortality, morbidity, and bleeding complications. Further studies are warranted to benchmark in low- and intermediate-risk patients and to adequately assess longer-term efficacy.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: [email protected]

Eur Heart J: 22 May 2020; epub ahead of print
Hirji SA, Percy ED, Zogg CK, Malarczyk A, ... Yazdchi F, Kaneko T
Eur Heart J: 22 May 2020; epub ahead of print | PMID: 32445575
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

FDA Initiative for Drug Facts Label for Over-the-Counter Naloxone.

Cohen BR, Mahoney KM, Baro E, Squire C, ... Izem R, Woodcock J
Background
The opioid crisis highlights the need to increase access to naloxone, possibly through regulatory approval for over-the-counter sales. To address industry-perceived barriers to such access, the Food and Drug Administration (FDA) developed a model drug facts label for such sales to assess whether consumers understood the key statements for safe and effective use.
Methods
In this label-comprehension study, we conducted individual structured interviews with 710 adults and adolescents, including 430 adults who use opioids and their family and friends. Eight primary end points were developed to assess user comprehension of each of the key steps in the label. Each of these end points included a prespecified target threshold ranging from 80 to 90% that was evaluated through a comparison of the lower boundary of the 95% exact confidence interval.
Results
The results for performance on six primary end points met or exceeded thresholds, including the steps \"Check for a suspected overdose\" (threshold, 85%; point estimate [PE], 95.8%; 95% confidence interval [CI], 94.0 to 97.1) and \"Give the first dose\" (threshold, 85%; PE, 98.2%; 95% CI, 96.9 to 99.0). The lower boundaries for four other primary end points ranged from 88.8 to 94.0%. One exception was comprehension of \"Call 911 immediately,\" but this instruction closely approximated the target of 90% (PE, 90.3%; 95% CI, 87.9 to 92.4). Another exception was comprehension of the composite step of \"Check, give, and call 911 immediately\" (threshold, 85%; PE, 81.1%; 95% CI, 78.0 to 83.9).
Conclusions
Consumers met thresholds for sufficient understanding of six of eight components of the instructions in the drug facts label for naloxone use and came close on two others. Overall, the FDA found that the model label was adequate for use in the development of a naloxone product intended for over-the-counter sales.

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 27 May 2020; 382:2129-2136
Cohen BR, Mahoney KM, Baro E, Squire C, ... Izem R, Woodcock J
N Engl J Med: 27 May 2020; 382:2129-2136 | PMID: 32459923
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

WWP1 Gain-of-Function Inactivation of PTEN in Cancer Predisposition.

Lee YR, Yehia L, Kishikawa T, Ni Y, ... Eng C, Pandolfi PP
Background
Patients withhamartoma tumor syndrome (PHTS) have germline mutations in the tumor-suppressor gene encoding phosphatase and tensin homologue (). Such mutations have been associated with a hereditary predisposition to multiple types of cancer, including the Cowden syndrome. However, a majority of patients who have PHTS-related phenotypes have tested negative formutations. In a previous study, we found that the E3 ubiquitin ligase WWP1 negatively regulates the function of PTEN.
Methods
In a prospective cohort study conducted from 2005 through 2015, we enrolled 431 patients with wild-typewho met at least the relaxed diagnostic criteria of the International Cowden Consortium. Patients were scanned forgermline variants. We used the Cancer Genome Atlas (TCGA) data set as representative of apparently sporadic cancers and the Exome Aggregation Consortium data set excluding TCGA (non-TCGA ExAC) and the noncancer Genome Aggregation Database (gnomAD) as representative of population controls without a reported cancer diagnosis. We established both in vitro and murine in vivo models to functionally characterize representativevariants.
Results
The existence of germlinevariants was first established in a family with wild-typewho had oligopolyposis and early-onset colon cancers. A validation series indicated thatgermline variants occurred in 5 of 126 unrelated patients (4%) with oligopolyposis as a predominant phenotype. Germlinevariants, particularly theK740N and N745S alleles, were enriched in patients who did not have PHTS but had prevalent sporadic cancers, including related cancer types in TCGA (odds ratio, 1.5; 95% confidence interval, 1.1 to 2.1; P = 0.01). The prioritizedvariants resulted in gain-of-function effects, which led to aberrant enzymatic activation with consequent PTEN inactivation, thereby triggering hyperactive growth-promoting PI3K signaling in cellular and murine models.
Conclusions
In this study involving patients with disorders resulting in a predisposition to the development of multiple malignant neoplasms withoutgermline mutations, we confirmed the function ofas a cancer-susceptibility gene through direct aberrant regulation of the PTEN-PI3K signaling axis. (Funded by the National Institutes of Health and others.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 27 May 2020; 382:2103-2116
Lee YR, Yehia L, Kishikawa T, Ni Y, ... Eng C, Pandolfi PP
N Engl J Med: 27 May 2020; 382:2103-2116 | PMID: 32459922
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Remdesivir for 5 or 10 Days in Patients with Severe Covid-19.

Goldman JD, Lye DCB, Hui DS, Marks KM, ... Subramanian A,
Background
Remdesivir is an RNA polymerase inhibitor with potent antiviral activity in vitro and efficacy in animal models of coronavirus disease 2019 (Covid-19).
Methods
We conducted a randomized, open-label, phase 3 trial involving hospitalized patients with confirmed SARS-CoV-2 infection, oxygen saturation of 94% or less while they were breathing ambient air, and radiologic evidence of pneumonia. Patients were randomly assigned in a 1:1 ratio to receive intravenous remdesivir for either 5 days or 10 days. All patients received 200 mg of remdesivir on day 1 and 100 mg once daily on subsequent days. The primary end point was clinical status on day 14, assessed on a 7-point ordinal scale.
Results
In total, 397 patients underwent randomization and began treatment (200 patients for 5 days and 197 for 10 days). The median duration of treatment was 5 days (interquartile range, 5 to 5) in the 5-day group and 9 days (interquartile range, 5 to 10) in the 10-day group. At baseline, patients randomly assigned to the 10-day group had significantly worse clinical status than those assigned to the 5-day group (P = 0.02). By day 14, a clinical improvement of 2 points or more on the ordinal scale occurred in 64% of patients in the 5-day group and in 54% in the 10-day group. After adjustment for baseline clinical status, patients in the 10-day group had a distribution in clinical status at day 14 that was similar to that among patients in the 5-day group (P = 0.14). The most common adverse events were nausea (9% of patients), worsening respiratory failure (8%), elevated alanine aminotransferase level (7%), and constipation (7%).
Conclusions
In patients with severe Covid-19 not requiring mechanical ventilation, our trial did not show a significant difference between a 5-day course and a 10-day course of remdesivir. With no placebo control, however, the magnitude of benefit cannot be determined. (Funded by Gilead Sciences; GS-US-540-5773 ClinicalTrials.gov number, NCT04292899.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 26 May 2020; epub ahead of print
Goldman JD, Lye DCB, Hui DS, Marks KM, ... Subramanian A,
N Engl J Med: 26 May 2020; epub ahead of print | PMID: 32459919
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Abnormalities of Potassium in Heart Failure: JACC State-of-the-Art Review.

Ferreira JP, Butler J, Rossignol P, Pitt B, ... Weir MR, Zannad F

Potassium (K) is the most abundant cation in humans and is essential for normal cellular function. Alterations in K regulation can lead to neuromuscular, gastrointestinal, and cardiac abnormalities. Dyskalemia (i.e., hypokalemia and hyperkalemia) in heart failure is common because of heart failure itself, related comorbidities, and medications. Dyskalemia has important prognostic implications. Hypokalemia is associated with excess morbidity and mortality in heart failure. The lower the K levels, the higher the risk, starting at K levels below approximately 4.0 mmol/l, with a steep risk increment with K levels <3.5 mmol/l. Hyperkalemia (>5.5 mmol/l) has also been associated with increased risk of adverse events; however, this association is prone to reverse-causation bias as stopping renin angiotensin aldosterone system inhibitor therapy in the advent of hyperkalemia likely contributes the observed risk. In this state-of-the-art review, practical and easy-to-implement strategies to deal with both hypokalemia and hyperkalemia are provided as well as guidance for the use of potassium-binders.

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 08 Jun 2020; 75:2836-2850
Ferreira JP, Butler J, Rossignol P, Pitt B, ... Weir MR, Zannad F
J Am Coll Cardiol: 08 Jun 2020; 75:2836-2850 | PMID: 32498812
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Recovery of Left Ventricular Systolic Function and Clinical Outcomes in Young Adults With Myocardial Infarction.

Wu WY, Biery DW, Singh A, Divakaran S, ... Bhatt DL, Blankstein R
Background
Left ventricular ejection fraction (EF) recovery is associated with better long-term outcomes after myocardial infarction (MI). However, the association between long-term outcomes and EF recovery among young MI patients has not been investigated.
Objectives
This study sought to evaluate the prevalence of left ventricular systolic dysfunction among patients who experience their first MI at a young age and to compare outcomes between those who recovered their EF versus those who did not.
Methods
The YOUNG-MI registry is a retrospective cohort study of patients who experienced an MI at ≤50 years of age. EF at the time of MI and within 180 days post-MI were determined from all available medical records. The primary outcomes were all-cause and cardiovascular mortality.
Results
There were 1,724 patients with baseline EF data: 503 (29%) had EF <50%, whereas 1,221 (71%) had a normal baseline EF. Patients with lower EF were more likely to have experienced ST-segment elevation MI, have higher troponin values, and have more severe angiographic coronary artery disease. Among patients with abnormal baseline EF, information on follow-up EF was available for 216, of whom 90 (42%) recovered their EF to ≥50%. Patients who experienced EF recovery had less severe angiographic disease, lower alcohol use, and a lower burden of comorbidities. Over a median follow-up of 11.1 years, EF recovery was associated with an ∼8-fold reduction in all-cause mortality (adjusted hazard ratio: 0.12; p = 0.001) and a ∼10-fold reduction in cardiovascular mortality (adjusted hazard ratio: 0.10; p = 0.025).
Conclusions
Nearly one-third of young patients presented with left ventricular dysfunction post-MI. Among them, EF recovery occurred in more than 40% and was independently associated with a substantial decrease in all-cause and cardiovascular mortality.

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 08 Jun 2020; 75:2804-2815
Wu WY, Biery DW, Singh A, Divakaran S, ... Bhatt DL, Blankstein R
J Am Coll Cardiol: 08 Jun 2020; 75:2804-2815 | PMID: 32498808
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Survival of Patients With Angina Pectoris Undergoing Percutaneous Coronary Intervention With Intracoronary Pressure Wire Guidance.

Völz S, Dworeck C, Redfors B, Pétursson P, ... Erlinge D, Omerovic E
Background
Intracoronary pressure wire measurement of fractional flow reserve (FFR) provides decision-making guidance during percutaneous coronary intervention (PCI). However, limited data exist on the effect of FFR on long-term clinical outcomes in patients with stable angina pectoris.
Objectives
The purpose of this study was to determine the association between the usage of FFR and all-cause mortality in patients with stable angina undergoing PCI.
Methods
Data was used from the SCAAR (Swedish Coronary Angiography and Angioplasty Registry) on all patients undergoing PCI (with or without FFR guidance) for stable angina pectoris in Sweden between January 2005 and March 2016. The primary endpoint was all-cause mortality, and the secondary endpoints were stent thrombosis (ST) or restenosis and peri-procedural complications. The primary model was multilevel Cox proportional hazards regression adjusted with Kernel-based propensity score matching.
Results
In total, 23,860 patients underwent PCI for stable angina pectoris; of these, FFR guidance was used in 3,367. After a median follow-up of 4.7 years (range 0 to 11.2 years), the FFR group had lower adjusted risk estimates for all-cause mortality (hazard ratio: 0.81; 95% confidence interval [CI]: 0.73 to 0.89; p < 0.001), and ST and restenosis (hazard ratio: 0.74; 95% CI: 0.57 to 0.96; p = 0.022). The number of peri-procedural complications did not differ between the groups (adjusted odds ratio: 0.96; 95% CI: 0.77 to 1.19; p = 0.697).
Conclusions
In this observational study, the use of FFR was associated with a lower risk of long-term mortality, ST, and restenosis in patients undergoing PCI for stable angina pectoris. This study supports the current European and American guidelines for the use of FFR during PCI and shows that intracoronary pressure wire guidance confers prognostic benefit in patients with stable angina pectoris.

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 08 Jun 2020; 75:2785-2799
Völz S, Dworeck C, Redfors B, Pétursson P, ... Erlinge D, Omerovic E
J Am Coll Cardiol: 08 Jun 2020; 75:2785-2799 | PMID: 32498806
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Limitations of Contemporary Guidelines for Managing Patients at High Genetic Risk of Coronary Artery Disease.

Aragam KG, Dobbyn A, Judy R, Chaffin M, ... Damrauer SM, Natarajan P
Background
Polygenic risk scores (PRS) for coronary artery disease (CAD) identify high-risk individuals more likely to benefit from primary prevention statin therapy. Whether polygenic CAD risk is captured by conventional paradigms for assessing clinical cardiovascular risk remains unclear.
Objectives
This study sought to intersect polygenic risk with guideline-based recommendations and management patterns for CAD primary prevention.
Methods
A genome-wide CAD PRS was applied to 47,108 individuals across 3 U.S. health care systems. The authors then assessed whether primary prevention patients at high polygenic risk might be distinguished on the basis of greater guideline-recommended statin eligibility and higher rates of statin therapy.
Results
Of 47,108 study participants, the mean age was 60 years, and 11,020 (23.4%) had CAD. The CAD PRS strongly associated with prevalent CAD (odds ratio: 1.4 per SD increase in PRS; p < 0.0001). High polygenic risk (top 20% of PRS) conferred 1.9-fold odds of developing CAD (p < 0.0001). However, among primary prevention patients (n = 33,251), high polygenic risk did not correspond with increased recommendations for statin therapy per the American College of Cardiology/American Heart Association (46.2% for those with high PRS vs. 46.8% for all others, p = 0.54) or U.S. Preventive Services Task Force (43.7% vs. 43.7%, p = 0.99) or higher rates of statin prescriptions (25.0% vs. 23.8%, p = 0.04). An additional 4.1% of primary prevention patients may be recommended for statin therapy if high CAD PRS were considered a guideline-based risk-enhancing factor.
Conclusions
Current paradigms for primary cardiovascular prevention incompletely capture a polygenic susceptibility to CAD. An opportunity may exist to improve CAD prevention efforts by integrating both genetic and clinical risk.

Copyright © 2020 American College of Cardiology Foundation. All rights reserved.

J Am Coll Cardiol: 08 Jun 2020; 75:2769-2780
Aragam KG, Dobbyn A, Judy R, Chaffin M, ... Damrauer SM, Natarajan P
J Am Coll Cardiol: 08 Jun 2020; 75:2769-2780 | PMID: 32498804
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Renal Denervation in High-Risk Patients With Hypertension.

Mahfoud F, Mancia G, Schmieder R, Narkiewicz K, ... Fahy M, Böhm M
Background
Renal denervation (RDN) is under investigation for treatment of uncontrolled hypertension and might represent an attractive treatment for patients with high cardiovascular (CV) risk. It is important to determine whether baseline CV risk affects the efficacy of RDN.
Objectives
The purpose of this study was to assess blood pressure (BP) reduction and event rates after RDN in patients with various comorbidities, testing the hypothesis that RDN is effective and durable in these high-risk populations.
Methods
BP reduction and adverse events over 3 years were evaluated for several high-risk subgroups in the GSR (Global proSpective registrY for syMPathetic renaL denervatIon in seleCted IndicatIons Through 3 Years Registry), an international registry of RDN in patients with uncontrolled hypertension (n = 2,652). Comparisons were made for patients age ≥65 years versus age <65 years, with versus without isolated systolic hypertension, with versus without atrial fibrillation, and with versus without diabetes mellitus. Baseline cardiovascular risk was estimated using the American Heart Association (AHA)/American College of Cardiology (ACC) atherosclerosis cardiovascular disease (ASCVD) risk score.
Results
Reduction in 24-h systolic BP at 3 years was -8.9 ± 20.1 mm Hg for the overall cohort, and for high-risk subgroups, BP reduction was -10.4 ± 21.0 mm Hg for resistant hypertension, -8.7 ± 17.4 mm Hg in patients age ≥65 years, -10.2 ± 17.9 mm Hg in patients with diabetes, -8.6 ± 18.7 mm Hg in isolated systolic hypertension, -10.1 ± 20.3 mm Hg in chronic kidney disease, and -10.0 ± 19.1 mm Hg in atrial fibrillation (p < 0.0001 compared with baseline for all). BP reduction in patients with measurements at 6, 12, 24, and 36 months showed similar reductions in office and 24-h BP for patients with varying baseline ASCVD risk scores, which was sustained to 3 years. Adverse event rates at 3 years were higher for patients with higher baseline CV risk.
Conclusions
BP reduction after RDN was similar for patients with varying high-risk comorbidities and across the range of ASCVD risk scores. The impact of baseline risk on clinical event reduction by RDN-induced BP changes could be evaluated in further studies. (Global proSpective registrY for syMPathetic renaL denervatIon in seleCted IndicatIons Through 3 Years Registry; NCT01534299).

Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 15 Jun 2020; 75:2879-2888
Mahfoud F, Mancia G, Schmieder R, Narkiewicz K, ... Fahy M, Böhm M
J Am Coll Cardiol: 15 Jun 2020; 75:2879-2888 | PMID: 32527396
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Hospitalization and Mortality among Black Patients and White Patients with Covid-19.

