Topic: Heart Failure

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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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Abstract

Baroreflex Activation Therapy in Patients With Heart Failure With Reduced Ejection Fraction.

Zile MR, Lindenfeld J, Weaver FA, Zannad F, ... Rogers T, Abraham WT
Background
This study demonstrated the safety and effectiveness of baroreflex activation therapy (BAT) in patients with heart failure with reduced ejection fraction (HFrEF).
Objectives
The BeAT-HF (Baroreflex Activation Therapy for Heart Failure) trial was a multicenter, prospective, randomized, controlled trial; subjects were randomized 1:1 to receive either BAT plus optimal medical management (BAT group) or optimal medical management alone (control group).
Methods
Four patient cohorts were created from 408 randomized patients with HFrEF using the following enrollment criteria: current New York Heart Association (NYHA) functional class III or functional class II (patients who had a recent history of NYHA functional class III); ejection fraction ≤35%; stable medical management for ≥4 weeks; and no Class I indication for cardiac resynchronization therapy. Effectiveness endpoints were the change from baseline to 6 months in 6-min hall walk distance (6MHW), Minnesota Living with HF Questionnaire quality-of-life (QOL) score, and N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels. The safety endpoint included the major adverse neurological or cardiovascular system or procedure-related event rate (MANCE).
Results
Results from, timeline and rationale for, cohorts A, B, and C are presented in detail in the text. Cohort D, which represented the intended use population that reflected the U.S. Food and Drug Administration-approved instructions for use (enrollment criteria plus NT-proBNP <1,600 pg/ml), consisted of 245 patients followed-up for 6 months (120 in the BAT group and 125 in the control group). BAT was safe and significantly improved QOL, 6MHW, and NT-proBNP. In the BAT group versus the control group, QOL score decreased (Δ = -14.1; 95% confidence interval [CI]: -19 to -9; p < 0.001), 6MHW distance increased (Δ = 60 m; 95% CI: 40 to 80 m; p < 0.001), NT-proBNP decreased (Δ = -25%; 95% CI: -38% to -9%; p = 0.004), and the MANCE free rate was 97% (95% CI: 93% to 100%; p < 0.001).
Conclusions
BAT was safe and significantly improved QOL, exercise capacity, and NT-proBNP. (Baroreflex Activation Therapy for Heart Failure [BeAT-HF]; NCT02627196).

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

J Am Coll Cardiol: 06 Jul 2020; 76:1-13
Zile MR, Lindenfeld J, Weaver FA, Zannad F, ... Rogers T, Abraham WT
J Am Coll Cardiol: 06 Jul 2020; 76:1-13 | PMID: 32616150
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Abstract

Publication Rates of Heart Failure Clinical Trials Remain Low.

Psotka MA, Latta F, Cani D, Fiuzat M, ... Metra M, O\'Connor CM
Background
Under-reporting of clinical trial results inhibits dissemination of knowledge, limits understanding of therapeutic interventions, and may ultimately harm patients.
Objectives
This study examined the rates and predictors of heart failure clinical trial publication and how they have changed over time.
Methods
This study assessed cross-sectional analysis of all heart failure clinical trials registered on ClinicalTrials.gov with at least 2 years follow-up after trial completion. The content area was chosen for the robust clinical trial activity in the field. The primary outcome was manuscript publication with multivariable proportional hazards adjustment to identify associations with publication.
Results
Of the 1,429 included studies, 806 (56%) were published as manuscripts, 623 were unpublished, and 97 (7%) reported results without manuscript publication. Of the total, 1,243 were completed after 2007, when the mean 1-year publication rate for interventional trials rose from 12.7% to 19.6% (p = 0.049), which was possibly associated with changes in government regulation. However, there was no further sustained improvement over time, and there was no multivariable association between later completion dates and reporting or publication of results. Funding from the National Institutes of Health and use of clinical (death, hospitalization, myocardial infarction, changes in functional classification) rather than nonclinical primary endpoints were associated with earlier publication. Whether the results were consistent with the primary study hypothesis was not associated with likelihood of publication.
Conclusions
The rates of heart failure clinical trial publication or reporting of results remain unacceptably low. Additional efforts by all stakeholders, including investigators, sponsors, regulators, societies, editors, and journals are needed to improve data dissemination.

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

J Am Coll Cardiol: 29 Jun 2020; 75:3151-3161
Psotka MA, Latta F, Cani D, Fiuzat M, ... Metra M, O'Connor CM
J Am Coll Cardiol: 29 Jun 2020; 75:3151-3161 | PMID: 32586589
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Abstract

Advancing Research on the Complex Interrelations Between Atrial Fibrillation and Heart Failure: A Report From a US National Heart, Lung, and Blood Institute Virtual Workshop.

Al-Khatib SM, Benjamin EJ, Albert CM, Alonso A, ... Cooper LS, Go AS

The interrelationships between atrial fibrillation (AF) and heart failure (HF) are complex and poorly understood, yet the number of patients with AF and HF continues to increase worldwide. Thus, there is a need for initiatives that prioritize research on the intersection between AF and HF. This article summarizes the proceedings of a virtual workshop convened by the US National Heart, Lung, and Blood Institute to identify important research opportunities in AF and HF. Key knowledge gaps were reviewed and research priorities were proposed for characterizing the pathophysiological overlap and deleterious interactions between AF and HF; preventing HF in people with AF; preventing AF in individuals with HF; and addressing symptom burden and health status outcomes in AF and HF. These research priorities will hopefully help inform, encourage, and stimulate innovative, cost-efficient, and transformative studies to enhance the outcomes of patients with AF and HF.



Circulation: 08 Jun 2020; 141:1915-1926
Al-Khatib SM, Benjamin EJ, Albert CM, Alonso A, ... Cooper LS, Go AS
Circulation: 08 Jun 2020; 141:1915-1926 | PMID: 32511001
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Abstract

New-onset atrial fibrillation: incidence, characteristics, and related events following a national COVID-19 lockdown of 5.6 million people.