Price-Haywood EG, Burton J, Fort D, Seoane L
Background
Many reports on coronavirus disease 2019 (Covid-19) have highlighted age- and sex-related differences in health outcomes. More information is needed about racial and ethnic differences in outcomes from Covid-19.
Methods
In this retrospective cohort study, we analyzed data from patients seen within an integrated-delivery health system (Ochsner Health) in Louisiana between March 1 and April 11, 2020, who tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, the virus that causes Covid-19) on qualitative polymerase-chain-reaction assay. The Ochsner Health population is 31% black non-Hispanic and 65% white non-Hispanic. The primary outcomes were hospitalization and in-hospital death.
Results
A total of 3626 patients tested positive, of whom 145 were excluded (84 had missing data on race or ethnic group, 9 were Hispanic, and 52 were Asian or of another race or ethnic group). Of the 3481 Covid-19-positive patients included in our analyses, 60.0% were female, 70.4% were black non-Hispanic, and 29.6% were white non-Hispanic. Black patients had higher prevalences of obesity, diabetes, hypertension, and chronic kidney disease than white patients. A total of 39.7% of Covid-19-positive patients (1382 patients) were hospitalized, 76.9% of whom were black. In multivariable analyses, black race, increasing age, a higher score on the Charlson Comorbidity Index (indicating a greater burden of illness), public insurance (Medicare or Medicaid), residence in a low-income area, and obesity were associated with increased odds of hospital admission. Among the 326 patients who died from Covid-19, 70.6% were black. In adjusted time-to-event analyses, variables that were associated with higher in-hospital mortality were increasing age and presentation with an elevated respiratory rate; elevated levels of venous lactate, creatinine, or procalcitonin; or low platelet or lymphocyte counts. However, black race was not independently associated with higher mortality (hazard ratio for death vs. white race, 0.89; 95% confidence interval, 0.68 to 1.17).
Conclusions
In a large cohort in Louisiana, 76.9% of the patients who were hospitalized with Covid-19 and 70.6% of those who died were black, whereas blacks comprise only 31% of the Ochsner Health population. Black race was not associated with higher in-hospital mortality than white race, after adjustment for differences in sociodemographic and clinical characteristics on admission.

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 26 May 2020; epub ahead of print
Price-Haywood EG, Burton J, Fort D, Seoane L
N Engl J Med: 26 May 2020; epub ahead of print | PMID: 32459916
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Association of Microvesicles With Graft Patency in Patients Undergoing CABG Surgery.

Camera M, Brambilla M, Canzano P, Cavallotti L, ... Rossetti L, Tremoli E
Background
Graft patency is one of the major determinants of long-term outcome following coronary artery bypass graft surgery (CABG). Biomarkers, if indicative of the underlying pathophysiological mechanisms, would suggest strategies to limit graft failure. The prognostic value of microvesicles (MVs) for midterm graft patency has never been tested.
Objectives
The aim of this study was to evaluate whether MV pre-operative signature (number, cellular origin, procoagulant phenotype) could predict midterm graft failure and to investigate potential functional role of MVs in graft occlusion.
Methods
This was a nested case-control substudy of the CAGE (CoronAry bypass grafting: factors related to late events and Graft patency) study that enrolled 330 patients undergoing elective CABG. Of these, 179 underwent coronary computed tomography angiography 18 months post-surgery showing 24% graft occlusion. Flow cytometry MV analysis was performed in 60 patients (30 per group with occluded [cases] and patent [control subjects] grafts) on plasma samples collected the day before surgery and at follow-up.
Results
Before surgery, cases had 2- and 4-fold more activated platelet-derived and tissue-factor positive MVs respectively than control subjects. The MV procoagulant capacity was also significantly greater. Altogether this MV signature properly classified graft occlusion (area under the curve 0.897 [95% confidence interval: 0.81 to 0.98]; p < 0.0001). By using an MV score (0 to 6), the odds ratio for occlusion for a score above 3 was 16.3 (95% confidence interval: 4.1 to 65.3; p < 0.0001).
Conclusions
The pre-operative signature of MVs is independently associated with midterm graft occlusion in CABG patients and a cumulative MV score stratifies patients\' risk. Because the MV signature mirrors platelet activation, patients with a high MV score could benefit from a personalized antiplatelet therapy.

Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 08 Jun 2020; 75:2819-2832
Camera M, Brambilla M, Canzano P, Cavallotti L, ... Rossetti L, Tremoli E
J Am Coll Cardiol: 08 Jun 2020; 75:2819-2832 | PMID: 32498810
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Trastuzumab Deruxtecan in Previously Treated HER2-Positive Gastric Cancer.

Shitara K, Bang YJ, Iwasa S, Sugimoto N, ... Yamaguchi K,
Background
Trastuzumab deruxtecan (DS-8201) is an antibody-drug conjugate consisting of an anti-HER2 (human epidermal growth factor receptor 2) antibody, a cleavable tetrapeptide-based linker, and a cytotoxic topoisomerase I inhibitor. The drug may have efficacy in patients with HER2-positive advanced gastric cancer.
Methods
In an open-label, randomized, phase 2 trial, we evaluated trastuzumab deruxtecan as compared with chemotherapy in patients with HER2-positive advanced gastric cancer. Patients with centrally confirmed HER2-positive gastric or gastroesophageal junction adenocarcinoma that had progressed while they were receiving at least two previous therapies, including trastuzumab, were randomly assigned in a 2:1 ratio to receive trastuzumab deruxtecan (6.4 mg per kilogram of body weight every 3 weeks) or physician\'s choice of chemotherapy. The primary end point was the objective response, according to independent central review. Secondary end points included overall survival, response duration, progression-free survival, confirmed response (response persisting ≥4 weeks), and safety.
Results
Of 187 treated patients, 125 received trastuzumab deruxtecan and 62 chemotherapy (55 received irinotecan and 7 paclitaxel). An objective response was reported in 51% of the patients in the trastuzumab deruxtecan group, as compared with 14% of those in the physician\'s choice group (P<0.001). Overall survival was longer with trastuzumab deruxtecan than with chemotherapy (median, 12.5 vs. 8.4 months; hazard ratio for death, 0.59; 95% confidence interval, 0.39 to 0.88; P = 0.01, which crossed the prespecified O\'Brien-Fleming boundary [0.0202 on the basis of number of deaths]). The most common adverse events of grade 3 or higher were a decreased neutrophil count (in 51% of the trastuzumab deruxtecan group and 24% of the physician\'s choice group), anemia (38% and 23%, respectively), and decreased white-cell count (21% and 11%). A total of 12 patients had trastuzumab deruxtecan-related interstitial lung disease or pneumonitis (grade 1 or 2 in 9 patients and grade 3 or 4 in 3), as adjudicated by an independent committee. One drug-related death (due to pneumonia) was noted in the trastuzumab deruxtecan group; no drug-related deaths occurred in the physician\'s choice group.
Conclusions
Therapy with trastuzumab deruxtecan led to significant improvements in response and overall survival, as compared with standard therapies, among patients with HER2-positive gastric cancer. Myelosuppression and interstitial lung disease were the notable toxic effects. (Funded by Daiichi Sankyo; DESTINY-Gastric01 ClinicalTrials.gov number, NCT03329690.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 28 May 2020; epub ahead of print
Shitara K, Bang YJ, Iwasa S, Sugimoto N, ... Yamaguchi K,
N Engl J Med: 28 May 2020; epub ahead of print | PMID: 32469182
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Coexistence and outcome of coronary artery disease in Takotsubo syndrome.

Napp LC, Cammann VL, Jaguszewski M, Szawan KA, ... Ghadri JR, Templin C
Aims
Takotsubo syndrome (TTS) is an acute heart failure syndrome, which shares many features with acute coronary syndrome (ACS). Although TTS was initially described with angiographically normal coronary arteries, smaller studies recently indicated a potential coexistence of coronary artery disease (CAD) in TTS patients. This study aimed to determine the coexistence, features, and prognostic role of CAD in a large cohort of patients with TTS.
Methods and results
Coronary anatomy and CAD were studied in patients diagnosed with TTS. Inclusion criteria were compliance with the International Takotsubo Diagnostic Criteria for TTS, and availability of original coronary angiographies with ventriculography performed during the acute phase. Exclusion criteria were missing views, poor quality of angiography loops, and angiography without ventriculography. A total of 1016 TTS patients were studied. Of those, 23.0% had obstructive CAD, 41.2% had non-obstructive CAD, and 35.7% had angiographically normal coronary arteries. A total of 47 patients (4.6%) underwent percutaneous coronary intervention, and 3 patients had acute and 8 had chronic coronary artery occlusion concomitant with TTS, respectively. The presence of CAD was associated with increased incidence of shock, ventilation, and death from any cause. After adjusting for confounders, the presence of obstructive CAD was associated with mortality at 30 days. Takotsubo syndrome patients with obstructive CAD were at comparable risk for shock and death and nearly at twice the risk for ventilation compared to an age- and sex-matched ACS cohort.
Conclusions
Coronary artery disease frequently coexists in TTS patients, presents with the whole spectrum of coronary pathology including acute coronary occlusion, and is associated with adverse outcome.
Trial registration
ClinicalTrials.gov number: NCT01947621.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: [email protected]

Eur Heart J: 01 Jun 2020; epub ahead of print
Napp LC, Cammann VL, Jaguszewski M, Szawan KA, ... Ghadri JR, Templin C
Eur Heart J: 01 Jun 2020; epub ahead of print | PMID: 32484517
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Enzalutamide and Survival in Nonmetastatic, Castration-Resistant Prostate Cancer.

Sternberg CN, Fizazi K, Saad F, Shore ND, ... Hussain M,
Background
Preliminary trial results showed that enzalutamide significantly improved metastasis-free survival among men who had nonmetastatic, castration-resistant prostate cancer and rapidly increasing prostate-specific antigen (PSA) levels while taking androgen-deprivation therapy. Results from the final analysis of overall survival have not yet been reported.
Methods
In this double-blind, phase 3 trial, men with nonmetastatic, castration-resistant prostate cancer (defined on the basis of conventional imaging and a PSA doubling time of ≤10 months) who were continuing to receive androgen-deprivation therapy were randomly assigned (in a 2:1 ratio) to receive enzalutamide at a dose of 160 mg or placebo once daily. Overall survival was assessed with a group sequential testing procedure and an O\'Brien-Fleming-type alpha-spending function.
Results
As of October 15, 2019, a total of 288 of 933 patients (31%) in the enzalutamide group and 178 of 468 (38%) in the placebo group had died. Median overall survival was 67.0 months (95% confidence interval [CI], 64.0 to not reached) in the enzalutamide group and 56.3 months (95% CI, 54.4 to 63.0) in the placebo group (hazard ratio for death, 0.73; 95% CI, 0.61 to 0.89; P = 0.001). The exposure-adjusted rate of adverse events of grade 3 or higher was 17 per 100 patient-years in the enzalutamide group and 20 per 100 patient-years in the placebo group. Adverse events in the enzalutamide group were consistent with those previously reported for enzalutamide; the most frequently reported events were fatigue and musculoskeletal events.
Conclusions
Enzalutamide plus androgen-deprivation therapy resulted in longer median overall survival than placebo plus androgen-deprivation therapy among men with nonmetastatic, castration-resistant prostate cancer and a rapidly rising PSA level. The risk of death associated with enzalutamide was 27% lower than with placebo. Adverse events were consistent with the established safety profile of enzalutamide. (Funded by Pfizer and Astellas Pharma; PROSPER ClinicalTrials.gov number, NCT02003924.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 28 May 2020; epub ahead of print
Sternberg CN, Fizazi K, Saad F, Shore ND, ... Hussain M,
N Engl J Med: 28 May 2020; epub ahead of print | PMID: 32469184
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Conducting clinical trials in heart failure during (and after) the COVID-19 pandemic: an Expert Consensus Position Paper from the Heart Failure Association (HFA) of the European Society of Cardiology (ESC).

Anker SD, Butler J, Khan MS, Abraham WT, ... Seferovic P, Coats AJS

The coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has important implications for the safety of participants in clinical trials and the research staff caring for them and, consequently, for the trials themselves. Patients with heart failure may be at greater risk of infection with COVID-19 and the consequences might also be more serious, but they are also at risk of adverse outcomes if their clinical care is compromised. As physicians and clinical trialists, it is our responsibility to ensure safe and effective care is delivered to trial participants without affecting the integrity of the trial. The social contract with our patients demands no less. Many regulatory authorities from different world regions have issued guidance statements regarding the conduct of clinical trials during this COVID-19 crisis. However, international trials may benefit from expert guidance from a global panel of experts to supplement local advice and regulations, thereby enhancing the safety of participants and the integrity of the trial. Accordingly, the Heart Failure Association of the European Society of Cardiology on 21 and 22 March 2020 conducted web-based meetings with expert clinical trialists in Europe, North America, South America, Australia, and Asia. The main objectives of this Expert Position Paper are to highlight the challenges that this pandemic poses for the conduct of clinical trials in heart failure and to offer advice on how they might be overcome, with some practical examples. While this panel of experts are focused on heart failure clinical trials, these discussions and recommendations may apply to clinical trials in other therapeutic areas.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: [email protected]

Eur Heart J: 03 Jun 2020; epub ahead of print
Anker SD, Butler J, Khan MS, Abraham WT, ... Seferovic P, Coats AJS
Eur Heart J: 03 Jun 2020; epub ahead of print | PMID: 32498081
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Association of Age of Onset of Hypertension With Cardiovascular Diseases and Mortality.

Wang C, Yuan Y, Zheng M, Pan A, ... Wu S, Xue H
Background
The relations of hypertension onset age with cardiovascular diseases (CVD) and all-cause mortality remain inconclusive.
Objectives
This study sought to examine the associations of hypertension onset age with CVD and all-cause mortality.
Methods
This prospective study included 71,245 participants free of hypertension and CVD in the first survey (July 2006 to October 2007) of the Kailuan study, a prospective cohort study in Tangshan, China. All participants were followed biennially until December 31, 2017. A total of 20,221 new-onset hypertension cases were identified during follow-up. We randomly selected 1 control participant for each new-onset hypertensive participant, matching for age (±1 year) and sex, and included 19,887 case-control pairs. We used weighted Cox regression models to calculate the average hazard ratios of incident CVD and all-cause mortality across the age groups.
Results
During an average follow-up of 6.5 years, we identified 1,672 incident CVD cases and 2,008 deaths. After multivariate adjustment, with the increase in hypertension onset age, the hazards of outcomes were gradually attenuated. The average hazard ratio (95% confidence interval) of CVD and all-cause mortality were 2.26 (1.19 to 4.30) and 2.59 (1.32 to 5.07) for the hypertension onset age <45 years old group, 1.62 (1.24 to 2.12) and 2.12 (1.55 to 2.90) for the 45- to 54-year age group, 1.42 (1.12 to 1.79) and 1.30 (1.03 to 1.62) for the 55- to 64-year age group, and 1.33 (1.04 to 1.69) and 1.29 (1.11 to 1.51) for the ≥65-year age group, respectively (p for interaction = 0.38 for CVD and <0.01 for death).
Conclusions
Hypertension was associated with a higher risk for CVD and all-cause mortality, and the associations were stronger with a younger age of onset.

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 15 Jun 2020; 75:2921-2930
Wang C, Yuan Y, Zheng M, Pan A, ... Wu S, Xue H
J Am Coll Cardiol: 15 Jun 2020; 75:2921-2930 | PMID: 32527401
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Oral Relugolix for Androgen-Deprivation Therapy in Advanced Prostate Cancer.

Shore ND, Saad F, Cookson MS, George DJ, ... Tombal B,
Background
Injectable luteinizing hormone-releasing hormone agonists (e.g., leuprolide) are the standard agents for achieving androgen deprivation for prostate cancer despite the initial testosterone surge and delay in therapeutic effect. The efficacy and safety of relugolix, an oral gonadotropin-releasing hormone antagonist, as compared with those of leuprolide are not known.
Methods
In this phase 3 trial, we randomly assigned patients with advanced prostate cancer, in a 2:1 ratio, to receive relugolix (120 mg orally once daily) or leuprolide (injections every 3 months) for 48 weeks. The primary end point was sustained testosterone suppression to castrate levels (<50 ng per deciliter) through 48 weeks. Secondary end points included noninferiority with respect to the primary end point, castrate levels of testosterone on day 4, and profound castrate levels (<20 ng per deciliter) on day 15. Testosterone recovery was evaluated in a subgroup of patients.
Results
A total of 622 patients received relugolix and 308 received leuprolide. Of men who received relugolix, 96.7% (95% confidence interval [CI], 94.9 to 97.9) maintained castration through 48 weeks, as compared with 88.8% (95% CI, 84.6 to 91.8) of men receiving leuprolide. The difference of 7.9 percentage points (95% CI, 4.1 to 11.8) showed noninferiority and superiority of relugolix (P<0.001 for superiority). All other key secondary end points showed superiority of relugolix over leuprolide (P<0.001). The percentage of patients with castrate levels of testosterone on day 4 was 56.0% with relugolix and 0% with leuprolide. In the subgroup of 184 patients followed for testosterone recovery, the mean testosterone levels 90 days after treatment discontinuation were 288.4 ng per deciliter in the relugolix group and 58.6 ng per deciliter in the leuprolide group. Among all the patients, the incidence of major adverse cardiovascular events was 2.9% in the relugolix group and 6.2% in the leuprolide group (hazard ratio, 0.46; 95% CI, 0.24 to 0.88).
Conclusions
In this trial involving men with advanced prostate cancer, relugolix achieved rapid, sustained suppression of testosterone levels that was superior to that with leuprolide, with a 54% lower risk of major adverse cardiovascular events. (Funded by Myovant Sciences; HERO ClinicalTrials.gov number, NCT03085095.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 28 May 2020; epub ahead of print
Shore ND, Saad F, Cookson MS, George DJ, ... Tombal B,
N Engl J Med: 28 May 2020; epub ahead of print | PMID: 32469183
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

A Randomized Trial of Hydroxychloroquine as Postexposure Prophylaxis for Covid-19.

Boulware DR, Pullen MF, Bangdiwala AS, Pastick KA, ... Lee TC, Hullsiek KH
Background
Coronavirus disease 2019 (Covid-19) occurs after exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). For persons who are exposed, the standard of care is observation and quarantine. Whether hydroxychloroquine can prevent symptomatic infection after SARS-CoV-2 exposure is unknown.
Methods
We conducted a randomized, double-blind, placebo-controlled trial across the United States and parts of Canada testing hydroxychloroquine as postexposure prophylaxis. We enrolled adults who had household or occupational exposure to someone with confirmed Covid-19 at a distance of less than 6 ft for more than 10 minutes while wearing neither a face mask nor an eye shield (high-risk exposure) or while wearing a face mask but no eye shield (moderate-risk exposure). Within 4 days after exposure, we randomly assigned participants to receive either placebo or hydroxychloroquine (800 mg once, followed by 600 mg in 6 to 8 hours, then 600 mg daily for 4 additional days). The primary outcome was the incidence of either laboratory-confirmed Covid-19 or illness compatible with Covid-19 within 14 days.
Results
We enrolled 821 asymptomatic participants. Overall, 87.6% of the participants (719 of 821) reported a high-risk exposure to a confirmed Covid-19 contact. The incidence of new illness compatible with Covid-19 did not differ significantly between participants receiving hydroxychloroquine (49 of 414 [11.8%]) and those receiving placebo (58 of 407 [14.3%]); the absolute difference was -2.4 percentage points (95% confidence interval, -7.0 to 2.2; P = 0.35). Side effects were more common with hydroxychloroquine than with placebo (40.1% vs. 16.8%), but no serious adverse reactions were reported.
Conclusions
After high-risk or moderate-risk exposure to Covid-19, hydroxychloroquine did not prevent illness compatible with Covid-19 or confirmed infection when used as postexposure prophylaxis within 4 days after exposure. (Funded by David Baszucki and Jan Ellison Baszucki and others; ClinicalTrials.gov number, NCT04308668.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 02 Jun 2020; epub ahead of print
Boulware DR, Pullen MF, Bangdiwala AS, Pastick KA, ... Lee TC, Hullsiek KH
N Engl J Med: 02 Jun 2020; epub ahead of print | PMID: 32492293
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Tepotinib in Non-Small-Cell Lung Cancer with Exon 14 Skipping Mutations.