Holt A, Gislason GH, Schou M, Zareini B, ... Torp-Pedersen C, Lamberts M
Aim
To determine the incidence, patient characteristics, and related events associated with new-onset atrial fibrillation (AF) during a national COVID-19 lockdown.
Methods and results
Using nationwide Danish registries, we included all patients, aged 18-90 years, receiving a new-onset AF diagnosis during the first 3 months of 2019 and 2020. The main comparison was between patients diagnosed during lockdown (12 March 12-1 April 2020) and patients diagnosed in the corresponding period 1 year previously. We found a lower incidence of new-onset AF during the 3 weeks of lockdown compared with the corresponding weeks in 2019 [incidence rate ratios with 95% confidence intervals (CIs) for the 3 weeks: 0.66 (0.56-0.78), 0.53 (0.45-0.64), and 0.41 (0.34-0.50)]. There was a 47% drop in total numbers (562 vs. 1053). Patients diagnosed during lockdown were younger and with a lower CHA2DS2-VASc score, while history of cancer, heart failure, and vascular disease were more prevalent. During lockdown, 30 (5.3%) patients with new-onset AF suffered an ischaemic stroke and 15 (2.7%) died, compared with 45 (4.3%) and 14 (1.3%) patients during the corresponding 2019 period, respectively. The adjusted odds ratio of a related event (ischaemic stroke or all-cause death) during lock-down compared with the corresponding weeks was 1.41 (95% CI 0.93-2.12).
Conclusions
Following a national lockdown in Denmark, a 47% drop in registered new-onset AF cases was observed. In the event of prolonged or subsequent lockdowns, the risk of undiagnosed AF patients developing complications could potentially translate into poorer outcomes in patients with AF during the COVID-19 pandemic.

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: 23 Jun 2020; epub ahead of print
Holt A, Gislason GH, Schou M, Zareini B, ... Torp-Pedersen C, Lamberts M
Eur Heart J: 23 Jun 2020; epub ahead of print | PMID: 32578859
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Abstract

Targeting muscle-enriched long non-coding RNA H19 reverses pathological cardiac hypertrophy.

Viereck J, Bührke A, Foinquinos A, Chatterjee S, ... Bär C, Thum T
Aims
Pathological cardiac remodelling and subsequent heart failure represents an unmet clinical need. Long non-coding RNAs (lncRNAs) are emerging as crucial molecular orchestrators of disease processes, including that of heart diseases. Here, we report on the powerful therapeutic potential of the conserved lncRNA H19 in the treatment of pathological cardiac hypertrophy.
Method and results
Pressure overload-induced left ventricular cardiac remodelling revealed an up-regulation of H19 in the early phase but strong sustained repression upon reaching the decompensated phase of heart failure. The translational potential of H19 is highlighted by its repression in a large animal (pig) model of left ventricular hypertrophy, in diseased human heart samples, in human stem cell-derived cardiomyocytes and in human engineered heart tissue in response to afterload enhancement. Pressure overload-induced cardiac hypertrophy in H19 knock-out mice was aggravated compared to wild-type mice. In contrast, vector-based, cardiomyocyte-directed gene therapy using murine and human H19 strongly attenuated heart failure even when cardiac hypertrophy was already established. Mechanistically, using microarray, gene set enrichment analyses and Chromatin ImmunoPrecipitation DNA-Sequencing, we identified a link between H19 and pro-hypertrophic nuclear factor of activated T cells (NFAT) signalling. H19 physically interacts with the polycomb repressive complex 2 to suppress H3K27 tri-methylation of the anti-hypertrophic Tescalcin locus which in turn leads to reduced NFAT expression and activity.
Conclusion
H19 is highly conserved and down-regulated in failing hearts from mice, pigs and humans. H19 gene therapy prevents and reverses experimental pressure-overload-induced heart failure. H19 acts as an anti-hypertrophic lncRNA and represents a promising therapeutic target to combat pathological cardiac remodelling.

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

Eur Heart J: 12 Jul 2020; epub ahead of print
Viereck J, Bührke A, Foinquinos A, Chatterjee S, ... Bär C, Thum T
Eur Heart J: 12 Jul 2020; epub ahead of print | PMID: 32657324
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Abstract

Estimating lifetime benefits of comprehensive disease-modifying pharmacological therapies in patients with heart failure with reduced ejection fraction: a comparative analysis of three randomised controlled trials.

Vaduganathan M, Claggett BL, Jhund PS, Cunningham JW, ... McMurray JJV, Solomon SD
Background
Three drug classes (mineralocorticoid receptor antagonists [MRAs], angiotensin receptor-neprilysin inhibitors [ARNIs], and sodium/glucose cotransporter 2 [SGLT2] inhibitors) reduce mortality in patients with heart failure with reduced ejection fraction (HFrEF) beyond conventional therapy consisting of angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) and β blockers. Each class was previously studied with different background therapies and the expected treatment benefits with their combined use are not known. Here, we used data from three previously reported randomised controlled trials to estimate lifetime gains in event-free survival and overall survival with comprehensive therapy versus conventional therapy in patients with chronic HFrEF.
Methods
In this cross-trial analysis, we estimated treatment effects of comprehensive disease-modifying pharmacological therapy (ARNI, β blocker, MRA, and SGLT2 inhibitor) versus conventional therapy (ACE inhibitor or ARB and β blocker) in patients with chronic HFrEF by making indirect comparisons of three pivotal trials, EMPHASIS-HF (n=2737), PARADIGM-HF (n=8399), and DAPA-HF (n=4744). Our primary endpoint was a composite of cardiovascular death or first hospital admission for heart failure; we also assessed these endpoints individually and assessed all-cause mortality. Assuming these relative treatment effects are consistent over time, we then projected incremental long-term gains in event-free survival and overall survival with comprehensive disease-modifying therapy in the control group of the EMPHASIS-HF trial (ACE inhibitor or ARB and β blocker).
Findings
The hazard ratio (HR) for the imputed aggregate treatment effects of comprehensive disease-modifying therapy versus conventional therapy on the primary endpoint of cardiovascular death or hospital admission for heart failure was 0·38 (95% CI 0·30-0·47). HRs were also favourable for cardiovascular death alone (HR 0·50 [95% CI 0·37-0·67]), hospital admission for heart failure alone (0·32 [0·24-0·43]), and all-cause mortality (0·53 [0·40-0·70]). Treatment with comprehensive disease-modifying pharmacological therapy was estimated to afford 2·7 additional years (for an 80-year-old) to 8·3 additional years (for a 55-year-old) free from cardiovascular death or first hospital admission for heart failure and 1·4 additional years (for an 80-year-old) to 6·3 additional years (for a 55-year-old) of survival compared with conventional therapy.
Interpretation
Among patients with HFrEF, the anticipated aggregate treatment effects of early comprehensive disease-modifying pharmacological therapy are substantial and support the combination use of an ARNI, β blocker, MRA, and SGLT2 inhibitor as a new therapeutic standard.
Funding
None.

Copyright © 2020 Elsevier Ltd. All rights reserved.

Lancet: 20 May 2020; epub ahead of print
Vaduganathan M, Claggett BL, Jhund PS, Cunningham JW, ... McMurray JJV, Solomon SD
Lancet: 20 May 2020; epub ahead of print | PMID: 32446323
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Abstract

Agrin Promotes Coordinated Therapeutic Processes Leading to Improved Cardiac Repair in Pigs.

Baehr A, Umansky KB, Bassat E, Jurisch V, ... Kupatt C, Tzahor E

Ischemic heart diseases are classified among the leading cause of death and reduced life quality worldwide. Although revascularization strategies significantly reduce mortality after acute myocardial infarction (MI), a significant number of MI patients develop chronic heart failure over time. We previously reported that a fragment of the extra cellular matrix (ECM) protein Agrin promotes cardiac regeneration following MI in adult mice.To test the therapeutic potential of Agrin in a preclinical porcine model we performed ischemia reperfusion (I/R) injuries using balloon occlusion for 60 minutes followed by either 3, 7 or 28 days reperfusion period.We first demonstrate that local (antegrade) delivery of recombinant human Agrin (rhAgrin) to the infarcted pig heart can target the affected regions in an efficient and clinically-relevant manner. Single dose of recombinant human Agrin improved heart function, infarct size, fibrosis and adverse remodeling parameters 28 days post MI. Short-term MI experiments along with complementary murine studies revealed myocardial protection, improved angiogenesis, inflammatory suppression and cell cycle re-entry, as Agrin\'s mechanisms of action.We show that a single dose of Agrin is capable of reducing ischemia reperfusion injury and improving heart function, demonstrating that Agrin could serve as a therapy for patients with acute MI and potentially heart failure.



Circulation: 07 Jun 2020; epub ahead of print
Baehr A, Umansky KB, Bassat E, Jurisch V, ... Kupatt C, Tzahor E
Circulation: 07 Jun 2020; epub ahead of print | PMID: 32508131
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Abstract

Cardiac Amyloidosis: Evolving Diagnosis and Management: A Scientific Statement From the American Heart Association.

Kittleson MM, Maurer MS, Ambardekar AV, Bullock-Palmer RP, ... Ruberg FL,

Transthyretin amyloid cardiomyopathy (ATTR-CM) results in a restrictive cardiomyopathy caused by extracellular deposition of transthyretin, normally involved in the transportation of the hormone thyroxine and retinol-binding protein, in the myocardium. Enthusiasm about ATTR-CM has grown as a result of 3 simultaneous areas of advancement: Imaging techniques allow accurate noninvasive diagnosis of ATTR-CM without the need for confirmatory endomyocardial biopsies; observational studies indicate that the diagnosis of ATTR-CM may be underrecognized in a significant proportion of patients with heart failure; and on the basis of elucidation of the mechanisms of amyloid formation, therapies are now approved for treatment of ATTR-CM. Because therapy for ATTR-CM may be most effective when administered before significant cardiac dysfunction, early identification of affected individuals with readily available noninvasive tests is essential. This scientific statement is intended to guide clinical practice and to facilitate management conformity by covering current diagnostic and treatment strategies, as well as unmet needs and areas of active investigation in ATTR-CM.



Circulation: 31 May 2020:CIR0000000000000792; epub ahead of print
Kittleson MM, Maurer MS, Ambardekar AV, Bullock-Palmer RP, ... Ruberg FL,
Circulation: 31 May 2020:CIR0000000000000792; epub ahead of print | PMID: 32476490
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Abstract

Temporal Trends in Prevalence & Prognostic Implications of Comorbidities Among Patients with Acute Decompensated Heart Failure: The ARIC Study Community Surveillance.

Pandey A, Vaduganathan M, Arora S, Qamar A, ... Rosamond WD, Caughey MC

Patients with heart failure (HF) have multiple co-existing comorbidities. The temporal trends in the burden of comorbidities and associated risk of mortality among patients with HF with preserved ejection fraction (HFpEF) and HF with reduced ejection fraction (HFrEF) are not well-established.HF related hospitalizations were sampled by stratified design from four US areas in 2005 to 2014 by the community surveillance component of the ARIC (Atherosclerosis Risk in Communities) study. Acute decompensated HF was classified by standardized physician review and a previously validated algorithm. An ejection fraction <50% was considered HFrEF. A total of 15 co-morbidities were abstracted from the medical record. Mortality outcomes were ascertained for up to 1-year post-admission, by linking hospital records with death files.A total of 5,460 hospitalizations (24,937 weighted hospitalizations) classified as acute decompensated HF had available ejection fraction data (53% female, 68% white, 53% HFrEF, 47% HFpEF). The average number of comorbidities was higher for patients with HFpEF vs. HFrEF, both for women (5.53 vs. 4.94, <0.0001) and men (5.20 vs. 4.82, <0.0001). There was a significant temporal increase in the overall burden of co-morbidities, both for patients with HFpEF (Women: 5.17 in 2005-2009 to 5.87 in 2010-2013; Men: 4.94 in 2005-2009 and 5.45 in 2010-2013) and HFrEF (Women: 4.78 in 2005-2009 to 5.14 in 2010-2013; Men: 4.62 in 2005-2009 and 5.06 in 2010-2013, -trend<0.0001 for all). Higher comorbidity burden was significantly associated with higher adjusted risk of 1-year mortality, with a stronger association noted for HFpEF [HR (95% CI) per 1-higher co-morbidity:1.19(1.14-1.25) vs. HFrEF [HR (95%CI): 1.10(1.05-1.14); -interaction by HF type = 0.02]. The associated mortality risk per 1-higher co-morbidity also increased significantly over time for patients with HFpEF as well HFrEF (P-for interaction with time =0.002 and 0.02 respectively).The burden of comorbidities among hospitalized patients with acute decompensated HFpEF and HFrEF has increased over time, as has its associated mortality risk. Higher burden of comorbidities is associated with higher risk of mortality, with a stronger association noted among patients with HFpEF vs. HFrEF.



Circulation: 02 Jun 2020; epub ahead of print
Pandey A, Vaduganathan M, Arora S, Qamar A, ... Rosamond WD, Caughey MC
Circulation: 02 Jun 2020; epub ahead of print | PMID: 32486833
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Abstract

Long-Term Outcomes of Implantable Cardioverter-Defibrillator Therapy in the SCD-HeFT.