Paik PK, Felip E, Veillon R, Sakai H, ... Heymach JV, Le X
Background
A splice-site mutation that results in a loss of transcription of exon 14 in the oncogenic driveroccurs in 3 to 4% of patients with non-small-cell lung cancer (NSCLC). We evaluated the efficacy and safety of tepotinib, a highly selective MET inhibitor, in this patient population.
Methods
In this open-label, phase 2 study, we administered tepotinib (at a dose of 500 mg) once daily in patients with advanced or metastatic NSCLC with a confirmedexon 14 skipping mutation. The primary end point was the objective response by independent review among patients who had undergone at least 9 months of follow-up. The response was also analyzed according to whether the presence of aexon 14 skipping mutation was detected on liquid biopsy or tissue biopsy.
Results
As of January 1, 2020, a total of 152 patients had received tepotinib, and 99 patients had been followed for at least 9 months. The response rate by independent review was 46% (95% confidence interval [CI], 36 to 57), with a median duration of response of 11.1 months (95% CI, 7.2 to could not be estimated) in the combined-biopsy group. The response rate was 48% (95% CI, 36 to 61) among 66 patients in the liquid-biopsy group and 50% (95% CI, 37 to 63) among 60 patients in the tissue-biopsy group; 27 patients had positive results according to both methods. The investigator-assessed response rate was 56% (95% CI, 45 to 66) and was similar regardless of the previous therapy received for advanced or metastatic disease. Adverse events of grade 3 or higher that were considered by investigators to be related to tepotinib therapy were reported in 28% of the patients, including peripheral edema in 7%. Adverse events led to permanent discontinuation of tepotinib in 11% of the patients. A molecular response, as measured in circulating free DNA, was observed in 67% of the patients with matched liquid-biopsy samples at baseline and during treatment.
Conclusions
Among patients with advanced NSCLC with a confirmedexon 14 skipping mutation, the use of tepotinib was associated with a partial response in approximately half the patients. Peripheral edema was the main toxic effect of grade 3 or higher. (Funded by Merck [Darmstadt, Germany]; VISION ClinicalTrials.gov number, NCT02864992.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 28 May 2020; epub ahead of print
Paik PK, Felip E, Veillon R, Sakai H, ... Heymach JV, Le X
N Engl J Med: 28 May 2020; epub ahead of print | PMID: 32469185
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Upright Cheyne-Stokes Respiration in Patients With Heart Failure.

Giannoni A, Gentile F, Sciarrone P, Borrelli C, ... Emdin M, Passino C
Background
Cheyne-Stokes respiration (CSR) is believed to only occur in supine and sleeping conditions, and thus, CSR treatment is applied to those specific states. Although CSR has also been described in patients with heart failure (HF) during wakefulness, its persistence in an upright position is still unknown.
Objectives
The purpose of this study was to assess the predictors, clinical correlates, and prognostic value of diurnal CSR in upright position.
Methods
Outpatients with systolic HF underwent a comprehensive evaluation, including short-term respiratory monitoring with a head-up tilt test to investigate the presence of upright CSR, assessment of chemoreflex response to hypoxia and hypercapnia, and 24-h cardiorespiratory recording. At follow-up, cardiac death was considered as the endpoint.
Results
Of 574 consecutive patients (left ventricular ejection fraction 32 ± 9%; age 65 ± 13 years; 80% men), 195 (34%) presented supine CSR only, 82 (14%) presented supine and upright CSR, and 297 patients (52%) had normal breathing. Patients with upright CSR had the greatest apnea-hypopnea and central apnea index (at daytime and nighttime), the worst hemodynamic profile and exercise performance, increased plasma norepinephrine and N-terminal pro-B-type natriuretic peptide, and chemosensitivity to hypercapnia, which was the only independent predictor of upright CSR (odds ratio: 3.96; 95% confidence interval [CI]: 1.45 to 10.76; p = 0.007 vs. normal breathing; odds ratio: 4.01; 95% CI: 1.54 to 10.46; p = 0.004 vs. supine CSR). At 8-year follow-up, patients with upright CSR had the worst outcome (log-rank = 14.05; p = 0.001) and the presence of upright CSR independently predicted 8-year cardiac death (hazard ratio: 2.39; 95% CI: 1.08 to 5.29; p = 0.032).
Conclusions
Upright CSR in HF patients is predicted by increased chemosensitivity to hypercapnia and is associated with worse clinical conditions and with a greater risk of cardiac death.

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 15 Jun 2020; 75:2934-2946
Giannoni A, Gentile F, Sciarrone P, Borrelli C, ... Emdin M, Passino C
J Am Coll Cardiol: 15 Jun 2020; 75:2934-2946 | PMID: 32527403
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

A Validated Model for Sudden Cardiac Death Risk Prediction in Pediatric Hypertrophic Cardiomyopathy.

Miron A, Lafreniere-Roula M, Fan CS, Armstrong KR, ... Ho CY, Mital S

Hypertrophic cardiomyopathy (HCM) is the leading cause of sudden cardiac death (SCD) in children and young adults. Our objective was to develop and validate a SCD risk prediction model in pediatric HCM to guide SCD prevention strategies.In an international multi-center observational cohort study, phenotype-positive patients with isolated HCM <18 years at diagnosis were eligible. The primary outcome variable was the time from diagnosis to a composite of SCD events at 5-year follow-up: SCD, resuscitated sudden cardiac arrest (SCA), and aborted SCD, i.e. appropriate shock following primary prevention ICD. Competing risk models with cause-specific hazard regression were used to identify and quantify clinical and genetic factors associated with SCD. The cause-specific regression model was implemented using boosting, and tuned with ten repeated four-fold cross-validations. The final model was fitted using all data with the tuned hyperparameter value that maximizes the c-statistic, and its performance was characterized using c-statistic for competing risk models. The final model was validated in an independent external cohort (SHaRe, n=285).Overall, 572 patients met eligibility criteria with 2855 patient-years of follow-up. The 5-year cumulative proportion of SCD events was 9.1% (14 SCD, 25 resuscitated SCA, 14 aborted SCD). Risk predictors included age at diagnosis, documented non-sustained ventricular tachycardia, unexplained syncope, septal diameter z-score, LV posterior wall diameter z-score, LA diameter z-score, peak LV outflow tract (LVOT) gradient, and presence of a pathogenic variant. Unlike adults, LVOT gradient had an inverse association, and family history of SCD had no association with SCD. Clinical and clinical/genetic models were developed to predict 5-year freedom from SCD. Both models adequately discriminated patients with and without SCD events with a c-statistic of 0.75 and 0.76 respectively and demonstrated good agreement between predicted and observed events in the primary and validation cohorts (validation c-statistic 0.71 and 0.72 respectively). Our study provides a validated SCD risk prediction model with over 70% prediction accuracy and incorporates risk factors that are unique to pediatric HCM. An individualized risk prediction model has the potential to improve the application of clinical practice guidelines and shared decision-making for ICD insertion. URL: https://clinicaltrials.gov Unique Identifier: NCT04036799.



Circulation: 17 May 2020; epub ahead of print
Miron A, Lafreniere-Roula M, Fan CS, Armstrong KR, ... Ho CY, Mital S
Circulation: 17 May 2020; epub ahead of print | PMID: 32418493
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Handgun Ownership and Suicide in California.

Studdert DM, Zhang Y, Swanson SA, Prince L, ... Wintemute GJ, Miller M
Background
Research has consistently identified firearm availability as a risk factor for suicide. However, existing studies are relatively small in scale, estimates vary widely, and no study appears to have tracked risks from commencement of firearm ownership.
Methods
We identified handgun acquisitions and deaths in a cohort of 26.3 million male and female residents of California, 21 years old or older, who had not previously acquired handguns. Cohort members were followed for up to 12 years 2 months (from October 18, 2004, to December 31, 2016). We used survival analysis to estimate the relationship between handgun ownership and both all-cause mortality and suicide (by firearm and by other methods) among men and women. The analysis allowed the baseline hazard to vary according to neighborhood and was adjusted for age, race and ethnic group, and ownership of long guns (i.e., rifles or shotguns).
Results
A total of 676,425 cohort members acquired one or more handguns, and 1,457,981 died; 17,894 died by suicide, of which 6691 were suicides by firearm. Rates of suicide by any method were higher among handgun owners, with an adjusted hazard ratio of 3.34 for all male owners as compared with male nonowners (95% confidence interval [CI], 3.13 to 3.56) and 7.16 for female owners as compared with female nonowners (95% CI, 6.22 to 8.24). These rates were driven by much higher rates of suicide by firearm among both male and female handgun owners, with a hazard ratio of 7.82 for men (95% CI, 7.26 to 8.43) and 35.15 for women (95% CI, 29.56 to 41.79). Handgun owners did not have higher rates of suicide by other methods or higher all-cause mortality. The risk of suicide by firearm among handgun owners peaked immediately after the first acquisition, but 52% of all suicides by firearm among handgun owners occurred more than 1 year after acquisition.
Conclusions
Handgun ownership is associated with a greatly elevated and enduring risk of suicide by firearm. (Funded by the Fund for a Safer Future and others.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 03 Jun 2020; 382:2220-2229
Studdert DM, Zhang Y, Swanson SA, Prince L, ... Wintemute GJ, Miller M
N Engl J Med: 03 Jun 2020; 382:2220-2229 | PMID: 32492303
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

An autoantibody profile detects Brugada syndrome and identifies abnormally expressed myocardial proteins.

Chatterjee D, Pieroni M, Fatah M, Charpentier F, ... Saguner AM, Hamilton RM
Aims
Brugada syndrome (BrS) is characterized by a unique electrocardiogram (ECG) pattern and life-threatening arrhythmias. However, the Type 1 Brugada ECG pattern is often transient, and a genetic cause is only identified in <25% of patients. We sought to identify an additional biomarker for this rare condition. As myocardial inflammation may be present in BrS, we evaluated whether myocardial autoantibodies can be detected in these patients.
Methods and results
For antibody (Ab) discovery, normal human ventricular myocardial proteins were solubilized and separated by isoelectric focusing (IEF) and molecular weight on two-dimensional (2D) gels and used to discover Abs by plating with sera from patients with BrS and control subjects. Target proteins were identified by mass spectrometry (MS). Brugada syndrome subjects were defined based on a consensus clinical scoring system. We assessed discovery and validation cohorts by 2D gels, western blots, and ELISA. We performed immunohistochemistry on myocardium from BrS subjects (vs. control). All (3/3) 2D gels exposed to sera from BrS patients demonstrated specific Abs to four proteins, confirmed by MS to be α-cardiac actin, α-skeletal actin, keratin, and connexin-43, vs. 0/8 control subjects. All (18/18) BrS subjects from our validation cohorts demonstrated the same Abs, confirmed by western blots, vs. 0/24 additional controls. ELISA optical densities for all Abs were elevated in all BrS subjects compared to controls. In myocardium obtained from BrS subjects, each protein, as well as SCN5A, demonstrated abnormal protein expression in aggregates.
Conclusion
A biomarker profile of autoantibodies against four cardiac proteins, namely α-cardiac actin, α-skeletal actin, keratin, and connexin-43, can be identified from sera of BrS patients and is highly sensitive and specific, irrespective of genetic cause for BrS. The four involved proteins, along with the SCN5A-encoded Nav1.5 alpha subunit are expressed abnormally in the myocardium of patients with BrS.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: [email protected]

Eur Heart J: 11 Jun 2020; epub ahead of print
Chatterjee D, Pieroni M, Fatah M, Charpentier F, ... Saguner AM, Hamilton RM
Eur Heart J: 11 Jun 2020; epub ahead of print | PMID: 32533187
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Rituximab for High-Risk, Mature B-Cell Non-Hodgkin\'s Lymphoma in Children.

Minard-Colin V, Aupérin A, Pillon M, Burke GAA, ... Gross TG,
Background
Rituximab added to chemotherapy prolongs survival among adults with B-cell cancer. Data on its efficacy and safety in children with high-grade, mature B-cell non-Hodgkin\'s lymphoma are limited.
Methods
We conducted an open-label, international, randomized, phase 3 trial involving patients younger than 18 years of age with high-risk, mature B-cell non-Hodgkin\'s lymphoma (stage III with an elevated lactate dehydrogenase level or stage IV) or acute leukemia to compare the addition of six doses of rituximab to standard lymphomes malins B (LMB) chemotherapy with standard LMB chemotherapy alone. The primary end point was event-free survival. Overall survival and toxic effects were also assessed.
Results
Analyses were based on 328 patients who underwent randomization (164 patients per group); 85.7% of the patients had Burkitt\'s lymphoma. The median follow-up was 39.9 months. Events were observed in 10 patients in the rituximab-chemotherapy group and in 28 in the chemotherapy group. Event-free survival at 3 years was 93.9% (95% confidence interval [CI], 89.1 to 96.7) in the rituximab-chemotherapy group and 82.3% (95% CI, 75.7 to 87.5) in the chemotherapy group (hazard ratio for primary refractory disease or first occurrence of progression, relapse after response, death from any cause, or second cancer, 0.32; 95% CI, 0.15 to 0.66; one-sided P = 0.00096, which reached the significance level required for this analysis). Eight patients in the rituximab-chemotherapy group died (4 deaths were disease-related, 3 were treatment-related, and 1 was from a second cancer), as did 20 in the chemotherapy group (17 deaths were disease-related, and 3 were treatment-related) (hazard ratio, 0.36; 95% CI, 0.16 to 0.82). The incidence of acute adverse events of grade 4 or higher after prephase treatment was 33.3% in the rituximab-chemotherapy group and 24.2% in the chemotherapy group (P = 0.07); events were related mainly to febrile neutropenia and infection. Approximately twice as many patients in the rituximab-chemotherapy group as in the chemotherapy group had a low IgG level 1 year after trial inclusion.
Conclusions
Rituximab added to standard LMB chemotherapy markedly prolonged event-free survival and overall survival among children and adolescents with high-grade, high-risk, mature B-cell non-Hodgkin\'s lymphoma and was associated with a higher incidence of hypogammaglobulinemia and, potentially, more episodes of infection. (Funded by the Clinical Research Hospital Program of the French Ministry of Health and others; ClinicalTrials.gov number, NCT01516580.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 03 Jun 2020; 382:2207-2219
Minard-Colin V, Aupérin A, Pillon M, Burke GAA, ... Gross TG,
N Engl J Med: 03 Jun 2020; 382:2207-2219 | PMID: 32492302
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Implementing the new European Regulations on medical devices-clinical responsibilities for evidence-based practice: a report from the Regulatory Affairs Committee of the European Society of Cardiology.

Fraser AG, Byrne RA, Kautzner J, Butchart EG, ... Vardas PE, Badimon L

The new European Union (EU) law governing the regulatory approval of medical devices that entered into force in May 2017 will now take effect from 26 May 2021. Here, we consider how it will change daily practice for cardiologists, cardiac surgeons, and healthcare professionals. Clinical evidence for any high-risk device must be reported by the manufacturer in a Summary of Safety and Clinical Performance (SSCP) that will be publicly available in the European Union Database on Medical Devices (Eudamed) maintained by the European Commission; this will facilitate evidence-based choices of which devices to recommend. Hospitals must record all device implantations, and each high-risk device will be trackable by Unique Device Identification (UDI). Important new roles are envisaged for clinicians, scientists, and engineers in EU Expert Panels-in particular to scrutinize clinical data submitted by manufacturers for certain high-risk devices and the evaluations of that data made by notified bodies. They will advise manufacturers on the design of their clinical studies and recommend to regulators when new technical specifications or guidance are needed. Physicians should support post-market surveillance by reporting adverse events and by contributing to comprehensive medical device registries. A second law on In Vitro Diagnostic Medical Devices will take effect from 2022. We encourage all healthcare professionals to contribute proactively to these new systems, in order to enhance the efficacy and safety of high-risk devices and to promote equitable access to effective innovations. The European Society of Cardiology will continue to advise EU regulators on appropriate clinical evaluation of high-risk devices.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: [email protected]

Eur Heart J: 01 Jun 2020; epub ahead of print
Fraser AG, Byrne RA, Kautzner J, Butchart EG, ... Vardas PE, Badimon L
Eur Heart J: 01 Jun 2020; epub ahead of print | PMID: 32484542
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Survival After Heart Transplantation in Patients Bridged With Mechanical Circulatory Support.

Moonsamy P, Axtell AL, Ibrahim NE, Funamoto M, ... D\'Alessandro DA, Villavicencio MA
Background
The United Network of Organ Sharing (UNOS) heart allocation policy designates patients on ECMO or with nondischargeable, surgically implanted, nonendovascular support devices (TCS-VAD) to higher listing statuses.
Objectives
This study aimed to explore whether temporary circulatory support-ventricular assist devices (TCS-VAD) have a survival advantage over extracorporeal membrane oxygenation (ECMO) as a bridge to transplant.
Methods
The UNOS database was used to conduct a retrospective analysis of adult heart transplants performed in the United States between 2005 and 2017. Survival analysis was performed to compare patients bridged to transplant with different modalities.
Results
Of the 24,905 adult transplants performed, 7,904 (32%) were bridged with durable left ventricular assist devices (LVADs), 177 (0.7%) with ECMO, 203 (0.8%) with TCS-VAD, 44 (0.2%) with percutaneous endovascular devices, and 8 (0.03%) with TandemHeart (LivaNova, London, United Kingdom). Unadjusted survival at 1 and 5 years post-transplant was 90 ± 0.4% and 77 ± 0.7% for durable LVAD, 84 ± 3% and 71 ± 4% for all TCS-VAD types, 79 ± 9% and 73 ± 14% for biventricular TCS-VAD, and 68 ± 3% and 61 ± 8% for ECMO. After propensity-matched pairwise comparisons were made, survival after all TCS-VAD types continued to be superior to ECMO (p = 0.019) and similar to LVAD (p = 0.380). ECMO was a predictor of post-transplant mortality in the Cox analysis compared with TCS-VAD (hazard ratio 2.40; 95% confidence interval: 1.44 to 4.01; p = 0.001).
Conclusions
Post-transplant survival with TCS-VAD is superior to ECMO and similar to LVAD in a national database.

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 15 Jun 2020; 75:2892-2905
Moonsamy P, Axtell AL, Ibrahim NE, Funamoto M, ... D'Alessandro DA, Villavicencio MA
J Am Coll Cardiol: 15 Jun 2020; 75:2892-2905 | PMID: 32527398
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Phase 3 Trial of RNAi Therapeutic Givosiran for Acute Intermittent Porphyria.

Balwani M, Sardh E, Ventura P, Peiró PA, ... Gouya L,
Background
Up-regulation of hepatic delta-aminolevulinic acid synthase 1 (ALAS1), with resultant accumulation of delta-aminolevulinic acid (ALA) and porphobilinogen, is central to the pathogenesis of acute attacks and chronic symptoms in acute hepatic porphyria. Givosiran, an RNA interference therapy, inhibits ALAS1 expression.
Methods
In this double-blind, placebo-controlled, phase 3 trial, we randomly assigned symptomatic patients with acute hepatic porphyria to receive either subcutaneous givosiran (2.5 mg per kilogram of body weight) or placebo monthly for 6 months. The primary end point was the annualized rate of composite porphyria attacks among patients with acute intermittent porphyria, the most common subtype of acute hepatic porphyria. (Composite porphyria attacks resulted in hospitalization, an urgent health care visit, or intravenous administration of hemin at home.) Key secondary end points were levels of ALA and porphobilinogen and the annualized attack rate among patients with acute hepatic porphyria, along with hemin use and daily worst pain scores in patients with acute intermittent porphyria.
Results
A total of 94 patients underwent randomization (48 in the givosiran group and 46 in the placebo group). Among the 89 patients with acute intermittent porphyria, the mean annualized attack rate was 3.2 in the givosiran group and 12.5 in the placebo group, representing a 74% lower rate in the givosiran group (P<0.001); the results were similar among the 94 patients with acute hepatic porphyria. Among the patients with acute intermittent porphyria, givosiran led to lower levels of urinary ALA and porphobilinogen, fewer days of hemin use, and better daily scores for pain than placebo. Key adverse events that were observed more frequently in the givosiran group were elevations in serum aminotransferase levels, changes in serum creatinine levels and the estimated glomerular filtration rate, and injection-site reactions.
Conclusions
Among patients with acute intermittent porphyria, those who received givosiran had a significantly lower rate of porphyria attacks and better results for multiple other disease manifestations than those who received placebo. The increased efficacy was accompanied by a higher frequency of hepatic and renal adverse events. (Funded by Alnylam Pharmaceuticals; ENVISION ClinicalTrials.gov number, NCT03338816.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 10 Jun 2020; 382:2289-2301
Balwani M, Sardh E, Ventura P, Peiró PA, ... Gouya L,
N Engl J Med: 10 Jun 2020; 382:2289-2301 | PMID: 32521132
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Outcomes in Patients With Hypertrophic Cardiomyopathy and Left Ventricular Systolic Dysfunction.

Rowin EJ, Maron BJ, Carrick RT, Patel PP, ... Wells S, Maron MS
Background
End-stage (ES) hypertrophic cardiomyopathy (HCM) has been considered a particularly grim and unfavorable disease complication, associated with substantial morbidity and mortality, frequently requiring heart transplant. Previous reports have included small numbers of patients with relatively short follow-up, predominantly in prior treatment eras.
Objectives
The purpose of this study was to re-evaluate clinical profile and prognosis for end-stage heart failure in a large HCM cohort with contemporary management strategies.
Methods
Patients at Tufts HCM Institute, from 2004 to 2017, were identified with ES and systolic dysfunction (ejection fraction [EF] <50%), followed for 5.8 ± 4.7 years (up to 18 years).
Results
Of the 2,447 patients, 118 (4.8%) had ES-HCM (EF 39 ± 9%; range 12% to 49%) at age 48 ± 15 years. Notably, over follow-up, 57 patients (48%) achieved clinical stability in New York Heart Association functional classes I/II with medical treatment (or cardiac resynchronization therapy), including 6 patients ≥10 years from ES diagnosis (up to 14 years). In total, 61 other patients (52%) developed refractory heart failure to disabling New York Heart Association functional classes III/IV (5.2%/year); 67% have survived, including 31 with heart transplant. Of the 118 ES patients, 21 had appropriate implantable cardioverter-defibrillator (ICD) therapy terminating potentially lethal tachyarrhythmias, with no difference in frequency of events in patients with EF 35% to 49% versus EF <35% (17% vs. 19%; p = 0.80). With all available treatment modalities, ES-related mortality was 1.9%/year, with 10-year survival of 85% (95% confidence interval: 77% to 94%). Mortality was 4-fold lower than previously reported for ES (8.0%/year), but exceeded 10-fold HCM with preserved EF (0.2%/year; p < 0.001).
Conclusions
Although ES remains an important complication of HCM, contemporary treatment strategies, including ICDs and heart transplant, are associated with significantly lower mortality than previously considered. Primary prevention ICDs should be considered when EF is <50% in HCM. Rapid heart failure progression is not an inevitable consequence of ES, and some patients experience extended periods of clinical stability.

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 22 Jun 2020; 75:3033-3043
Rowin EJ, Maron BJ, Carrick RT, Patel PP, ... Wells S, Maron MS
J Am Coll Cardiol: 22 Jun 2020; 75:3033-3043 | PMID: 32553256
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Disseminated Coccidioidomycosis Treated with Interferon-γ and Dupilumab.

Tsai M, Thauland TJ, Huang AY, Bun C, ... Garcia-Lloret MI, Butte MJ

We describe a case of life-threatening disseminated coccidioidomycosis in a previously healthy child. Like most patients with disseminated coccidioidomycosis, this child had no genomic evidence of any known, rare immune disease. However, comprehensive immunologic testing showed exaggerated production of interleukin-4 and reduced production of interferon-γ. Supplementation of antifungal agents with interferon-γ treatment slowed disease progression, and the addition of interleukin-4 and interleukin-13 blockade with dupilumab resulted in rapid resolution of the patient\'s clinical symptoms. This report shows that blocking of type 2 immune responses can treat infection. This immunomodulatory approach could be used to enhance immune clearance of refractory fungal, mycobacterial, and viral infections. (Supported by the Jeffrey Modell Foundation and the National Institutes of Health.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 10 Jun 2020; 382:2337-2343
Tsai M, Thauland TJ, Huang AY, Bun C, ... Garcia-Lloret MI, Butte MJ
N Engl J Med: 10 Jun 2020; 382:2337-2343 | PMID: 32521134
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Association of hypertension and antihypertensive treatment with COVID-19 mortality: a retrospective observational study.

Gao C, Cai Y, Zhang K, Zhou L, ... Tao L, Li F
Aims
It remains unknown whether the treatment of hypertension influences the mortality of patients diagnosed with coronavirus disease 2019 (COVID-19).
Methods and results
This is a retrospective observational study of all patients admitted with COVID-19 to Huo Shen Shan Hospital. The hospital was dedicated solely to the treatment of COVID-19 in Wuhan, China. Hypertension and the treatments were stratified according to the medical history or medications administrated prior to the infection. Among 2877 hospitalized patients, 29.5% (850/2877) had a history of hypertension. After adjustment for confounders, patients with hypertension had a two-fold increase in the relative risk of mortality as compared with patients without hypertension [4.0% vs. 1.1%, adjusted hazard ratio (HR) 2.12, 95% confidence interval (CI) 1.17-3.82, P = 0.013]. Patients with a history of hypertension but without antihypertensive treatment (n = 140) were associated with a significantly higher risk of mortality compared with those with antihypertensive treatments (n = 730) (7.9% vs. 3.2%, adjusted HR 2.17, 95% CI 1.03-4.57, P = 0.041). The mortality rates were similar between the renin-angiotensin-aldosterone system (RAAS) inhibitor (4/183) and non-RAAS inhibitor (19/527) cohorts (2.2% vs. 3.6%, adjusted HR 0.85, 95% CI 0.28-2.58, P = 0.774). However, in a study-level meta-analysis of four studies, the result showed that patients with RAAS inhibitor use tend to have a lower risk of mortality (relative risk 0.65, 95% CI 0.45-0.94, P = 0.20).
Conclusion
While hypertension and the discontinuation of antihypertensive treatment are suspected to be related to increased risk of mortality, in this retrospective observational analysis, we did not detect any harm of RAAS inhibitors in patients infected with COVID-19. However, the results should be considered as exploratory and interpreted cautiously.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: [email protected]

Eur Heart J: 03 Jun 2020; epub ahead of print
Gao C, Cai Y, Zhang K, Zhou L, ... Tao L, Li F
Eur Heart J: 03 Jun 2020; epub ahead of print | PMID: 32498076
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Thrombectomy for Stroke in the Public Health Care System of Brazil.

Martins SO, Mont\'Alverne F, Rebello LC, Abud DG, ... Nogueira RG,
Background
Randomized trials involving patients with stroke have established that outcomes are improved with the use of thrombectomy for large-vessel occlusion. These trials were performed in high-resource countries and have had limited effects on medical practice in low- and middle-income countries.
Methods
We studied the safety and efficacy of thrombectomy in the public health system of Brazil. In 12 public hospitals, patients with a proximal intracranial occlusion in the anterior circulation that could be treated within 8 hours after the onset of stroke symptoms were randomly assigned in a 1:1 ratio to receive standard care plus mechanical thrombectomy (thrombectomy group) or standard care alone (control group). The primary outcome was the score on the modified Rankin scale (range, 0 [no symptoms] to 6 [death]) at 90 days.
Results
A total of 300 patients were enrolled, including 79 who had undergone thrombectomy during an open-label roll-in period. Approximately 70% in the two groups received intravenous alteplase. The trial was stopped early because of efficacy when 221 of a planned 690 patients had undergone randomization (111 to the thrombectomy group and 110 to the control group). The common odds ratio for a better distribution of scores on the modified Rankin scale at 90 days was 2.28 (95% confidence interval [CI], 1.41 to 3.69; P = 0.001), favoring thrombectomy. The percentage of patients with a score on the modified Rankin scale of 0 to 2, signifying an absence of or minor neurologic deficit, was 35.1% in the thrombectomy group and 20.0% in the control group (difference, 15.1 percentage points; 95% CI, 2.6 to 27.6). Asymptomatic intracranial hemorrhage occurred in 51.4% of the patients in the thrombectomy group and 24.5% of those in the control group; symptomatic intracranial hemorrhage occurred in 4.5% of the patients in each group.
Conclusions
In this randomized trial conducted in the public health care system of Brazil, endovascular treatment within 8 hours after the onset of stroke symptoms in conjunction with standard care resulted in better functional outcomes at 90 days than standard care alone. (Funded by the Brazilian Ministry of Health; RESILIENT ClinicalTrials.gov number, NCT02216643.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 10 Jun 2020; 382:2316-2326
Martins SO, Mont'Alverne F, Rebello LC, Abud DG, ... Nogueira RG,
N Engl J Med: 10 Jun 2020; 382:2316-2326 | PMID: 32521133
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Prevalence and Impact of Myocardial Injury in Patients Hospitalized with COVID-19 Infection.

Lala A, Johnson KW, Januzzi JL, Russak AJ, ... Fuster V,
Background
The degree of myocardial injury, as reflected by troponin elevation, and associated outcomes among US hospitalized patients with Coronavirus Disease 2019 (COVID-19) are unknown.
Objectives
To describe the degree of myocardial injury and associated outcomes in a large hospitalized cohort with laboratory-confirmed COVID-19.
Methods
Patients with COVID-19 admitted to one of five Mount Sinai Health System hospitals in New York City between February 27th and April 12th, 2020 with troponin-I (normal value <0.03ng/mL) measured within 24 hours of admission were included (n=2,736). Demographics, medical history, admission labs, and outcomes were captured from the hospitals\' EHR.
Results
The median age was 66.4 years, with 59.6% men. Cardiovascular disease (CVD) including coronary artery disease, atrial fibrillation, and heart failure, was more prevalent in patients with higher troponin concentrations, as were hypertension and diabetes. A total of 506 (18.5%) patients died during hospitalization. In all, 985 (36%) patients had elevated troponin concentrations. After adjusting for disease severity and relevant clinical factors, even small amounts of myocardial injury (e.g. troponin I 0.03-0.09ng/mL, n=455, 16.6%) were significantly associated with death (adjusted HR: 1.75, 95% CI 1.37-2.24; P<0.001) while greater amounts (e.g. troponin I>0.09 ng/dL, n=530, 19.4%) were significantly associated with higher risk (adjusted HR 3.03, 95% CI 2.42-3.80; P<0.001).
Conclusions
Myocardial injury is prevalent among patients hospitalized with COVID-19 however troponin concentrations were generally present at low levels. Patients with CVD are more likely to have myocardial injury than patients without CVD. Troponin elevation among patients hospitalized with COVID-19 is associated with higher risk of mortality.

Copyright © 2020. Published by Elsevier Inc.

J Am Coll Cardiol: 04 Jun 2020; epub ahead of print
Lala A, Johnson KW, Januzzi JL, Russak AJ, ... Fuster V,
J Am Coll Cardiol: 04 Jun 2020; epub ahead of print | PMID: 32517963
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Practice Changes at U.S. Transplant Centers After the New Adult Heart Allocation Policy.

Parker WF, Chung K, Anderson AS, Siegler M, Huang ES, Churpek MM
Background
In October 2018, the U.S. heart allocation system expanded the number of priority \"status\" tiers from 3 to 6 and added cardiogenic shock requirements for some heart transplant candidates listed with specific types of treatments.
Objectives
This study sought to determine the impact of the new policy on the treatment practices of transplant centers.
Methods
Initial listing data on all adult heart candidates listed from December 1, 2017 to April 30, 2019 were collected from the Scientific Registry of Transplant Recipients. The status-qualifying treatments (or exception requests) and hemodynamic values at listing of a post-policy cohort (December 2018 to April 2019) were compared with a seasonally matched pre-policy cohort (December 2017 to April 2018). Candidates in the pre-policy cohort were reclassified into the new priority system statuses by using treatment, diagnosis, and hemodynamics.
Results
Comparing the post-policy cohort (N = 1,567) with the pre-policy cohort (N = 1,606), there were significant increases in listings with extracorporeal membrane oxygenation (+1.2%), intra-aortic balloon pumps (+ 4 %), and exceptions (+ 12%). Listings with low-dose inotropes (-18%) and high-dose inotropes (-3%) significantly decreased. The new priority status distribution had more status 2 (+14%) candidates than expected and fewer status 3 (-5%), status 4 (- 4%) and status 6 (-8%) candidates than expected (p values <0.01 for all comparisons).
Conclusions
After implementation of the new heart allocation policy, transplant centers listed more candidates with extracorporeal membrane oxygenation, intra-aortic balloon pumps, and exception requests and fewer candidates with inotrope therapy than expected, thus leading to significantly more high-priority status listings than anticipated. If these early trends persist, the new allocation system may not function as intended.

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 15 Jun 2020; 75:2906-2916
Parker WF, Chung K, Anderson AS, Siegler M, Huang ES, Churpek MM
J Am Coll Cardiol: 15 Jun 2020; 75:2906-2916 | PMID: 32527399
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Transethnic Genome-Wide Association Study Provides Insights in the Genetic Architecture and Heritability of Long QT Syndrome.

Lahrouchi N, Tadros R, Crotti L, Mizusawa Y, ... Tanck MWT, Bezzina CR

Long QT syndrome (LQTS) is a rare genetic disorder and a major preventable cause of sudden cardiac death in the young. A causal rare genetic variant with large effect size is identified in up to 80% of probands (genotype positive) and cascade family screening shows incomplete penetrance of genetic variants. Furthermore, a proportion of cases meeting diagnostic criteria for LQTS remain genetically elusive despite genetic testing of established genes (genotype negative). These observations raise the possibility that common genetic variants with small effect size contribute to the clinical picture of LQTS. This study aimed to characterize and quantify the contribution of common genetic variation to LQTS disease susceptibility.We conducted genome-wide association studies (GWAS) followed by transethnic meta-analysis in 1,656 unrelated LQTS patients of European or Japanese ancestry and 9,890 controls to identify susceptibility single nucleotide polymorphisms (SNPs). We estimated the SNP heritability () of LQTS and tested the genetic correlation between LQTS susceptibility and other cardiac traits. Furthermore, we tested the aggregate effect of the 68 SNPs previously associated with QTc in the general population using a polygenic risk score (PRS).Genome-wide association analysis identified three loci associated with LQTS at genome-wide statistical significance (P<5x10) near ,and , and one missense variant in(p.Asp85Asn) at the suggestive threshold (P<10). Heritability analyses showed that ~15% of variance in overall LQTS susceptibility was attributable to common genetic variation ( 0.148; standard error [SE] 0.019). LQTS susceptibility showed a strong genome-wide genetic correlation with the QT interval in the general population (r=0.40, P=3.2x10). PRS was greater in LQTS cases compared to controls (P<10), and notably, among LQTS patients PRS was greater in genotype negative compared to genotype positive patients (P<0.005).This work establishes an important role for common genetic variation in susceptibility to LQTS. We demonstrate overlap between genetic control of the QT interval in the general population and genetic factors contributing to LQTS susceptibility. Using polygenic risk score analyses aggregating common genetic variants that modulate the QT interval in the general population, we provide evidence for a polygenic architecture in genotype negative LQTS.



Circulation: 19 May 2020; epub ahead of print
Lahrouchi N, Tadros R, Crotti L, Mizusawa Y, ... Tanck MWT, Bezzina CR
Circulation: 19 May 2020; epub ahead of print | PMID: 32429735
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Ramipril in High Risk Patients with COVID-19.