Poole JE, Olshansky B, Mark DB, Anderson J, ... Bardy GH,
Background
The SCD-HeFT (Sudden Cardiac Death in Heart Failure Trial) randomized 2,521 patients with moderate heart failure (HF) to amiodarone, placebo drug, or implantable cardioverter-defibrillator (ICD) therapy. Original trial follow-up ended October 31, 2003. Over a median 45.5-month follow-up, amiodarone, compared with placebo, did not affect survival, whereas randomization to an ICD significantly decreased all-cause mortality by 23%.
Objectives
This study sought to describe the extended treatment group survival of the SCD-HeFT cohort.
Methods
Mortality outcomes for the 1,855 patients alive at the end of the SCD-HeFT trial were collected between 2010 and 2011. These data were combined with the 666 deaths from the original study to compare long-term outcomes overall and for key pre-specified subgroups.
Results
Median (25th to 75th percentiles) follow-up was 11.0 (10.0 to 12.2) years. On the basis of intention-to-treat analysis, the ICD group had overall survival benefit versus placebo drug (hazard ratio [HR]: 0.87; 95% confidence interval [CI]: 0.76 to 0.98; p = 0.028). When treatment benefit was examined as a function of time from randomization, attenuation of the ICD benefit was observed after 6 years (p value for the interaction = 0.0015). Subgroup analysis revealed long-term ICD benefit varied according to HF etiology and New York Heart Association (NYHA) functional class: ischemic HF HR: 0.81; 95% CI: 0.69 to 0.95; p = 0.009; nonischemic HF HR: 0.97; 95% CI: 0.79 to 1.20; p = 0.802; NYHA functional class II HR: 0.76; 95% CI: 0.65 to 0.90; p = 0.001; NYHA functional class III HR: 1.06; 95% CI: 0.86 to 1.31; p = 0.575.
Conclusions
Follow-up of SCD-HeFT patients to 11 years demonstrated heterogenous treatment-related patterns of long-term survival with ICD benefit most evident at 11 years for ischemic HF patients and for those with NYHA functional class II symptoms at trial enrollment. (SCD-HeFT 10 Year Follow-up [SCD-HeFT10 Yr]; NCT01058837).

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

J Am Coll Cardiol: 27 Jul 2020; 76:405-415
Poole JE, Olshansky B, Mark DB, Anderson J, ... Bardy GH,
J Am Coll Cardiol: 27 Jul 2020; 76:405-415 | PMID: 32703511
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Abstract

Cardiac Troponin for the Diagnosis and Risk-Stratification of Myocardial Injury in COVID-19: JACC Review Topic of the Week.

Sandoval Y, Januzzi JL, Jaffe AS

Increases in cardiac troponin (cTn) indicative of myocardial injury are common in patients with COVID-19 and associated with adverse outcomes such as arrhythmias and death. These increases are more likely to occur in those with chronic cardiovascular conditions and in those with severe COVID-19 presentations. The increased inflammatory, prothrombotic, and procoagulant responses following SARS-CoV-2 infection increase the risk for acute nonischemic myocardial injury and acute myocardial infarction, particularly type 2 myocardial infarction because of respiratory failure with hypoxia and hemodynamic instability in critically ill patients. Myocarditis, stress cardiomyopathy, acute heart failure, and direct injury from SARS-CoV-2 are important etiologies, but primary non-cardiac conditions such as pulmonary embolism, critical illness, and sepsis probably cause more of the myocardial injury. The structured use of serial cTn has the potential to facilitate risk stratification, help make decisions about when to use imaging, and inform stage categorization and disease phenotyping among hospitalized COVID-19 patients.

Copyright © 2020. Published by Elsevier Inc.

J Am Coll Cardiol: 02 Jul 2020; epub ahead of print
Sandoval Y, Januzzi JL, Jaffe AS
J Am Coll Cardiol: 02 Jul 2020; epub ahead of print | PMID: 32652195
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Abstract

Calcineurin Aβ-Specific Anchoring Confers Isoform-Specific Compartmentation and Function in Pathological Cardiac Myocyte Hypertrophy.

Li X, Li J, Martinez EC, Froese A, ... Nikolaev VO, Kapiloff MS

The Ca/calmodulin-dependent phosphatase calcineurin is a key regulator of cardiac myocyte hypertrophy in disease. An unexplained paradox is how the Aβ isoform of calcineurin (CaNAβ) is required for induction of pathological myocyte hypertrophy, despite calcineurin Aα expression in the same cells. In addition, it is unclear how the pleiotropic second messenger Ca drives excitation-contraction coupling, while not stimulating hypertrophy via calcineurin in the normal heart. Elucidation of the mechanisms conferring this selectively in calcineurin signaling should reveal new strategies for targeting the phosphatase in disease.Primary adult rat ventricular myocytes were studied for morphology and intracellular signaling. New Forster Resonance Energy Transfer (FRET) reporters were used to assay Ca and calcineurin activity in living cells. Conditional gene deletion and adeno-associated virus (AAV)-mediated gene delivery in the mouse were used to study calcineurin signaling following transverse aortic constriction .Cdc42-interacting protein (CIP4/TRIP10) was identified as a new polyproline domain-dependent scaffold for CaNAβ2 by yeast-2-hybrid screen. Cardiac myocyte-specific CIP4 gene deletion in mice attenuated pressure overload-induced pathological cardiac remodeling and heart failure. Accordingly, blockade of CaNAβ polyproline-dependent anchoring using a competing peptide inhibited concentric hypertrophy in cultured myocytes, while disruption of anchoringusing an AAV gene therapy vector inhibited cardiac hypertrophy and improved systolic function after pressure overload. Live cell FRET biosensor imaging of cultured myocytes revealed that Ca levels and calcineurin activity associated with the CIP4 compartment were increased by neurohormonal stimulation, but minimally by pacing. Conversely, Ca levels and calcineurin activity detected by non-localized FRET sensors were induced by pacing and minimally by neurohormonal stimulation, providing functional evidence for differential intracellular compartmentation of Ca and calcineurin signal transduction.These results support a structural model for Ca and CaNAβ compartmentation in cells based upon an isoform-specific mechanism for calcineurin protein-protein interaction and localization. This mechanism provides an explanation for the specific role of CaNAβ in hypertrophy and its selective activation under conditions of pathologic stress. Disruption of CaNAβ polyproline-dependent anchoring constitutes a rational strategy for therapeutic targeting of CaNAβ-specific signaling responsible for pathological cardiac remodeling in cardiovascular disease deserving of further pre-clinical investigation.



Circulation: 01 Jul 2020; epub ahead of print
Li X, Li J, Martinez EC, Froese A, ... Nikolaev VO, Kapiloff MS
Circulation: 01 Jul 2020; epub ahead of print | PMID: 32611257
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Impact:
Abstract

Transcatheter Valve-in-Valve Aortic Valve Replacement as an Alternative to Surgical Re-Replacement.