Amat-Santos IJ, Santos-Martinez S, López-Otero D, Nombela-Franco L, ... Ibañez B, San Román JA
Background
The coronavirus disease 2019 (COVID-19) is caused by SARS-CoV2 that interfaces with the renin-angiotensin-aldosterone system (RAAS) through angiotensin-converting enzyme 2 (ACE-2). This interaction has been proposed as a potential risk factor in patients treated with RAAS-inhibitors.
Objectives
To analyze if RAAS-inhibitors modify the risk for COVID-19.
Methods
RASTAVI (NCT03201185) is an ongoing randomized clinical trial randomly allocating Ramipril or control after successful transcatheter aortic valve replacement at 14 centers is Spain. We performed a non-pre-specified interim analysis to evaluate its impact on COVID-19 risk in this vulnerable population.
Results
As in April 1 2020, 102 patients (50 Ramipril and 52 controls) were included in the trial. Mean age was 82.3±6.1 years, 56.9% males. Median time of Ramipril treatment was 6 months [IQR:2.9-11.4]. Eleven patients (10.8%) have been diagnosed with COVID-19 (6 in control group and 5 receiving Ramipril, HR=1.150 [95%CI: 0.351-3.768]). The risk of COVID-19 was increased in older patients (p=0.019), those with atrial fibrillation (p=0.066), lower hematocrit (p=0.084), and more comorbidities according to Society of thoracic surgeons score (p=0.065). Admission and oxygen supply was required in 4.9% (2 patients in the Ramipril and 3 in control), and 4 of them died (two in each randomized group). A higher body mass index was the only factor increasing the mortality rate (p=0.039).
Conclusions
In a high risk population of old patients with cardiovascular disease, randomization to Ramipril had no impact in the incidence or severity of COVID-19. This analysis supports the maintenance of RAAS-inhibitor treatment during COVID-19 crisis.

Copyright © 2020. Published by Elsevier Inc.

J Am Coll Cardiol: 21 May 2020; epub ahead of print
Amat-Santos IJ, Santos-Martinez S, López-Otero D, Nombela-Franco L, ... Ibañez B, San Román JA
J Am Coll Cardiol: 21 May 2020; epub ahead of print | PMID: 32470515
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Performance of the GRACE 2.0 score in patients with type 1 and type 2 myocardial infarction.

Hung J, Roos A, Kadesjö E, McAllister DA, ... Chapman AR, Holzmann MJ
Aims
The Global Registry of Acute Coronary Events (GRACE) score was developed to evaluate risk in patients with myocardial infarction. However, its performance in type 2 myocardial infarction is uncertain.
Methods and results
In two cohorts of consecutive patients with suspected acute coronary syndrome from 10 hospitals in Scotland (n = 48 282) and a tertiary care hospital in Sweden (n = 22 589), we calculated the GRACE 2.0 score to estimate death at 1 year. Discrimination was evaluated by the area under the receiver operating curve (AUC), and compared for those with an adjudicated diagnosis of type 1 and type 2 myocardial infarction using DeLong\'s test. Type 1 myocardial infarction was diagnosed in 4981 (10%) and 1080 (5%) patients in Scotland and Sweden, respectively. At 1 year, 720 (15%) and 112 (10%) patients died with an AUC for the GRACE 2.0 score of 0.83 [95% confidence interval (CI) 0.82-0.85] and 0.85 (95% CI 0.81-0.89). Type 2 myocardial infarction occurred in 1121 (2%) and 247 (1%) patients in Scotland and Sweden, respectively, with 258 (23%) and 57 (23%) deaths at 1 year. The AUC was 0.73 (95% CI 0.70-0.77) and 0.73 (95% CI 0.66-0.81) in type 2 myocardial infarction, which was lower than for type 1 myocardial infarction in both cohorts (P < 0.001 and P = 0.008, respectively).
Conclusion
The GRACE 2.0 score provided good discrimination for all-cause death at 1 year in patients with type 1 myocardial infarction, and moderate discrimination for those with type 2 myocardial infarction.
Trial registration
ClinicalTrials.gov number, NCT01852123.

© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.

Eur Heart J: 08 Jun 2020; epub ahead of print
Hung J, Roos A, Kadesjö E, McAllister DA, ... Chapman AR, Holzmann MJ
Eur Heart J: 08 Jun 2020; epub ahead of print | PMID: 32516805
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Use of Administrative Claims to Assess Outcomes and Treatment Effect in Randomized Clinical Trials for Transcatheter Aortic Valve Replacement: Findings from the Extending Trial-Based Evaluations of Medical Therapies Using Novel Sources of Data (EXTEND) Study.

Strom JB, Faridi KF, Butala NM, Zhao Y, ... Kazi DS, Yeh RW

Whether passively collected data can substitute for adjudicated outcomes to reproduce the magnitude and direction of treatment effect observed in cardiovascular clinical trials is not well known.We linked adults aged ≥65 in the US CoreValve Pivotal High Risk (HiR) and Surgical or Transcatheter Aortic Valve Replacement in Intermediate-Risk Patients (SURTAVI) Trials to 100% Medicare inpatient claims, 1/1/2003-12/31/2016. Primary (e.g. death and stroke) and secondary trial endpoints, were compared across treatment arms (e.g. TAVR vs. SAVR) using trial-adjudicated outcomes versus outcomes derived from claims at 1-year (HiR) or 2-years (SURTAVI).Among 600 linked CoreValve HiR participants (linkage rate 80.0%), the rate of the trial\'s primary endpoint of all-cause mortality occurred in 13.7% of patients receiving TAVR and 16.4% of patients receiving SAVR at 1-year using both trial data (HR 0.84, 95% CI 0.65-1.09; p= 0.33) and claims data (HR 0.86, 95% CI 0.66-1.11; p = 0.34; interaction p-value = 0.80). Noninferiority of TAVR relative to SAVR was seen using both trial and claims-based outcomes (p < 0.001 for both). Among 1005 linked SURTAVI trial participants (linkage rate 60.5%), the trial\'s primary endpoint was 12.9% for TAVR and 13.1% for SAVR using trial data (HR 1.08, 95% CI 0.79-1.48, p = 0.90), and 11.3% for TAVR and 12.5% for SAVR patients using claims data (HR 1.02, 95% CI 0.73-1.41, p = 0.58; interaction p-value = 0.89). TAVR was noninferior to SAVR when compared using both trial and claims (p < 0.001 for both). Rates of procedural secondary outcomes (e.g. aortic valve reintervention, pacemaker rates) were more closely concordant between trial and claims data than non-procedural outcomes (e.g., stroke, bleeding, cardiogenic shock).In the CoreValve HiR and SURTAVI trials, ascertainment of trial primary endpoints using claims reproduced both the magnitude and direction of treatment effect compared with adjudicated event data, but non-fatal and non-procedural secondary outcomes were not as well reproduced. Use of claims to substitute for adjudicated outcomes in traditional trial treatment comparisons may be valid and feasible for all-cause mortality and certain procedural outcomes, but may be less suitable for other endpoints.



Circulation: 20 May 2020; epub ahead of print
Strom JB, Faridi KF, Butala NM, Zhao Y, ... Kazi DS, Yeh RW
Circulation: 20 May 2020; epub ahead of print | PMID: 32436390
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

The Natural History of Severe Calcific Mitral Stenosis.

Kato N, Padang R, Scott CG, Guerrero M, Pislaru SV, Pellikka PA
Background
Prevalence of calcific mitral stenosis (MS) increases with age; however, its natural history and relation to cardiac symptoms or comorbidities are not well defined.
Objectives
This study assessed the prevalence of symptoms, comorbidities, and determinants of all-cause mortality in patients with severe calcific MS.
Methods
The authors retrospectively investigated adults with isolated severe calcific MS and mitral valve area ≤1.5 cm from July 2003 to December 2017. Inactivity was defined as requirement for assistance with activities of daily living.
Results
Of 491 patients with isolated severe MS, calcific MS was present in 200 (41%; age 78 ± 11 years, 18% men, 32% with atrial fibrillation). Charlson Comorbidity Index was 5.1 ± 1.7 and 14 (7%) were inactive. Mitral valve area and transmitral gradient (TMG) were 1.26 ± 0.19 cm and 8.1 ± 3.8 mm Hg, respectively. Symptoms were present at baseline in 120 (60%); 20 (10%) developed symptoms during follow-up of 2.8 ± 3.0 years. Kaplan-Meier survival at 1 year was 72% without intervention. Inactivity (hazard ratio [HR]: 6.59; 95% confidence interval [CI]: 3.54 to 12.3; p < 0.01), Charlson Comorbidity Index >5 (HR: 1.53; 95% CI: 1.04 to 2.26; p < 0.01), TMG ≥8 mm Hg (HR: 1.68; 95% CI: 1.12 to 2.51; p = 0.012), and right ventricular systolic pressure ≥50 mm Hg (HR: 2.27; 95% CI: 1.50 to 3.43; p < 0.01) were independently associated with mortality. Symptoms were not associated with mortality.
Conclusion
Patients with isolated severe calcific MS had a high burden of comorbidities, resulting in high mortality without intervention. Symptoms were reported in 60%, but not associated with mortality. TMG ≥8 mm Hg and right ventricular systolic pressure ≥50 mm Hg were independently associated with mortality.

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 22 Jun 2020; 75:3048-3057
Kato N, Padang R, Scott CG, Guerrero M, Pislaru SV, Pellikka PA
J Am Coll Cardiol: 22 Jun 2020; 75:3048-3057 | PMID: 32553258
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

COVID-19: from epidemiology to treatment.

Pericàs JM, Hernandez-Meneses M, Sheahan TP, Quintana E, ... Miro JM,

The COVID-19 pandemic has greatly impacted the daily clinical practice of cardiologists and cardiovascular surgeons. Preparedness of health workers and health services is crucial to tackle the enormous challenge posed by SARS-CoV-2 in wards, operating theatres, intensive care units, and interventionist laboratories. This Clinical Review provides an overview of COVID-19 and focuses on relevant aspects on prevention and management for specialists within the cardiovascular field.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: [email protected]

Eur Heart J: 06 Jun 2020; 41:2092-2112
Pericàs JM, Hernandez-Meneses M, Sheahan TP, Quintana E, ... Miro JM,
Eur Heart J: 06 Jun 2020; 41:2092-2112 | PMID: 32511724
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

The COMPASS Trial: Net Clinical Benefit of Low-Dose Rivaroxaban Plus Aspirin as Compared to Aspirin in Patients Chronic Vascular Disease.

Steffel J, Eikelboom JW, Anand SS, Shestakovska O, Yusuf S, Fox KAA

Rivaroxaban 2.5mg twice daily plus aspirin 100mg reduced the risk of cardiovascular events as compared to aspirin monotherapy in the COMPASS (Cardiovascular Outcomes for People Using Anticoagulation Strategies) trial but increased the risk of major bleedings. Analysis of net clinical benefit (NCB) is of key clinical relevance and represents an integrated measure of overall patient outcome.The current pre-specified analysis was performed to assess the NCB of adding rivaroxaban 2.5mg twice daily to aspirin monotherapy in patients with chronic vascular disease in the COMPASS study cohort (intention-to treat study population), with a specific focus on high-risk subgroups. The pre-defined NCB outcome was the composite of cardiovascular death, stroke, myocardial infarction, fatal bleeding, or symptomatic bleeding into a critical organ.A lower number of NCB adverse outcomes was observed with rivaroxaban 2.5mg twice daily + ASA vs. ASA alone (Hazard Ratio (HR) 0.80, 95% Confidence Interval (CI) 0.70-0.91), p=0.0005), which became increasingly favorable with longer treatment duration. The main drivers of NCB outcomes were \'efficacy\' events, in particular stroke (0.5%/yr vs. 0.8%/yr, HR 0.58, 95% CI 0.44-0.76, p<0.0001) and cardiovascular death (0.9%/vr vs. 1.2%/yr, HR 0.78, 95% CI 0.64-0.96, p=0.02), while the bleeding components of the NCB, in particular fatal bleeding (0.09%/yr vs. 0.06%/yr, HR 1.49, 95% CI 0.67-3.33, p=0.32), only represented a minority of NCB events. In selected high-risk subgroups, including patients with polyvascular disease (≥2 vascular beds affected with atherosclerosis), impaired renal function, heart failure, and / or diabetes, a larger absolute risk reduction for experiencing a NCB event was observed.Compared to ASA monotherapy the combination of rivaroxaban 2.5mg twice daily+ ASA resulted in fewer NCB events primarily by preventing adverse efficacy events, particularly stroke and cardiovascular mortality, whereas severe bleedings were less frequent and with less clinical impact. The NCB was particularly favorable in high-risk subgroups and those with multiple risk characteristics.URL: https://www.clinicaltrials.gov. Unique identifier: NCT01776424.



Circulation: 20 May 2020; epub ahead of print
Steffel J, Eikelboom JW, Anand SS, Shestakovska O, Yusuf S, Fox KAA
Circulation: 20 May 2020; epub ahead of print | PMID: 32436455
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Long-term β-blocker therapy and clinical outcomes after acute myocardial infarction in patients without heart failure: nationwide cohort study.

Kim J, Kang D, Park H, Kang M, ... Cho J, Hahn JY
Aims
To investigate the association between long-term β-blocker therapy and clinical outcomes in patients without heart failure (HF) after acute myocardial infarction (AMI).
Method and results
Between 2010 and 2015, a total of 28 970 patients who underwent coronary revascularization for AMI with β-blocker prescription at hospital discharge and were event-free from death, recurrent myocardial infarction (MI), or HF for 1 year were enrolled from Korean nationwide medical insurance data. The primary outcome was all-cause death. The secondary outcomes were recurrent MI, hospitalization for new HF, and a composite of all-cause death, recurrent MI, or hospitalization for new HF. Outcomes were compared between β-blocker therapy for ≥1 year (N = 22 707) and β-blocker therapy for <1 year (N = 6263) using landmark analysis at 1 year after index MI. Compared with patients receiving β-blocker therapy for <1 year, those receiving β-blocker therapy for ≥1 year had significantly lower risks of all-cause death [adjusted hazard ratio (HR) 0.81; 95% confidence interval (CI) 0.72-0.91] and composite of all-cause death, recurrent MI, or hospitalization for new HF (adjusted HR 0.82; 95% CI 0.75-0.89), but not the risks of recurrent MI or hospitalization for new HF. The lower risk of all-cause death associated with persistent β-blocker therapy was observed beyond 2 years (adjusted HR 0.86; 95% CI 0.75-0.99) but not beyond 3 years (adjusted HR 0.87; 95% CI 0.73-1.03) after MI.
Conclusion
In this nationwide cohort, β-blocker therapy for ≥1 year after MI was associated with reduced all-cause death among patients with AMI without HF.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: [email protected]

Eur Heart J: 14 Jun 2020; epub ahead of print
Kim J, Kang D, Park H, Kang M, ... Cho J, Hahn JY
Eur Heart J: 14 Jun 2020; epub ahead of print | PMID: 32542362
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Acute heart failure in multisystem inflammatory syndrome in children (MIS-C) in the context of global SARS-CoV-2 pandemic.

Belhadjer Z, Méot M, Bajolle F, Khraiche D, ... Renolleau S, Bonnet D

Cardiac injury and myocarditis have been described in adults with COVID-19. SARS-CoV-2 infection in children is typically minimally symptomatic. We report a series of febrile pediatric patients with acute heart failure potentially associated with SARS-CoV-2 infection and the multisystem inflammatory syndrome in children (MIS-C) as defined by the US Centers for Disease Control.Over a two-month period contemporary with the SARS-CoV-2 pandemic in France and Switzerland, we retrospectively collected clinical, biological, therapeutic, and early outcomes data in children who were admitted to pediatric intensive care units in 14 centers for cardiogenic shock, left ventricular dysfunction and severe inflammatory state.Thirty-five children were identified and included in the study. Median age at admission was 10 years (range 2-16 years). Co-morbidities were present in 28% including asthma and overweight. Gastrointestinal symptoms were prominent. Left ventricular ejection fraction was <30% in one third; 80% required inotropic support with 28% treated with ECMO. Inflammation markers were suggestive of cytokine storm (interleukin 6 median 135 pg/mL) and macrophage activation (D-dimer median 5284 ng/mL). Mean brain natriuretic peptide was elevated (5743 pg/mL). Thirty-one/35 (88%) patients tested positive for SARS-CoV-2 infection by PCR of nasopharyngeal swab or serology. All patients received intravenous immune globulin, with adjunctive steroid therapy used in one third. Left ventricular function was restored in the 25/35 of those discharged from the intensive care unit. No patient died, and all patients treated with ECMO were successfully weaned.Children may experience an acute cardiac decompensation due to severe inflammatory state following SARS-CoV-2 infection (multisystem inflammatory syndrome in children - MIS-C). Treatment with immune globulin appears to be associated with recovery of left ventricular systolic function.



Circulation: 16 May 2020; epub ahead of print
Belhadjer Z, Méot M, Bajolle F, Khraiche D, ... Renolleau S, Bonnet D
Circulation: 16 May 2020; epub ahead of print | PMID: 32418446
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Empagliflozin in Heart Failure: Diuretic and Cardio-Renal Effects.

Griffin M, Rao VS, Ivey-Miranda J, Fleming J, ... Inzucchi SE, Testani JM

Sodium-glucose cotransporter-2 inhibitors (SGLT-2i\'s) improve heart failure (HF) related outcomes. The mechanisms underlying these benefits are not well understood, but diuretic properties may contribute. Traditional diuretics, such as furosemide, induce substantial neurohormonal activation contributing to the limited improvement in intravascular volume often seen with these agents. However, the proximal tubular site of action of the SGLT-2i\'s may help circumvent these limitations.20 patients with type-2 diabetes and chronic, stable HF completed a randomized placebo-controlled crossover study of empagliflozin 10mg daily vs. placebo. Patients underwent an intensive 6-hour biospecimen collection and cardio-renal phenotyping at baseline and again after 14 days of study drug. After a 2-week washout, patients crossed over to the alternate therapy with repeat of the above protocol.Oral empagliflozin was rapidly absorbed as evidenced by a 27-fold increase in urinary glucose excretion by 3 hours (p<0.0001). Fractional excretion of sodium (FENa) increased significantly with empagliflozin monotherapy vs. placebo (FENa 1.2 ± 0.7% vs. 0.7 ± 0.4% p=0.001) and there was a synergistic effect in combination with bumetanide (FENa 5.8 ± 2.5% vs. 3.9 ± 1.9%, p=0.001). At 14 days, the natriuretic effect of empagliflozin persisted, resulting in a reduction in blood volume (-208mL, IQR -536 to 153 mL vs -14mL, IQR -282 to 335 mL, p=0.035), and plasma volume (-138mL, IQR -379 to 154mL ± 453 mL, p=0.04). This natriuresis was not, however, associated with evidence of neurohormonal activation as change in norepinephrine was superior (p = 0.02) and all other neurohormones similar (p<0.34) during the empagliflozin vs. placebo period. Furthermore, there was no evidence of potassium wasting (p=0.20), or renal dysfunction (p>0.11 for all biomarkers), whereas both serum magnesium (p<0.001) and uric acid levels (p=0.008) improved. Empagliflozin causes significant natriuresis, particularly when combined with loop diuretics, resulting in an improvement in blood volume. However, off-target electrolyte wasting, renal dysfunction, and neurohormonal activation were not observed. This favorable diuretic profile may offer significant advantage in the management of volume status in HF patients and may represent a mechanism contributing to the superior long-term HF outcomes observed with these agents.URL: https://clinicaltrials.gov Unique Identifier: NCT03029760.



Circulation: 14 May 2020; epub ahead of print
Griffin M, Rao VS, Ivey-Miranda J, Fleming J, ... Inzucchi SE, Testani JM
Circulation: 14 May 2020; epub ahead of print | PMID: 32410463
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Declines in Hospitalizations for Acute Cardiovascular Conditions During the COVID-19 Pandemic: A Multicenter Tertiary Care Experience.

Bhatt AS, Moscone A, McElrath EE, Varshney AS, ... Solomon SD, Vaduganathan M
Background
While patients with cardiovascular disease face excess risks of severe illness with coronavirus disease-2019 (COVID-19), there may be indirect consequences of the pandemic on this high-risk patient segment.
Objectives
To examine longitudinal trends in hospitalizations for acute cardiovascular conditions across a tertiary care healthcare system.
Methods
We tracked acute cardiovascular hospitalizations between January 1, 2019 and March 31, 2020. We estimated daily hospitalization rates using negative binomial models. Temporal trends in hospitalization rates were compared across the first 3 months of 2020, with the first 3 months of 2019 as a reference.
Results
From January 1, 2019 to March 31, 2020, 6,083 patients experienced 7,187 hospitalizations for primary acute cardiovascular reasons. There was 43.4% (27.4% to 56.0%) fewer estimated daily hospitalizations in March 2020 as compared with March 2019 (P<0.001). The daily rate of hospitalizations did not change throughout 2019 (-0.01% per day [-0.04% to +0.02%], P=0.50), January 2020 (-0.5% per day [-1.6% to +0.5%], P=0.31), or February 2020 (+0.7% per day [-0.6% to +2.0%], P=0.27). There was significant daily decline in hospitalizations in March 2020 (-5.9% per day [-7.6% to -4.3%], P<0.001). Length of stay was shorter (4.8 [2.4,8.3] days vs. 6.0 [3.1,9.6] days; P=0.003) and in-hospital mortality was not significantly different (6.2% vs. 4.4%; P=0.30) in March 2020 compared with March 2019.
Conclusions
During the first phase of the COVID-19 pandemic, there was a marked decline in acute cardiovascular hospitalizations and patients who were admitted had shorter lengths of stay. These data substantiate concerns that acute care of cardiovascular conditions may be delayed, deferred, or abbreviated during the COVID-19 pandemic.

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 20 May 2020; epub ahead of print
Bhatt AS, Moscone A, McElrath EE, Varshney AS, ... Solomon SD, Vaduganathan M
J Am Coll Cardiol: 20 May 2020; epub ahead of print | PMID: 32470516
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Coronary F-Sodium Fluoride Uptake Predicts Outcomes in Patients With Coronary Artery Disease.

Kwiecinski J, Tzolos E, Adamson PD, Cadet S, ... Slomka PJ, Dweck MR
Background
Reliable methods for predicting myocardial infarction in patients with established coronary artery disease are lacking. Coronary F-sodium fluoride (F-NaF) positron emission tomography (PET) provides an assessment of atherosclerosis activity.
Objectives
This study assessed whether F-NaF PET predicts myocardial infarction and provides additional prognostic information to current methods of risk stratification.
Methods
Patients with known coronary artery disease underwent F-NaF PET computed tomography and were followed up for fatal or nonfatal myocardial infarction over 42 months (interquartile range: 31 to 49 months). Total coronary F-NaF uptake was determined by the coronary microcalcification activity (CMA).
Results
In a post hoc analysis of data collected for prospective observational studies, the authors studied 293 study participants (age: 65 ± 9 years; 84% men), of whom 203 (69%) showed increased coronary F-NaF activity (CMA >0). Fatal or nonfatal myocardial infarction occurred only in patients with increased coronary F-NaF activity (20 of 203 with a CMA >0 vs. 0 of 90 with a CMA of 0; p < 0.001). On receiver operator curve analysis, fatal or nonfatal myocardial infarction prediction was highest for F-NaF CMA, outperforming coronary calcium scoring, modified Duke coronary artery disease index and Reduction of Atherothrombosis for Continued Health (REACH) and Secondary Manifestations of Arterial Disease (SMART) risk scores (area under the curve: 0.76 vs. 0.54, 0.62, 0.52, and 0.54, respectively; p < 0.001 for all). Patients with CMA >1.56 had a >7-fold increase in fatal or nonfatal myocardial infarction (hazard ratio: 7.1; 95% confidence interval: 2.2 to 25.1; p = 0.003) independent of age, sex, risk factors, segment involvement and coronary calcium scores, presence of coronary stents, coronary stenosis, REACH and SMART scores, the Duke coronary artery disease index, and recent myocardial infarction.
Conclusions
In patients with established coronary artery disease, F-NaF PET provides powerful independent prediction of fatal or nonfatal myocardial infarction.

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 22 Jun 2020; 75:3061-3074
Kwiecinski J, Tzolos E, Adamson PD, Cadet S, ... Slomka PJ, Dweck MR
J Am Coll Cardiol: 22 Jun 2020; 75:3061-3074 | PMID: 32553260
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Cardiac Energetics in Patients with Aortic Stenosis and Preserved versus Reduced Ejection Fraction.

Peterzan MA, Clarke WT, Lygate CA, Lake HA, ... Rodgers C, Rider OJ

Why some but not all patients with severe AS (SevAS) develop otherwise unexplained reduced systolic function is unclear. We investigate the hypothesis that reduced creatine kinase (CK) capacity and/or flux is associated with this transition.102 participants were recruited to five groups: moderate AS (ModAS, n=13), severe AS, LVEF ≥55% (SevAS-pEF, n=37), severe AS, LVEF<55% (SevAS-rEF, n=15), healthy volunteers with non-hypertrophied hearts with normal systolic function (NHv, n=30), and patients with non-hypertrophied, non-pressure loaded hearts with normal systolic function undergoing cardiac surgery and donating LV biopsy (NHbx, n=7). All underwent CMR imaging and P magnetic resonance spectroscopy (MRS) for myocardial energetics. LV biopsies (AS and NHBx) were analysed for; CK total activity, CK isoforms, citrate synthase (CS) activity and total creatine. Using serial block-face scanning electron microscopy, mitochondria-sarcomere diffusion distances were calculated.In the absence of failure, CK flux was lower in the presence of AS (by 32%, p=0.04), driven primarily by reduction in PCr/ATP (by 17%, p <0.001), with CK k unchanged (p=0.46),and is present in ModAS. Although lowest in the SevAS-rEF group, CK flux was not different to the SevAS-pEF group (p>0.99). Accompanying the fall in CK flux, total CK and CS activities, and absolute activities of MtCK and CK-MM were also lower (p<0.02, all analyses). Median mitochondria-sarcomere diffusion distances correlated well with CK total activity (r=0.86, p=.003).Total CK capacity is reduced in SevAS, with median values lowest in those with systolic failure, consistent with reduced energy supply reserve. Despite this, in vivo MRS measures of resting CK flux suggest that ATP delivery is reduced earlier, at the moderate AS stage, but where LV function remains preserved. These findings show that significant energetic impairment is already established in moderate AS, and suggest a fall in CK flux is not per se the cause of transition to systolic failure. However, as ATP demands increase with AS severity this could increase susceptibility to systolic failure. As such, targeting CK capacity and/or flux may be a therapeutic strategy to prevent/treat systolic failure in AS.



Circulation: 21 May 2020; epub ahead of print
Peterzan MA, Clarke WT, Lygate CA, Lake HA, ... Rodgers C, Rider OJ
Circulation: 21 May 2020; epub ahead of print | PMID: 32438845
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Infective Endocarditis After Transcatheter Aortic Valve Replacement.

Stortecky S, Heg D, Tueller D, Pilgrim T, ... Windecker S, Conen A
Background
Infective endocarditis may affect patients after transcatheter aortic valve replacement (TAVR).
Objectives
The purpose of this study was to provide detailed information on incidence rates, types of microorganisms, and outcomes of infective endocarditis after TAVR.
Methods
Between February 2011 and July 2018, consecutive patients from the SwissTAVI Registry were eligible. Infective endocarditis was classified into early (peri-procedural [<100 days] and delayed-early [100 days to 1 year]) and late (>1 year) endocarditis. Clinical events were adjudicated according to the Valve Academic Research Consortium-2 endpoint definitions.
Results
During the observational period, 7,203 patients underwent TAVR at 15 hospitals in Switzerland. During follow-up of 14,832 patient-years, endocarditis occurred in 149 patients. The incidence for peri-procedural, delayed-early, and late endocarditis after TAVR was 2.59, 0.71, and 0.40 events per 100 person-years, respectively. Among patients with early endocarditis, Enterococcus species were the most frequently isolated microorganisms (30.1%). Among those with peri-procedural endocarditis, 47.9% of patients had a pathogen that was not susceptible to the peri-procedural antibiotic prophylaxis. Younger age (subhazard ratio [SHR]: 0.969; 95% confidence interval [CI]: 0.944 to 0.994), male sex (SHR: 1.989; 95% CI: 1.403 to 2.818), lack of pre-dilatation (SHR: 1.485; 95% CI: 1.065 to 2.069), and treatment in a catheterization laboratory as opposed to hybrid operating room (SHR: 1.648; 95% CI: 1.187 to 2.287) were independently associated with endocarditis. In a case-control matched analysis, patients with endocarditis were at increased risk of mortality (hazard ratio: 6.55; 95% CI: 4.44 to 9.67) and stroke (hazard ratio: 4.03; 95% CI: 1.54 to 10.52).
Conclusions
Infective endocarditis after TAVR most frequently occurs during the early period, is commonly caused by Enterococcus species, and results in considerable risks of mortality and stroke. (NCT01368250).

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 22 Jun 2020; 75:3020-3030
Stortecky S, Heg D, Tueller D, Pilgrim T, ... Windecker S, Conen A
J Am Coll Cardiol: 22 Jun 2020; 75:3020-3030 | PMID: 32553254
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Subclinical Leaflet Thrombosis in Transcatheter and Surgical Bioprosthetic Valves: PARTNER 3 Cardiac Computed Tomography Substudy.

Makkar RR, Blanke P, Leipsic J, Thourani V, ... Mack M, Leon MB
Background
Subclinical leaflet thrombosis, characterized by hypoattenuated leaflet thickening (HALT) and reduced leaflet motion observed on 4-dimensional computed tomography (CT), may represent a form of bioprosthetic valve dysfunction.
Objectives
The U.S. Food and Drug Administration mandated CT studies to understand the natural history of this finding, differences between transcatheter and surgical valves, and its association with valve hemodynamics and clinical outcomes.
Methods
The PARTNER 3 (The Safety and Effectiveness of the SAPIEN 3 Transcatheter Heart Valve in Low-Risk Patients With Aortic Stenosis) CT substudy randomized 435 patients with low-surgical-risk aortic stenosis to undergo transcatheter aortic valve replacement (n = 221) or surgery (n = 214). Serial 4-dimensional CTs were performed at 30 days and 1 year and were analyzed independently by a core laboratory.
Results
The incidence of HALT increased from 10% at 30 days to 24% at 1 year. Spontaneous resolution of 30-day HALT occurred in 54% of patients at 1 year, whereas new HALT appeared in 21% of patients at 1 year. HALT was more frequent in transcatheter versus surgical valves at 30 days (13% vs. 5%; p = 0.03), but not at 1 year (28% vs. 20%; p = 0.19). The presence of HALT did not significantly affect aortic valve mean gradients at 30 days or 1 year. Patients with HALT at both 30 days and 1 year, compared with those with no HALT at 30 days and 1 year, had significantly increased aortic valve gradients at 1 year (17.8 ± 2.2 mm Hg vs. 12.7. ± 0.3 mm Hg; p = 0.04).
Conclusions
Subclinical leaflet thrombosis was more frequent in transcatheter compared with surgical valves at 30 days, but not at 1 year. The impact of HALT on thromboembolic complications and structural valve degeneration needs further assessment.

Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 22 Jun 2020; 75:3003-3015
Makkar RR, Blanke P, Leipsic J, Thourani V, ... Mack M, Leon MB
J Am Coll Cardiol: 22 Jun 2020; 75:3003-3015 | PMID: 32553252
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

The Environment-Sensing Aryl-Hydrocarbon Receptor Inhibits the Chondrogenic Fate of Modulated Smooth Muscle Cells in Atherosclerotic Lesions.

Kim JB, Zhao Q, Nguyen T, Pjanic M, ... Kundu R, Quertermous T

Smooth muscle cells (SMC) play a critical role in atherosclerosis. The Aryl hydrocarbon receptor (AHR) is an environment-sensing transcription factor that contributes to vascular development, and has been implicated in coronary artery disease (CAD) risk. We hypothesized that AHR can affect atherosclerosis by regulating phenotypic modulation of SMC.We combined RNA-Seq, ChIP-Seq, ATAC-Seq and in-vitro assays in human coronary artery SMC (HCASMC), with single-cell RNA-Seq (scRNA-Seq), histology, and RNAscope in an SMC-specific lineage-tracingknockout mouse model of atherosclerosis to better understand the role ofin vascular disease.Genomic studies coupled with functional assays in cultured HCASMC revealed thatmodulates HCASMC phenotype and suppresses ossification in these cells. Lineage tracing and activity tracing studies in the mouse aortic sinus showed that thepathway is active in modulated SMC in the atherosclerotic lesion cap. Furthermore, scRNA-Seq studies of the SMC-specific Ahr knockout mice showed a significant increase in the proportion of modulated SMC expressing chondrocyte markers such asand , which localized to the lesion neointima. These cells, which we term \"chondromyocytes\" (CMC), were also identified in the neointima of human coronary arteries. In histological analyses, these changes manifested as larger lesion size, increased lineage-traced SMC participation in the lesion, decreased lineage-traced SMC in the lesion cap, and increased alkaline phosphatase activity in lesions in theknockout compared to wild-type mice. We propose thatis likely protective based on these data and inference from human genetic analyses.Overall, we conclude thatpromotes maintenance of lesion cap integrity and diminishes the disease related SMC-to-CMC transition in atherosclerotic tissues.



Circulation: 21 May 2020; epub ahead of print
Kim JB, Zhao Q, Nguyen T, Pjanic M, ... Kundu R, Quertermous T
Circulation: 21 May 2020; epub ahead of print | PMID: 32441123
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Single-Cell RNA Sequencing to Dissect the Immunological Network of Autoimmune Myocarditis.

Hua X, Hu G, Hu Q, Chang Y, ... Li M, Song J

Myocarditis can develop into dilated cardiomyopathy (DCM), which may require heart transplantation (HTx). The immunological network of myocarditis phases remains unknown. This study aimed to investigate the immunological network during the transition from myocarditis to cardiomyopathy and to identify the genes contributing to the inflammatory response to myocarditis.Mice were treated with myosin heavy-chain-α peptides to generate an experimental autoimmune myocarditis (EAM) model. We performed single-cell RNA sequencing (scRNA-seq) analysis ofcells extracted from mouse hearts during different EAM phases, including normal control, acute inflammatory, subacute inflammatory and myopathy phases. Human heart tissues were collected from the surgically removed hearts of patients who had undergone HTx.We identified 26 cell subtypes among 34,665 cells. Macrophages constituted the main immune cell population at all disease phases (greater than 60%), and an inflammation-associated macrophage cluster was identified in which the expression of -regulated genes was upregulated. The neutrophil population was increased after the induction of EAM, and neutrophils then releasedto participate in the EAM process. T cells were observed at the highest percentage at the subacute inflammatory phase. Th17 cells, in which the expression of -regulated genes was upregulated, constituted the main T cell population detected at the acute inflammatory phase, while Treg cells were the main T cell population detected at the subacute inflammatory phase, and γδ T cells releasingwere the main T cell population observed at the myopathy phase. Moreover, theexpression level correlated with the extent of inflammation. Additionally, PX-478 could alleviate the inflammatory responses of the different EAM phases. Finally,was expressed at higher levels in acute autoimmune myocarditis patients than in DCM patients and healthy controls.We herein present a comprehensive single-cell landscape of the cardiac immune cells in different EAM phases. In addition, we elucidated the contribution ofto the inflammatory response through the regulation of immune cell activity, particularly of macrophage cluster 2 and Th17 cells. Moreover, ainhibitor alleviated inflammatory cell infiltration of the EAM model and may serve as a potential therapeutic target in the clinic.



Circulation: 19 May 2020; epub ahead of print
Hua X, Hu G, Hu Q, Chang Y, ... Li M, Song J
Circulation: 19 May 2020; epub ahead of print | PMID: 32431172
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Randomised Comparison of the Polymer-Free Biolimus-Coated BioFreedom Stent with the Ultrathin Strut Biodegradable Polymer Sirolimus-Eluting Orsiro Stent in an All-Comers Population Treated with Percutaneous Coronary Intervention: The SORT OUT IX Trial.

Jensen LO, Maeng M, Raungaard B, Kahlert J, ... Steen Hansen H, Christiansen EH

In patients with increased bleeding risk, the biolimus A9-coated BioFreedom stent, a stainless steel drug-coated stent free from polymer, has shown superiority compared to a bare-metal stent. The aim of this study was to investigate whether the BioFreedom stent is non-inferior to a modern ultrathin strut biodegradable polymer cobalt-chromium sirolimus-eluting Orsiro stent in an all-comers patient population treated with percutaneous coronary intervention.The Scandinavian Organization for Randomized Trials with Clinical Outcome (SORT OUT) IX trial, was a large-scale, registry-based, randomized, multicenter, single-blind, two-arm, non-inferiority trial. The primary endpoint, major adverse cardiovascular events (MACE), was defined as the composite of cardiac death, myocardial infarction not related to any segment other than the target lesion or target lesion revascularization within 1 year, analyzed by intention-to-treat. The trial was powered to assess non-inferiority for MACE of the BioFreedom stent compared with the Orsiro stent with a predetermined non-inferiority margin of 0.021. The trial is registered with ClinicalTrials.gov, NCT02623140.Between December 14, 2015 and April 21, 2017, 3,151 patients were assigned to treatment with the BioFreedom stent (1,572 patients, 1,966 lesions) or to the Orsiro stent (1,579 patients, 1,985 lesions). Five patients were lost to follow-up because of emigration (99.9% follow-up rate). Mean age was 66.3 {plus minus} 10.9, diabetes was seen in 19.3% of patients and 53% of the patients had acute coronary syndromes. At 1 year, intention-to-treat analysis showed that 79 (5.0%) patients, who were assigned the BioFreedom stent, and 59 (3.7%), who were assigned the Orsiro stent, met the primary endpoint (absolute risk difference 1.29% [upper limit of one-sided 95% CI 2.50%]; p(non-inferiority)=0.14). Significantly more patients in the BioFreedom stent group had target lesion revascularization than those in the Orsiro stent group (55 [3.5%] vs 20 [1.3%], rate ratio 2.77 [95% CI 1.66-4.62]; p<0.0001). The biolimus A9-coated BioFreedom polymer-free stent did not meet criteria for non-inferiority for MACE at 12 months when compared with the ultrathin strut biodegradable polymer sirolimus-eluting Orsiro stent in an all-comers populationURL: https://clinicaltrials.gov Unique Identifier: NCT02623140.