Deharo P, Bisson A, Herbert J, Lacour T, ... Cuisset T, Fauchier L
Background
Valve-in-valve (VIV) transcatheter aortic valve replacement (TAVR) and redo surgical aortic valve replacement (SAVR) represent the 2 treatments for aortic bioprosthesis failure. Clinical comparison of both therapies remains limited by the number of patients analyzed.
Objectives
The purpose of this study was to analyze the outcomes of VIV TAVR versus redo SAVR at a nationwide level in France.
Methods
Based on the French administrative hospital-discharge database, the study collected information for patients treated for aortic bioprosthesis failure with isolated VIV TAVR or redo SAVR between 2010 and 2019. Propensity score matching was used for the analysis of outcomes.
Results
A total of 4,327 patients were found in the database. After matching on baseline characteristics, 717 patients were analyzed in each arm. At 30 days, VIV TAVR was associated with lower rates of the composite of all-cause mortality, all-cause stroke, myocardial infarction, and major or life-threatening bleeding (odds ratio: 0.62; 95% confidence interval: 0.44 to 0.88; p = 0.03). During follow-up (median 516 days), the combined endpoint of cardiovascular death, all-cause stroke, myocardial infarction, or rehospitalization for heart failure was not different between the 2 groups (odds ratio: 1.18; 95% confidence interval: 0.99 to 1.41; p = 0.26). Rehospitalization for heart failure and pacemaker implantation were more frequently reported in the VIV TAVR group. A time-dependent interaction between all-cause and cardiovascular mortality following VIV TAVR was reported (p-interaction <0.05).
Conclusions
VIV TAVR was observed to be associated with better short-term outcomes than redo SAVR. Major cardiovascular outcomes were not different between the 2 treatments during long-term follow-up.

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

J Am Coll Cardiol: 03 Aug 2020; 76:489-499
Deharo P, Bisson A, Herbert J, Lacour T, ... Cuisset T, Fauchier L
J Am Coll Cardiol: 03 Aug 2020; 76:489-499 | PMID: 32731926
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Impact:
Abstract

Effect of Sacubitril/Valsartan on Biomarkers of Extracellular Matrix Regulation in Patients With HFpEF.

Cunningham JW, Claggett BL, O\'Meara E, Prescott MF, ... Solomon SD, Zile MR
Background
Myocardial fibrosis may contribute to the pathophysiology of heart failure with preserved ejection fraction. Given the biochemical targets of sacubitril/valsartan, this study hypothesized that circulating biomarkers reflecting the mechanisms that determine extracellular matrix homeostasis are altered by sacubitril/valsartan compared with valsartan alone.
Objectives
This study investigated the effects of sacubitril/valsartan on biomarkers of extracellular matrix homeostasis and the association between biomarkers and the primary endpoint (total heart failure hospitalizations and cardiovascular death).
Methods
N-terminal propeptide of collagen I and III, tissue inhibitor of matrix metalloproteinase 1, carboxyl-terminal telopeptide of collagen type I, and soluble ST2 were measured at baseline (n = 1,135) and 16 (n = 1,113) and 48 weeks (n = 1,016) after randomization. The effects of sacubitril/valsartan on these biomarkers were compared with those of valsartan alone. Baseline biomarker values and changes from baseline to 16 weeks were related to primary endpoint.
Results
At baseline, all 5 biomarkers were higher than published referent control values. Sixteen weeks after randomization, sacubitril/valsartan decreased tissue inhibitor of matrix metalloproteinase 1 by 8% (95% confidence interval [CI]: 6% to 10%; p < 0.001), soluble ST2 by 4% (95% CI: 1% to 7%; p = 0.002), and N-terminal propeptide of collagen III by 3% (95% CI: 0% to 6%; p = 0.04) and increased carboxyl-terminal telopeptide of collagen type I by 4% (95% CI: 1% to 8%; p = 0.02) compared with valsartan alone, consistently in men and women and patients with left ventricular ejection fraction above or below the median of 57%. Higher levels of tissue inhibitor of matrix metalloproteinase 1 and soluble ST2 at baseline and increases in these markers at 16 weeks were associated with higher primary endpoint event rates.
Conclusions
Biomarkers reflecting extracellular matrix homeostasis are elevated in heart failure with preserved ejection fraction, favorably altered by sacubitril/valsartan, and have important prognostic value. (Prospective Comparison of ARNI With ARB Global Outcomes in HF With Preserved Ejection Fraction [PARAGON-HF]; NCT01920711).

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

J Am Coll Cardiol: 03 Aug 2020; 76:503-514
Cunningham JW, Claggett BL, O'Meara E, Prescott MF, ... Solomon SD, Zile MR
J Am Coll Cardiol: 03 Aug 2020; 76:503-514 | PMID: 32731928
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Abstract

Multimodality Imaging in Evaluation of Cardiovascular complications in Patients with COVID-19.

Rudski L, Januzzi JL, Rigolin VH, Bohula EA, ... Villines TC, Di Carli MF

Standard evaluation and management of the patient with suspected or proven cardiovascular complications of COVID-19, the disease caused by severe acute respiratory syndrome-related coronavirus-2 (SARS-CoV-2), is challenging. Routine history, physical examination, laboratory testing, electrocardiography and plain x-ray imaging may often suffice for such patients but given overlap between COVID-19 and typical cardiovascular diagnoses such as heart failure and acute myocardial infarction, need frequently arises for advanced imaging techniques to assist in differential diagnosis and management. This document provides guidance in several common scenarios among patients with confirmed or suspected COVID-19 infection and possible cardiovascular involvement, including chest discomfort with electrocardiographic changes, acute hemodynamic instability, newly-recognized left ventricular dysfunction, as well as imaging during the sub-acute/chronic phase of COVID-19. For each, we consider the role of biomarker testing to guide imaging decision-making, provide differential diagnostic considerations, and offer general suggestions regarding application of various advanced imaging techniques. CONDENSED ABSTRACT: Standard evaluation and management of the patient with suspected or proven cardiovascular complications due to COVID-19 infection often requires advanced imaging techniques to assist in differential diagnosis and management. This document provides guidance in several common scenarios among patients with COVID-19 infection and for each provides advice regarding the role of biomarker testing to guide imaging decision-making, provides differential diagnostic considerations, and offers general suggestions regarding application of various advanced imaging techniques.

Copyright © 2020. Published by Elsevier Inc.