Circulation: 20 May 2020; epub ahead of print
Jensen LO, Maeng M, Raungaard B, Kahlert J, ... Steen Hansen H, Christiansen EH
Circulation: 20 May 2020; epub ahead of print | PMID: 32434381
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Implications of Altered Ketone Metabolism and Therapeutic Ketosis in Heart Failure.

Selvaraj S, Kelly DP, Margulies KB

Despite existing therapy, patients with heart failure (HF) experience substantial morbidity and mortality, highlighting the urgent need to identify novel pathophysiological mechanisms and therapies, as well. Traditional models for pharmacological intervention have targeted neurohormonal axes and hemodynamic disturbances in HF. However, several studies have now highlighted the potential for ketone metabolic modulation as a promising treatment paradigm. During the pathophysiological progression of HF, the failing heart reduces fatty acid and glucose oxidation, with associated increases in ketone metabolism. Recent studies indicate that enhanced myocardial ketone use is adaptive in HF, and limited data demonstrate beneficial effects of exogenous ketone therapy in studies of animal models and humans with HF. This review will summarize current evidence supporting a salutary role for ketones in HF including (1) normal myocardial ketone use, (2) alterations in ketone metabolism in the failing heart, (3) effects of therapeutic ketosis in animals and humans with HF, and (4) the potential significance of ketosis associated with sodium-glucose cotransporter 2 inhibitors. Although a number of important questions remain regarding the use of therapeutic ketosis and mechanism of action in HF, current evidence suggests potential benefit, in particular, in HF with reduced ejection fraction, with theoretical rationale for its use in HF with preserved ejection fraction. Although it is early in its study and development, therapeutic ketosis across the spectrum of HF holds significant promise.



Circulation: 01 Jun 2020; 141:1800-1812
Selvaraj S, Kelly DP, Margulies KB
Circulation: 01 Jun 2020; 141:1800-1812 | PMID: 32479196
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Genomewide Association Study of Severe Covid-19 with Respiratory Failure.

Ellinghaus D, Degenhardt F, Bujanda L, Buti M, ... Karlsen TH,
Background
There is considerable variation in disease behavior among patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus disease 2019 (Covid-19). Genomewide association analysis may allow for the identification of potential genetic factors involved in the development of Covid-19.
Methods
We conducted a genomewide association study involving 1980 patients with Covid-19 and severe disease (defined as respiratory failure) at seven hospitals in the Italian and Spanish epicenters of the SARS-CoV-2 pandemic in Europe. After quality control and the exclusion of population outliers, 835 patients and 1255 control participants from Italy and 775 patients and 950 control participants from Spain were included in the final analysis. In total, we analyzed 8,582,968 single-nucleotide polymorphisms and conducted a meta-analysis of the two case-control panels.
Results
We detected cross-replicating associations with rs11385942 at locus 3p21.31 and with rs657152 at locus 9q34.2, which were significant at the genomewide level (P<5×10) in the meta-analysis of the two case-control panels (odds ratio, 1.77; 95% confidence interval [CI], 1.48 to 2.11; P = 1.15×10; and odds ratio, 1.32; 95% CI, 1.20 to 1.47; P = 4.95×10, respectively). At locus 3p21.31, the association signal spanned the genes , , , ,and . The association signal at locus 9q34.2 coincided with theblood group locus; in this cohort, a blood-group-specific analysis showed a higher risk in blood group A than in other blood groups (odds ratio, 1.45; 95% CI, 1.20 to 1.75; P = 1.48×10) and a protective effect in blood group O as compared with other blood groups (odds ratio, 0.65; 95% CI, 0.53 to 0.79; P = 1.06×10).
Conclusions
We identified a 3p21.31 gene cluster as a genetic susceptibility locus in patients with Covid-19 with respiratory failure and confirmed a potential involvement of the ABO blood-group system. (Funded by Stein Erik Hagen and others.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 16 Jun 2020; epub ahead of print
Ellinghaus D, Degenhardt F, Bujanda L, Buti M, ... Karlsen TH,
N Engl J Med: 16 Jun 2020; epub ahead of print | PMID: 32558485
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Left Atrial Appendage Closure Versus Direct Oral Anticoagulants in High-Risk Patients With Atrial Fibrillation.

Osmancik P, Herman D, Neuzil P, Hala P, ... Reddy VY,
Background
Percutaneous left atrial appendage closure (LAAC) is noninferior to vitamin K antagonists (VKAs) for preventing atrial fibrillation (AF)-related stroke. However, direct oral anticoagulants (DOACs) have an improved safety profile over VKAs, and their effect on cardiovascular and neurological outcomes relative to LAAC is unknown.
Objectives
This study sought to compare DOACs with LAAC in high-risk patients with AF.
Methods
Left Atrial Appendage Closure vs. Novel Anticoagulation Agents in Atrial Fibrillation (PRAGUE-17) was a multicenter, randomized, noninferiority trial comparing LAAC with DOACs. Patients were eligible to be enrolled if they had nonvalvular AF; were indicated for oral anticoagulation (OAC); and had a history of bleeding requiring intervention or hospitalization, a history of a cardioembolic event while taking an OAC, and/or a CHADS-VASc of ≥3 and HAS-BLED of >2. Patients were randomized to receive LAAC or DOAC. The primary composite outcome was stroke, transient ischemic attack, systemic embolism, cardiovascular death, major or nonmajor clinically relevant bleeding, or procedure-/device-related complications. The primary analysis was by modified intention to treat.
Results
A high-risk patient cohort (CHADS-VASc: 4.7 ± 1.5) was randomized to receive LAAC (n = 201) or DOAC (n = 201). LAAC was successful in 181 of 201 (90.0%) patients. In the DOAC group, apixaban was most frequently used (192 of 201; 95.5%). At a median 19.9 months of follow-up, the annual rates of the primary outcome were 10.99% with LAAC and 13.42% with DOAC (subdistribution hazard ratio [sHR]: 0.84; 95% confidence interval [CI]: 0.53 to 1.31; p = 0.44; p = 0.004 for noninferiority). There were no differences between groups for the components of the composite endpoint: all-stroke/TIA (sHR: 1.00; 95% CI: 0.40 to 2.51), clinically significant bleeding (sHR: 0.81; 95% CI: 0.44 to 1.52), and cardiovascular death (sHR: 0.75; 95% CI: 0.34 to 1.62). Major LAAC-related complications occurred in 9 (4.5%) patients.
Conclusions
Among patients at high risk for stroke and increased risk of bleeding, LAAC was noninferior to DOAC in preventing major AF-related cardiovascular, neurological, and bleeding events. (Left Atrial Appendage Closure vs. Novel Anticoagulation Agents in Atrial Fibrillation [PRAGUE-17]; NCT02426944).

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 29 Jun 2020; 75:3122-3135
Osmancik P, Herman D, Neuzil P, Hala P, ... Reddy VY,
J Am Coll Cardiol: 29 Jun 2020; 75:3122-3135 | PMID: 32586585
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Clinical Features and Natural History of PRKAG2 Variant Cardiac Glycogenosis.

Lopez-Sainz A, Dominguez F, Lopes LR, Ochoa JP, ... Garcia-Pavia P,
Background
PRKAG2 gene variants cause a syndrome characterized by cardiomyopathy, conduction disease, and ventricular pre-excitation. Only a small number of cases have been reported to date, and the natural history of the disease is poorly understood.
Objectives
The aim of this study was to describe phenotype and natural history of PRKAG2 variants in a large multicenter European cohort.
Methods
Clinical, electrocardiographic, and echocardiographic data from 90 subjects with PRKAG2 variants (53% men; median age 33 years; interquartile range [IQR]: 15 to 50 years) recruited from 27 centers were retrospectively studied.
Results
At first evaluation, 93% of patients were in New York Heart Association functional class I or II. Maximum left ventricular wall thickness was 18 ± 8 mm, and left ventricular ejection fraction was 61 ± 12%. Left ventricular hypertrophy (LVH) was present in 60 subjects (67%) at baseline. Thirty patients (33%) had ventricular pre-excitation or had undergone accessory pathway ablation; 17 (19%) had pacemakers (median age at implantation 36 years; IQR: 27 to 46 years), and 16 (18%) had atrial fibrillation (median age 43 years; IQR: 31 to 54 years). After a median follow-up period of 6 years (IQR: 2.3 to 13.9 years), 71% of subjects had LVH, 29% had AF, 21% required de novo pacemakers (median age at implantation 37 years; IQR: 29 to 48 years), 14% required admission for heart failure, 8% experienced sudden cardiac death or equivalent, 4% required heart transplantation, and 13% died.
Conclusions
PRKAG2 syndrome is a progressive cardiomyopathy characterized by high rates of atrial fibrillation, conduction disease, advanced heart failure, and life-threatening arrhythmias. Classical features of pre-excitation and severe LVH are not uniformly present, and diagnosis should be considered in patients with LVH who develop atrial fibrillation or require permanent pacemakers at a young age.

Copyright © 2020 American College of Cardiology Foundation. All rights reserved.

J Am Coll Cardiol: 13 Jul 2020; 76:186-197
Lopez-Sainz A, Dominguez F, Lopes LR, Ochoa JP, ... Garcia-Pavia P,
J Am Coll Cardiol: 13 Jul 2020; 76:186-197 | PMID: 32646569
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Extracellular Vesicle-Mediated Delivery of CircSCMH1 Promotes Functional Recovery in Rodent and Nonhuman Primate Ischemic Stroke Models.

Yang L, Han B, Zhang Z, Wang S, ... Wang J, Yao H

Stroke is a leading cause of adult disability that can severely compromise patients\' quality of life, yet no effective medication currently exists to accelerate rehabilitation. A variety of circular RNA (circRNAs) molecules are known to function in ischemic brain injury. Lentivirus-based expression systems have been widely used in basic studies of circRNAs, but safety issues with such delivery systems have limited exploration of potential therapeutic roles for circRNAs.Circular RNA SCMH1 (circSCMH1) was screened from the plasma of acute ischemic stroke (AIS) patients using circRNA microarrays. Engineered RVG-circSCMH1-extracellular vesicles (RVG-circSCMH1-EVs) were generated to selectively deliver circSCMH1 to the brain. Nissl staining was used to examine infarct size. Behavioral tasks were performed to evaluate motor functions in both rodent and nonhuman primate ischemic stroke models. Golgi staining and immunostaining were used to examine neuroplasticity and glial activation. Proteomic assays and RNA-seq data combined with transcriptional profiling were used to identify downstream targets of circSCMH1.CircSCMH1 levels were significantly decreased in plasma of AIS patients, offering significant power in predicting stroke outcomes. The decreased levels of circSCMH1 were further confirmed in the plasma and peri-infarct cortex of photothrombotic (PT) stroke mice. Beyond demonstrating proof-of-concept for an RNA drug delivery technology, we observed that circSCMH1 treatment improved functional recovery post stroke in both mice and monkeys, and discovered that circSCMH1 enhanced the neuronal plasticity and also inhibited glial activation and peripheral immune cell infiltration. Mechanistically, circSCMH1 binds to the transcription factor MeCP2, thereby releasing repression of MeCP2 target gene transcription.RVG-circSCMH1-EVs afford protection by promoting functional recovery in the rodent and the nonhuman primate ischemic stroke models. Our study presents a potentially widely applicable nucleotide drug delivery technology and demonstrates the basic mechanism of how circRNAs can be therapeutically exploited to improve post-stroke outcomes.



Circulation: 21 May 2020; epub ahead of print
Yang L, Han B, Zhang Z, Wang S, ... Wang J, Yao H
Circulation: 21 May 2020; epub ahead of print | PMID: 32441115
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Artificial intelligence and the future of global health.

Schwalbe N, Wahl B

Concurrent advances in information technology infrastructure and mobile computing power in many low and middle-income countries (LMICs) have raised hopes that artificial intelligence (AI) might help to address challenges unique to the field of global health and accelerate achievement of the health-related sustainable development goals. A series of fundamental questions have been raised about AI-driven health interventions, and whether the tools, methods, and protections traditionally used to make ethical and evidence-based decisions about new technologies can be applied to AI. Deployment of AI has already begun for a broad range of health issues common to LMICs, with interventions focused primarily on communicable diseases, including tuberculosis and malaria. Types of AI vary, but most use some form of machine learning or signal processing. Several types of machine learning methods are frequently used together, as is machine learning with other approaches, most often signal processing. AI-driven health interventions fit into four categories relevant to global health researchers: (1) diagnosis, (2) patient morbidity or mortality risk assessment, (3) disease outbreak prediction and surveillance, and (4) health policy and planning. However, much of the AI-driven intervention research in global health does not describe ethical, regulatory, or practical considerations required for widespread use or deployment at scale. Despite the field remaining nascent, AI-driven health interventions could lead to improved health outcomes in LMICs. Although some challenges of developing and deploying these interventions might not be unique to these settings, the global health community will need to work quickly to establish guidelines for development, testing, and use, and develop a user-driven research agenda to facilitate equitable and ethical use.

Copyright © 2020 Elsevier Ltd. All rights reserved.

Lancet: 15 May 2020; 395:1579-1586
Schwalbe N, Wahl B
Lancet: 15 May 2020; 395:1579-1586 | PMID: 32416782
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Duration of Pre-Operative Antibiotic Treatment and Culture Results in Patients With Infective Endocarditis.

Gisler V, Dürr S, Irincheeva I, Limacher A, ... Englberger L, Sendi P
Background
Bacterial growth in cultures of resected heart valves of patients with infective endocarditis (IE) is influenced by pre-operative antibiotic treatment (preop-AT).
Objectives
This study sought to evaluate the time dependency of valve culture results (positive valve culture [PVC] vs. negative valve culture) on preop-AT.
Methods
A total of 352 IE episodes in 344 adult patients of our tertiary referral hospital were retrospectively investigated (2005 to 2016). The primary endpoint was PVC results. The study used a logistic additive model adjusted for bacterial species, the McCabe-Jackson classification, and the existence of foreign valve material as covariables.
Results
The 231 included IE cases (187 [81%] men, median age 62 years, 153 [66%] native valves) comprised 58 (25%) PVC results and 173 (75%) negative valve culture results. A multivariable analysis adjusted for bacterial species, McCabe-Jackson classification, and valve type resulted in odds ratios for PVC of 6.35 (95% confidence interval [CI]: 1.94 to 20.78; p = 0.002) and 3.93 (95% CI: 1.57 to 9.84; p = 0.003) for Enterococcus spp. and Staphylococcus spp., respectively. Model-based odds ratios for PVC risk reduction in 2-day intervals of preop-AT ranged from 0.64 (95% CI: 0.61 to 0.68) at day 7 to 0.74 (95% CI: 0.70 to 0.78) at day 13 and 0.98 (95% CI: 0.93 to 1.02) at day 21.
Conclusions
In IE cases treated with valve surgery, Staphylococcus aureus and Enterococcus spp. were associated with valve culture growth. After 7 days of antibiotic treatment, the additional effect of preop-AT on valve culture results per 2-day interval was minor. Antibiotic treatment beyond 21 days had no influence on culture results.

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 06 Jul 2020; 76:31-40
Gisler V, Dürr S, Irincheeva I, Limacher A, ... Englberger L, Sendi P
J Am Coll Cardiol: 06 Jul 2020; 76:31-40 | PMID: 32616160
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Safety of Transesophageal Echocardiography to Guide Structural Cardiac Interventions.

Freitas-Ferraz AB, Bernier M, Vaillancourt R, Ugalde PA, ... Beaudoin J, Rodés-Cabau J
Background
Despite the widespread use of transesophageal echocardiography (TEE) to guide structural cardiac interventions, studies evaluating safety in this context are lacking.
Objectives
This study sought to determine the incidence, types of complications, and factors associated with esophageal or gastric lesions following TEE manipulation during structural cardiac interventions.
Methods
This was a prospective study including 50 patients undergoing structural cardiac interventions in which TEE played a central role in guiding the procedure (mitral and tricuspid valve repair, left atrial appendage closure, and paravalvular leak closure). An esophagogastroduodenoscopy (EGD) was performed before and immediately after the procedure to look for new injuries that might have arisen during the course of the intervention. Patients were divided in 2 cohorts according to the type of injury: complex lesions (intramural hematoma, mucosal laceration) and minor lesions (petechiae, ecchymosis). The factors associated with an increased risk of complications were assessed.
Results
Post-procedural EGD showed a new injury in 86% (n = 43 of 50) of patients, with complex lesions accounting for 40% (n = 20 of 50) of cases. Patients with complex lesions presented more frequently with an abnormal baseline EGD (70% vs. 37%; p = 0.04) and had a higher incidence of post-procedural dysphagia or odynophagia (40% vs. 10%; p = 0.02). Independent factors associated with an increased risk of complex lesions were a longer procedural time under TEE manipulation (for each 10-min increment in imaging time, odds ratio: 1.27; 95% confidence interval: 1.01 to 1.59) and poor or suboptimal image quality (odds ratio: 4.93; 95% confidence interval: 1.10 to 22.02).
Conclusions
Most patients undergoing structural cardiac interventions showed some form of injury associated with TEE, with longer procedural time and poor or suboptimal image quality determining an increased risk. Imaging experts performing this technique should be aware of the nature of potential complications, to take the necessary precautions to prevent their occurrence and facilitate early diagnosis and treatment.