J Am Coll Cardiol: 19 Jul 2020; epub ahead of print
Rudski L, Januzzi JL, Rigolin VH, Bohula EA, ... Villines TC, Di Carli MF
J Am Coll Cardiol: 19 Jul 2020; epub ahead of print | PMID: 32710927
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Abstract

Dapagliflozin and Diuretic Use in Patients with Heart Failure and Reduced Ejection Fraction in DAPA-HF.

Jackson AM, Dewan P, Anand IS, Bělohlávek J, ... Jhund PS, McMurray JJV

In the DAPA-HF trial, the SGLT2 inhibitor dapagliflozin reduced the risk of worsening heart failure and death in patients with heart failure and reduced ejection fraction. We examined efficacy and tolerability of dapagliflozin in relation to background diuretic treatment and change in diuretic therapy following randomization to dapagliflozin or placebo.We examined the effects of study treatment in the following subgroups: no diuretic, diuretic dose equivalent to furosemide <40mg daily, 40mg daily and >40mg daily at baseline. We examined the primary composite endpoint of cardiovascular (CV) death or a worsening HF event, its components, all-cause death and symptoms.Of 4616 analyzable patients, 736 (15.9%) were on no diuretic, 1311 (28.4%) were on <40mg, 1365 (29.6%) on 40 mg and 1204 (26.1%) of patients were taking >40 mg. Compared with placebo, dapagliflozin reduced the risk of the primary endpoint across each of these subgroups: hazard ratio [HR]: 0.57 (95% CI 0.36-0.92), 0.83 (0.63-1.10), 0.77 (0.60-0.99) and 0.78 (0.63-0.97), respectively (P-interaction 0.61). The HR in patients taking any diuretic was 0.78 (0.68-0.90). Improvement in symptoms and treatment toleration was consistent across the diuretic subgroups. Diuretic dose did not change in most patients during follow-up and mean diuretic dose did not differ between the dapagliflozin and placebo group after randomization.The efficacy and safety of dapagliflozin was consistent across the diuretic subgroups examined in DAPA-HF.DAPA-HF: ClinicalTrials.gov Identifier NCT03036124.



Circulation: 15 Jul 2020; epub ahead of print
Jackson AM, Dewan P, Anand IS, Bělohlávek J, ... Jhund PS, McMurray JJV
Circulation: 15 Jul 2020; epub ahead of print | PMID: 32673497
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Abstract

Factors associated with hospital admission and critical illness among 5279 people with coronavirus disease 2019 in New York City: prospective cohort study.

Petrilli CM, Jones SA, Yang J, Rajagopalan H, ... Francois F, Horwitz LI
Objective
To describe outcomes of people admitted to hospital with coronavirus disease 2019 (covid-19) in the United States, and the clinical and laboratory characteristics associated with severity of illness.
Design
Prospective cohort study.
Setting
Single academic medical center in New York City and Long Island.
Participants
5279 patients with laboratory confirmed severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) infection between 1 March 2020 and 8 April 2020. The final date of follow up was 5 May 2020.
Main outcome measures
Outcomes were admission to hospital, critical illness (intensive care, mechanical ventilation, discharge to hospice care, or death), and discharge to hospice care or death. Predictors included patient characteristics, medical history, vital signs, and laboratory results. Multivariable logistic regression was conducted to identify risk factors for adverse outcomes, and competing risk survival analysis for mortality.
Results
Of 11 544 people tested for SARS-Cov-2, 5566 (48.2%) were positive. After exclusions, 5279 were included. 2741 of these 5279 (51.9%) were admitted to hospital, of whom 1904 (69.5%) were discharged alive without hospice care and 665 (24.3%) were discharged to hospice care or died. Of 647 (23.6%) patients requiring mechanical ventilation, 391 (60.4%) died and 170 (26.2%) were extubated or discharged. The strongest risk for hospital admission was associated with age, with an odds ratio of >2 for all age groups older than 44 years and 37.9 (95% confidence interval 26.1 to 56.0) for ages 75 years and older. Other risks were heart failure (4.4, 2.6 to 8.0), male sex (2.8, 2.4 to 3.2), chronic kidney disease (2.6, 1.9 to 3.6), and any increase in body mass index (BMI) (eg, for BMI >40: 2.5, 1.8 to 3.4). The strongest risks for critical illness besides age were associated with heart failure (1.9, 1.4 to 2.5), BMI >40 (1.5, 1.0 to 2.2), and male sex (1.5, 1.3 to 1.8). Admission oxygen saturation of <88% (3.7, 2.8 to 4.8), troponin level >1 (4.8, 2.1 to 10.9), C reactive protein level >200 (5.1, 2.8 to 9.2), and D-dimer level >2500 (3.9, 2.6 to 6.0) were, however, more strongly associated with critical illness than age or comorbidities. Risk of critical illness decreased significantly over the study period. Similar associations were found for mortality alone.
Conclusions
Age and comorbidities were found to be strong predictors of hospital admission and to a lesser extent of critical illness and mortality in people with covid-19; however, impairment of oxygen on admission and markers of inflammation were most strongly associated with critical illness and mortality. Outcomes seem to be improving over time, potentially suggesting improvements in care.

© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

BMJ: 21 May 2020; 369:m1966
Petrilli CM, Jones SA, Yang J, Rajagopalan H, ... Francois F, Horwitz LI
BMJ: 21 May 2020; 369:m1966 | PMID: 32444366
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Abstract

Heart Regeneration by Endogenous Stem Cells and Cardiomyocyte Proliferation: Controversy, Fallacy, and Progress.

He L, Nguyen NB, Ardehali R, Zhou B

Ischemic heart disease is the leading cause of death worldwide. Myocardial infarction results in an irreversible loss of cardiomyocytes with subsequent adverse remodeling and heart failure. Identifying new sources for cardiomyocytes and promoting their formation represents a goal of cardiac biology and regenerative medicine. Within the past decade, many types of putative cardiac stem cells (CSCs) have been reported to regenerate the injured myocardium by differentiating into new cardiomyocytes. Some of these CSCs have been translated from bench to bed with reported therapeutic effectiveness. However, recent basic research studies on stem cell tracing have begun to question their fundamental biology and mechanisms of action, raising serious concerns over the myogenic potential of CSCs. We review the history of different types of CSCs within the past decade and provide an update of recent cell tracing studies that have challenged the origin and existence of CSCs. In addition to the potential role of CSCs in heart regeneration, proliferation of preexisting cardiomyocytes has recently gained more attention. This review will also evaluate the methodologic and technical aspects of past and current studies on CSCs and cardiomyocyte proliferation, with emphasis on technical strengths, advantages, and potential limitations of research approaches. While our understanding of cardiomyocyte generation and regeneration continues to evolve, it is important to address the shortcomings and inaccuracies in this field. This is best achieved by embracing technological advancements and improved methods to label single cardiomyocytes/progenitors and accurately investigate their developmental potential and fate/lineage commitment.



Circulation: 20 Jul 2020; 142:275-291
He L, Nguyen NB, Ardehali R, Zhou B
Circulation: 20 Jul 2020; 142:275-291 | PMID: 32687441
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Abstract

Intracoronary ALLogeneic heart STem cells to Achieve myocardial Regeneration (ALLSTAR): a randomized, placebo-controlled, double-blinded trial.

Makkar RR, Kereiakes DJ, Aguirre F, Kowalchuk G, ... Marbán E, Henry TD
Aims
Cardiosphere-derived cells (CDCs) are cardiac progenitor cells that exhibit disease-modifying bioactivity in various models of cardiomyopathy and in previous clinical studies of acute myocardial infarction (MI), dilated cardiomyopathy, and Duchenne muscular dystrophy. The aim of the study was to assess the safety and efficacy of intracoronary administration of allogeneic CDCs in the multicentre, randomized, double-blinded, placebo-controlled, intracoronary ALLogeneic heart STem cells to Achieve myocardial Regeneration (ALLSTAR) trial.
Methods and results
We enrolled patients 4 weeks to 12 months after MI, with left ventricular ejection fraction (LVEF) ≤45% and LV scar size ≥15% of LV mass by magnetic resonance imaging (MRI). A pre-specified interim analysis was performed when 6-month MRI data were available. The trial was subsequently stopped due to the low probability of detecting a significant treatment effect of CDCs based on the primary endpoint. Patients were randomly allocated in a 2:1 ratio to receive CDCs or placebo in the infarct-related artery by stop-flow technique. The primary safety endpoint was the occurrence, during 1-month post-intracoronary infusion, of acute myocarditis attributable to allogeneic CDCs, ventricular tachycardia- or ventricular fibrillation-related death, sudden unexpected death, or a major adverse cardiac event (death or hospitalization for heart failure or non-fatal MI or need for left ventricular assist device or heart transplant). The primary efficacy endpoint was the relative percentage change in infarct size at 12 months post-infusion as assessed by contrast-enhanced cardiac MRI. We randomly allocated 142 eligible patients of whom 134 were treated (90 to the CDC group and 44 to the placebo group). The mean baseline LVEF was 40% and the mean scar size was 22% of LV mass. No primary safety endpoint events occurred. There was no difference in the percentage change from baseline in scar size (P = 0.51) between CDCs and placebo groups at 6 months. Compared with placebo, there were significant reductions in LV end-diastolic volume (P = 0.02), LV end-systolic volume (P = 0.02), and N-terminal pro b-type natriuretic peptide (NT-proBNP) (P = 0.02) at 6 months in CDC-treated patients.
Conclusion
Intracoronary infusion of allogeneic CDCs in patients with post-MI LV dysfunction was safe but did not reduce scar size relative to placebo at 6 months. Nevertheless, the reductions in LV volumes and NT-proBNP reveal disease-modifying bioactivity of CDCs.
Trial registration
Clinicaltrials.gov identifier: NCT01458405.

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 Aug 2020; epub ahead of print
Makkar RR, Kereiakes DJ, Aguirre F, Kowalchuk G, ... Marbán E, Henry TD
Eur Heart J: 03 Aug 2020; epub ahead of print | PMID: 32749459
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Abstract

Thiazide Use and Decreased Risk of Heart Failure in Nondiabetic Patients Receiving Intensive Blood Pressure Treatment.

Tsujimoto T, Kajio H

The SPRINT (Systolic Blood Pressure Intervention Trial) study reported that intensive blood pressure (BP) treatment with a systolic BP target of <120 mm Hg decreased the risks of cardiovascular events. However, it remains unknown whether specific medications can further improve cardiovascular outcome in patients receiving intensive BP treatment. This study examined whether thiazide use improves cardiovascular outcome in patients receiving intensive BP treatment. We used data of nondiabetic patients receiving intensive BP treatment in the SPRINT study. The primary outcome was a composite end point of myocardial infarction, acute coronary syndrome, stroke, heart failure, or cardiovascular death. We analyzed hazard ratios for outcomes with 95% CIs in patients taking thiazides compared with those not taking thiazides using Cox proportional hazard models. This study included 2847 patients and the mean follow-up period was 3.3 years. The risk of primary outcome events was significantly lower in patients taking thiazides than in those not taking thiazides in both entire and propensity score-matched cohorts. Particularly, heart failure risk was significantly lower in those taking thiazides. These associations were also observed in various subgroups. In addition, thiazide use was associated with decreased risk of all-cause mortality. Hypokalemia occurred more frequently in patients taking thiazides than in those not taking thiazides. Thiazide use decreased risk of cardiovascular events, particularly heart failure, in nondiabetic high-risk patients receiving intensive BP treatment.



Hypertension: 30 Jul 2020; 76:432-441
Tsujimoto T, Kajio H
Hypertension: 30 Jul 2020; 76:432-441 | PMID: 32639892
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Abstract

Macrophage (Drp1) Dynamin-Related Protein 1 Accelerates Intimal Thickening After Vascular Injury.

Umezu R, Koga JI, Matoba T, Katsuki S, ... Tsutsui H, Egashira K
Objective
Mitochondria consistently change their morphology in a process regulated by proteins, including Drp1 (dynamin-related protein 1), a protein promoting mitochondrial fission. Drp1 is involved in the mechanisms underlying various cardiovascular diseases, such as myocardial ischemia/reperfusion injury, heart failure, and pulmonary arterial hypertension. However, its role in macrophages, which promote various vascular diseases, is poorly understood. We therefore tested our hypothesis that macrophage Drp1 promotes vascular remodeling after injury.
Method and results
To explore the selective role of macrophage Drp1, we created macrophage-selective Drp1-deficient mice and performed femoral arterial wire injury. In these mice, intimal thickening and negative remodeling were attenuated at 4 weeks after injury when compared with control mice. Deletion of macrophage Drp1 also attenuated the macrophage accumulation and cell proliferation in the injured arteries. Gain- and loss-of-function experiments using cultured macrophages indicated that Drp1 induces the expression of molecules associated with inflammatory macrophages. Morphologically, mitochondrial fission was induced in inflammatory macrophages, whereas mitochondrial fusion was induced in less inflammatory/reparative macrophages. Pharmacological inhibition or knockdown of Drp1 decreased the mitochondrial reactive oxygen species and chemotactic activity in cultured macrophages. Co-culture experiments of macrophages with vascular smooth muscle cells indicated that deletion of macrophage Drp1 suppresses growth and migration of vascular smooth muscle cells induced by macrophage-derived soluble factors.
Conclusions
Macrophage Drp1 accelerates intimal thickening after vascular injury by promoting macrophage-mediated inflammation. Macrophage Drp1 may be a potential therapeutic target of vascular diseases.