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 29 Jun 2020; 75:3164-3173
Freitas-Ferraz AB, Bernier M, Vaillancourt R, Ugalde PA, ... Beaudoin J, Rodés-Cabau J
J Am Coll Cardiol: 29 Jun 2020; 75:3164-3173 | PMID: 32586591
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Long-term clinical outcomes of losartan in patients with Marfan syndrome: follow-up of the multicentre randomized controlled COMPARE trial.

van Andel MM, Indrakusuma R, Jalalzadeh H, Balm R, ... de Waard V, Groenink M
Aims
The COMPARE trial showed a small but significant beneficial effect of 3-year losartan treatment on aortic root dilatation rate in adults with Marfan syndrome (MFS). However, no significant effect was found on clinical endpoints, possibly due to a short follow-up period. The aim of the current study was therefore to investigate the long-term clinical outcomes after losartan treatment.
Methods and results
In the original COMPARE study (inclusion 2008-2009), adult patients with MFS (n = 233) were randomly allocated to either the angiotensin-II receptor blocker losartan® on top of regular treatment (β-blockers in 71% of the patients) or no additional medication. After the COMPARE trial period of 3 years, study subjects chose to continue their losartan medication or not. In a median follow-up period of 8 years, 75 patients continued losartan medication, whereas 78 patients, originally allocated to the control group, never used losartan after inclusion. No differences existed between baseline characteristics of the two groups except for age at inclusion [losartan 34 (interquartile range, IQR 26-43) years, control 41 (IQR 30-52) years; P = 0.031], and β-blocker use (losartan 81%, control 64%; P = 0.022). A pathological FBN1 mutation was present in 76% of patients and 58% of the patients were male. Clinical endpoints, defined as all-cause mortality, aortic dissection/rupture, elective aortic root replacement, reoperation, and vascular graft implantation beyond the aortic root, were compared between the two groups. A per-patient composite endpoint was also analysed. Five deaths, 14 aortic dissections, 23 aortic root replacements, 3 reoperations, and 3 vascular graft implantations beyond the aortic root occurred during follow-up. Except for aortic root replacement, all endpoints occurred in patients with an operated aortic root. Patients who used losartan during the entire follow-up period showed a reduced number of events compared to the control group (death: 0 vs. 5, P = 0.014; aortic dissection: 3 vs. 11, P = 0.013; elective aortic root replacement: 10 vs. 13, P = 0.264; reoperation: 1 vs. 2, P = 0.463; vascular graft implantations beyond the aortic root 0 vs. 3, P = 0.071; and composite endpoint: 14 vs. 26, P = 0.019). These results remained similar when corrected for age and β-blocker use in a multivariate analysis.
Conclusion
These results suggest a clinical benefit of combined losartan and β-blocker treatment in patients with MFS.

© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.

Eur Heart J: 14 Jun 2020; epub ahead of print
van Andel MM, Indrakusuma R, Jalalzadeh H, Balm R, ... de Waard V, Groenink M
Eur Heart J: 14 Jun 2020; epub ahead of print | PMID: 32548624
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Cardiovascular Risk of Isolated Systolic or Diastolic Hypertension in Young Adults.

Lee H, Yano Y, Cho SMJ, Park JH, ... Lloyd-Jones DM, Kim HC
Background
Little is known regarding health outcomes associated with isolated systolic hypertension (ISH), isolated diastolic hypertension (IDH), or systolic and diastolic hypertension (SDH) among young adults with stage 1 hypertension, defined using the 2017 American College of Cardiology/American Heart Association blood pressure (BP) guideline.
Methods
From a nationwide health screening database, we included 6 424 090 participants, aged 20 to 39 years, who were not taking antihypertensive medication at the baseline examination in 2003 to 2007. Participants were categorized as having normal BP (untreated systolic BP [SBP] <120/diastolic BP [DBP] <80 mm Hg; n=2 665 310); elevated BP (SBP 120-129/DBP <80 mm Hg; n=705 344); stage 1 IDH (SBP <130/DBP 80-89 mm Hg; n=1 271 505); stage 1 ISH (SBP 130-139/DBP <80 mm Hg; n=255 588); stage 1 SDH (SBP 130-139/DBP 80-89 mm Hg; n=711 503); and stage 2 hypertension (SBP ≥140, DBP ≥90 mm Hg; n=814 840). The primary outcome was composite cardiovascular disease (CVD) events, including myocardial infarction, stroke, heart failure, and CVD-related death.
Results
The median age of the participants was 30 years and 60.9% were male. Over a median follow-up of 13.2 years, 44 070 new CVD events occurred. With normal BP as the reference, multivariable-adjusted hazard ratios (95% CIs) for CVD events were 1.14 (1.09-1.18) for elevated BP, 1.32 (1.28-1.36) for stage 1 IDH, 1.36 (1.29-1.43) for stage 1 ISH, 1.67 (1.61-1.72) for stage 1 SDH, and 2.40 (2.33-2.47) for stage 2 hypertension.
Conclusions
Among young adults, stage 1 ISH, IDH, and SDH were all associated with higher CVD risks than normal BP. The CVD risks of stage 1 ISH and IDH were similar to each other but lower than the risk of stage 1 SDH. Categorizing young adults with stage 1 hypertension further into stage 1 ISH, IDH, and SDH may improve risk stratification for identifying high-risk individuals.



Circulation: 01 Jun 2020; 141:1778-1786
Lee H, Yano Y, Cho SMJ, Park JH, ... Lloyd-Jones DM, Kim HC
Circulation: 01 Jun 2020; 141:1778-1786 | PMID: 32479205
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Early Cardiac Remodeling Promotes Tumor Growth and Metastasis.

Avraham S, Abu-Sharki S, Shofti R, Haas T, ... Shaked Y, Aronheim A

Recent evidence suggests that cancer and cardiovascular diseases are associated. Chemotherapy drugs are known to result in cardiotoxicity, and studies have shown that heart failure (HF) and stress correlate with poor cancer prognosis. Yet, whether cardiac remodeling in the absence of HF is sufficient to promote cancer is unknown.To investigate the effect of early cardiac remodeling on tumor growth and metastasis colonization, we used transverse aortic constriction (TAC), a model for pressure overload-induced cardiac hypertrophy, and followed it by cancer cell implantation.TAC-operated mice developed larger primary tumors with higher proliferation rate and displayed more metastatic lesions compared with controls. Serum derived from TAC-operated mice potentiated cancer cell proliferation , suggesting the existence of secreted tumor-promoting factors. Using RNA-seq data, we identified elevated mRNA levels ofin the hearts of TAC-operated mice. Periostin levels were also found high in the serum following TAC. Interestingly, depletion of Periostin from the serum abrogated the proliferation of cancer cells, conversely, the addition of Periostin enhanced cancer cell proliferation . Collectively, this is the first study to show that early cardiac remodeling nurtures tumor growth and metastasis, and therefore promotes cancer progression.Our study highlights the importance of early diagnosis and treatment of cardiac remodeling as it may attenuate cancer progression and improve cancer outcome.



Circulation: 31 May 2020; epub ahead of print
Avraham S, Abu-Sharki S, Shofti R, Haas T, ... Shaked Y, Aronheim A
Circulation: 31 May 2020; epub ahead of print | PMID: 32475164
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Recurrence of Atrial Fibrillation After Catheter Ablation or Antiarrhythmic Drug Therapy in the CABANA Trial.

Poole JE, Bahnson TD, Monahan KH, Johnson G, ... Packer DL,
Background
The CABANA (Catheter Ablation Versus Antiarrhythmic Drug Therapy for Atrial Fibrillation) trial randomized 2,204 patients with atrial fibrillation (AF) to catheter ablation or drug therapy. Analysis by intention-to-treat showed a nonsignificant 14% relative reduction in the primary outcome of death, disabling stroke, serious bleeding, or cardiac arrest.
Objectives
The purpose of this study was to assess recurrence of AF in the CABANA trial.
Methods
The authors prospectively studied CABANA patients using a proprietary electrocardiogram recording monitor for symptom-activated and 24-h AF auto detection. The AF recurrence endpoint was any post-90-day blanking atrial tachyarrhythmias lasting 30 s or longer. Biannual 96-h Holter monitoring was used to assess AF burden. Patients who used the CABANA monitors and provided 90-day post-blanking recordings qualified for this analysis (n = 1,240; 56% of CABANA population). Treatment comparisons were performed using a modified intention-to-treat approach.
Results
Median age of the 1,240 patients was 68 years, 34.4% were women, and AF was paroxysmal in 43.0%. Over 60 months of follow-up, first recurrence of any symptomatic or asymptomatic AF (hazard ratio: 0.52; 95% confidence interval: 0.45 to 0.60; p < 0.001) or first symptomatic-only AF (hazard ratio: 0.49; 95% confidence interval: 0.39 to 0.61; p < 0.001) were both significantly reduced in the catheter ablation group. Baseline Holter AF burden in both treatment groups was 48%. At 12 months, AF burden in ablation patients averaged 6.3%, and in drug-therapy patients, 14.4%. AF burden was significantly less in catheter ablation compared with drug-therapy patients across the 5-year follow-up (p < 0.001). These findings were not sensitive to the baseline pattern of AF.
Conclusions
Catheter ablation was effective in reducing recurrence of any AF by 48% and symptomatic AF by 51% compared with drug therapy over 5 years of follow-up. Furthermore, AF burden was also significantly reduced in catheter ablation patients, regardless of their baseline AF type. (Catheter Ablation vs Anti-arrhythmic Drug Therapy for Atrial Fibrillation Trial [CABANA]; NCT00911508).

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 29 Jun 2020; 75:3105-3118
Poole JE, Bahnson TD, Monahan KH, Johnson G, ... Packer DL,
J Am Coll Cardiol: 29 Jun 2020; 75:3105-3118 | PMID: 32586583
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Loss of Protease-Activated Receptor 4 Prevents Inflammation Resolution and Predisposes the Heart to Cardiac Rupture after Myocardial Infarction.

Kolpakov MA, Guo X, Rafiq K, Vlasenko L, ... Houser SR, Sabri A

Cardiac rupture is a major lethal complication of acute myocardial infarction (MI). Despite significant advances in reperfusion strategies, mortality from cardiac rupture remains high. Studies suggest that cardiac rupture can be accelerated by thrombolytic therapy, but the relevance of this risk factor remains controversial.We analyzed protease activated receptor (Par)4 expression in mouse hearts with MI and investigated the effects of Par4 deletion on cardiac remodeling and function post-MI by echocardiography, quantitative immunohistochemistry and flow cytometry.Par4 mRNA and protein levels were increased in mouse hearts after MI and in isolated cardiomyocytes in response to hypertrophic and inflammatory stimuli. Par4-deficient mice showed less myocyte apoptosis, reduced infarct size and improved functional recovery after acute MI relative to wild-type (WT). Conversely, Par4 mice showed impaired cardiac function, greater rates of myocardial rupture and increased mortality after chronic MI relative to WT. Pathological evaluation of hearts from Par4 mice demonstrated a greater infarct expansion, increased cardiac hemorrhage and delayed neutrophil accumulation, which resulted in impaired post-MI healing compared to WT. Par4 deficiency also attenuated neutrophil apoptosisand after MIand impaired inflammation resolution in infarcted myocardium. Transfer of Par4 neutrophils, but not of Par4 platelets, in WT recipient mice delayed inflammation resolution, increased cardiac hemorrhage and enhanced cardiac dysfunction. In parallel, adoptive transfer of WT neutrophils into Par4 mice restored inflammation resolution, reduced cardiac rupture incidence and improved cardiac function post-MI.These findings reveal essential roles of Par4 in neutrophil apoptosis and inflammation resolution during myocardial healing and point to Par4 inhibition as potential therapy that should be limited to the acute phases of ischemic insult and to be avoided for chronic treatment post-MI.



Circulation: 02 Jun 2020; epub ahead of print
Kolpakov MA, Guo X, Rafiq K, Vlasenko L, ... Houser SR, Sabri A
Circulation: 02 Jun 2020; epub ahead of print | PMID: 32489148
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Sex differences and temporal trends in aortic dissection: a population-based study of incidence, treatment strategies, and outcome in Swedish patients during 15 years.

Smedberg C, Steuer J, Leander K, Hultgren R
Aims
As large population-based studies of aortic dissection are lacking, the incidence numbers and knowledge about time-trends and sex differences are uncertain. The objective was to describe incidence, temporal trends and outcome of aortic dissection with particular emphasis on sex differences.
Methods and results
During the study period 2002-2016, 8057 patients in Sweden were diagnosed with aortic dissection, identified from the National Patient Register and the Cause of Death Register. A total of 5757 (71%) patients were hospitalized, whereas 2300 (29%) patients were deceased without concurrent hospital stay. The annual incidence was 7.2 per 100 000 (9.1 in men and 5.4 in women), decreasing over time in men (P = 0.005). Mean age in the hospitalized patients was 68 years (SD 13), 2080 (36%) were women. Within the first 14 days after onset, 1807 patients (32%) underwent surgical repair. The proportion of surgically treated increased from the 5-year period 2002-2006 to 2012-2016 [27% vs. 35%, odds ratio (OR) 1.61, 95% confidence interval (CI) 1.39-1.86; P < 0.001]. In hospitalized patients, 30-day mortality decreased between the same periods (26% vs. 21%, OR 0.68, 95% CI 0.59-0.80; P < 0.001). Long-term mortality decreased as well (hazard ratio 0.74, 95% CI 0.67-0.82; P < 0.001). Women had higher 30-day mortality than men after acute repair, a sex difference that remained after age adjustment (17% vs. 12%, OR 1.38, 95% CI 1.04-1.82; P = 0.006).
Conclusion
This population-based study detected a higher incidence of aortic dissection than prior reports, but a decreasing incidence in men. Surgical therapy was increasingly used and with more favourable outcome but was less frequently offered to elderly patients. The sustained sex differences regarding both incidence and outcome require further attention.

© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.

Eur Heart J: 18 Jun 2020; epub ahead of print
Smedberg C, Steuer J, Leander K, Hultgren R
Eur Heart J: 18 Jun 2020; epub ahead of print | PMID: 32558879
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Evaluation of Risk-Adjusted Home Time After Acute Myocardial Infarction as a Novel Hospital-Level Performance Metric for Medicare Beneficiaries.

Pandey A, Keshvani N, Vaughan-Sarrazin MS, Gao Y, Girotra S

Utility of 30-day risk-standardized readmission rate (RSRR) as a hospital performance metric has been a matter of debate. Home time is a patient-centered outcome measure that accounts for rehospitalization, mortality, and post-discharge care. We aim to characterize risk-adjusted 30-day home time in patients with acute myocardial infarction (AMI) as a hospital-level performance metric and evaluate associations with 30-day RSRR, 30-day risk-standardized mortality rate (RSMR), and 1-year RSMR.The study included 984,612 patients with AMI hospitalization across 2,379 hospitals between 2009 to 2015 derived from 100% Medicare claims data. Home time was defined as the number of days alive and spent outside of a hospital, skilled nursing facility (SNF), or intermediate/long-term acute care facility 30-days after discharge. Correlation between hospital-level risk-adjusted 30-day home time and 30-day RSRR, RSMR, and 1-year RSMR were estimated using Pearson\'s correlation. Reclassification in hospital performance using 30-day home time vs. 30-day RSRR & 30-day RSMR was also evaluated.Median hospital-level risk-adjusted 30-day home time was 24.0 days (range: 15.3-29.0). Hospitals with higher home time were more commonly academic centers, had available cardiac surgery and rehabilitation services, and had higher AMI volume and PCI utilization during the AMI hospitalization. Of the mean 30-day home time days lost, 58% were to intermediate/long-term care or SNF stays (4.7 days), 30% to death (2.5 days), and 12% to readmission (1.0 days). Hospital-level risk adjusted 30-day home time was inversely correlated with 30-day RSMR (r = -0.22, p<0.0001) and 30-day RSRR (r = -0.25, p<0.0001). Patients admitted to hospitals with higher risk-adjusted 30-day home time had lower 30-day readmission (Q1 vs. Q4: 21% vs. 17%), 30-day mortality rate (5% vs. 3%), and 1-year mortality rate (18% vs. 12%). Furthermore, 30-day home time reclassified hospital performance status in approximately 30% of hospitals versus 30-day RSRR and 30-day RSMR.30-day home time for patients with AMI can be assessed as a hospital-level performance metric using Medicare claims data. It varies across hospitals, is associated with post-discharge readmission and mortality outcomes, and meaningfully reclassifies hospital performance compared with the 30-day RSRR and 30-day RSMR metric.



Circulation: 14 May 2020; epub ahead of print
Pandey A, Keshvani N, Vaughan-Sarrazin MS, Gao Y, Girotra S
Circulation: 14 May 2020; epub ahead of print | PMID: 32408764
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Higher Activation of the Rostromedial Prefrontal Cortex during Mental Stress Predicts Major Cardiovascular Disease Events in Individuals with Coronary Artery Disease.

Moazzami K, Wittbrodt MT, Lima BB, Nye JA, ... Vaccarino V, Shah AJ

Psychological stress is a risk factor for major adverse cardiovascular events (MACE) in individuals with coronary artery disease (CAD). Certain brain regions that control both emotional states and cardiac physiology may be involved in this relationship. The rostromedial prefrontal cortex (rmPFC) is an important brain region that processes stress and regulates immune and autonomic functions. Changes in rmPFC activity with emotional stress (reactivity) may be informative of future risk for MACE.Participants with stable CAD underwent acute mental stress testing using a series of standardized speech/arithmetic stressors and simultaneous brain imaging with high resolution-positron emission tomography brain imaging. We defined high rmPFC activation as a difference between stress and control scans greater than the median value for the entire cohort. Interleukin-6 (IL-6) levels 90 minutes post-stress, and high-frequency heart rate variability (HF-HRV) during stress were also assessed. We defined MACE as a composite of cardiovascular death, myocardial infarction, unstable angina with revascularization and heart failure hospitalization.We studied 148 subjects (69% male) with mean ± SD age of 62 ± 8 years. After adjustment for baseline demographics, risk factors, and baseline levels of IL-6 and HF-HRV, higher rmPFC stress reactivity was independently associated with higher IL-6 and lower HF-HRV with stress. During a median follow-up of 3 years, 34 subjects (21.3%) experienced a MACE. Each 1SD increase in rmPFC activation with mental stress was associated with a 21% increase risk of MACE (HR 1.21, 95% CI 1.08-1.37). Stress-induced IL-6 and HF-HRV explained 15.5% and 32.5% of the relationship between rmPFC reactivity and MACE, respectively. Addition of rmPFC reactivity to conventional risk factors improved risk reclassification for MACE prediction, and C-statistic improved from 0.71 to 0.76 (p=0.03).Greater rmPFC stress reactivity is associated with incident MACE. Immune and autonomic responses to mental stress may play a contributory role.



Circulation: 10 Jun 2020; epub ahead of print
Moazzami K, Wittbrodt MT, Lima BB, Nye JA, ... Vaccarino V, Shah AJ
Circulation: 10 Jun 2020; epub ahead of print | PMID: 32522022
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Older ...

This program is still in alpha version.