Arterioscler Thromb Vasc Biol: 03 Jun 2020:ATVBAHA120314383; epub ahead of print
Umezu R, Koga JI, Matoba T, Katsuki S, ... Tsutsui H, Egashira K
Arterioscler Thromb Vasc Biol: 03 Jun 2020:ATVBAHA120314383; epub ahead of print | PMID: 32493171
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Abstract

Role of Cardiac Lymphatics in Myocardial Edema and Fibrosis: JACC Review Topic of the Week.

Brakenhielm E, González A, Díez J

The cardiac lymphatic network plays a key role in regulation of myocardial extracellular volume and immune cell homeostasis. In different pathological conditions cardiac lymphatics undergo significant remodeling, with insufficient lymphatic function and/or lymphangiogenesis leading to fluid accumulation and development of edema. Additionally, by modulating the reuptake of tissue-infiltrating immune cells, lymphatics regulate immune responses. Available evidence suggests that both edema and inadequate immune response resolution may contribute to extracellular matrix remodeling and interstitial myocardial fibrosis. Interestingly, stimulation of lymphangiogenesis has been shown to improve cardiac function and reduce the progression of myocardial fibrosis during heart failure development after myocardial infarction. This review goes through the available clinical and experimental data supporting a role for cardiac lymphatics in cardiac disease, focusing on the current evidence linking poor cardiac lymphatic transport to the fibrogenic process and discussing potential avenues for novel biomarkers and therapeutic targets to limit cardiac fibrosis and dysfunction.

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

J Am Coll Cardiol: 10 Aug 2020; 76:735-744
Brakenhielm E, González A, Díez J
J Am Coll Cardiol: 10 Aug 2020; 76:735-744 | PMID: 32762908
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Abstract

Heart Failure With Recovered Left Ventricular Ejection Fraction: JACC Scientific Expert Panel.

Wilcox JE, Fang JC, Margulies KB, Mann DL

Reverse left ventricular (LV) remodeling and recovery of LV function are associated with improved clinical outcomes in patients with heart failure with reduced ejection fraction. A growing body of evidence suggests that even among patients who experience a complete normalization of LV ejection fraction, a significant proportion will develop recurrent LV dysfunction accompanied by recurrent heart failure events. This has led to intense interest in understanding how to manage patients with heart failure with recovered ejection fraction (HFrecEF). Because of the lack of a standard definition for HFrecEF, and the paucity of clinical data with respect to the natural history of HFrecEF patients, there are no current guidelines on how these patients should be followed up and managed. Accordingly, this JACC Scientific Expert Panel reviews the biology of reverse LV remodeling and the clinical course of patients with HFrecEF, as well as provides guidelines for defining, diagnosing, and managing patients with HFrecEF.

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

J Am Coll Cardiol: 10 Aug 2020; 76:719-734
Wilcox JE, Fang JC, Margulies KB, Mann DL
J Am Coll Cardiol: 10 Aug 2020; 76:719-734 | PMID: 32762907
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Abstract

Transvalvular Ventricular Unloading Before Reperfusion in Acute Myocardial Infarction.

Swain L, Reyelt L, Bhave S, Qiao X, ... O\'Neill W, Kapur NK
Background
Myocardial damage due to acute ST-segment elevation myocardial infarction (STEMI) remains a significant global health problem. New approaches to limit myocardial infarct size and reduce progression to heart failure after STEMI are needed. Mechanically reducing left ventricular (LV) workload (LV unloading) before coronary reperfusion is emerging as a potential approach to reduce infarct size.
Objectives
Given the central importance of mitochondria in reperfusion injury, we hypothesized that compared with immediate reperfusion (IR), LV unloading before reperfusion improves myocardial energy substrate use and preserves mitochondrial structure and function.
Methods
To explore the effect of LV unloading duration on infarct size, we analyzed data from the STEMI-Door to Unload (STEMI-DTU) trial and then tested the effect of LV unloading on ischemia and reperfusion injury, cardiac metabolism, and mitochondrial function in swine models of acute myocardial infarction.
Results
The duration of LV unloading before reperfusion was inversely associated with infarct size in patients with large anterior STEMI. In preclinical models, LV unloading reduced the expression of hypoxia-sensitive proteins and myocardial damage due to ischemia alone. LV unloading with a transvalvular pump (TV-P) but not with venoarterial extracorporeal membrane oxygenation (ECMO) reduced infarct size. Using unbiased and blinded metabolic profiling, TV-P improved myocardial energy substrate use and preserved mitochondrial structure including cardiolipin content after reperfusion compared with IR or ECMO. Functional testing in mitochondria isolated from the infarct zone showed an intact mitochondrial structure including cardiolipin content, preserved activity of the electron transport chain including mitochondrial complex I, and reduced oxidative stress with TV-P-supported reperfusion but not with IR or ECMO.
Conclusions
These novel findings identify that transvalvular unloading limits ischemic injury before reperfusion, improves myocardial energy substrate use, and preserves mitochondrial structure and function after reperfusion.

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

J Am Coll Cardiol: 10 Aug 2020; 76:684-699
Swain L, Reyelt L, Bhave S, Qiao X, ... O'Neill W, Kapur NK
J Am Coll Cardiol: 10 Aug 2020; 76:684-699 | PMID: 32762903
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Abstract

Mid- to Late-Life Time-Averaged Cumulative Blood Pressure and Late-Life Cardiac Structure, Function, and Heart Failure.

Teramoto K, Nadruz Junior W, Matsushita K, Claggett B, ... Cheng S, Shah AM

Limited data exist regarding systolic blood pressure (SBP) through mid- to late-life and late-life cardiac function and heart failure (HF) risk. Among 4578 HF-free participants in the ARIC study (Atherosclerosis Risk in Communities) attending the fifth visit (2011-2013; age 75±5 years), time-averaged cumulative SBP was calculated as the sum of averaged SBPs from adjacent consecutive visits (visits 1-5) indexed to total observation time (24±1 years). Calculations were performed using measured SBPs and also incorporating antihypertensive medication specific effect constants (underlying SBP). Outcomes included comprehensive echocardiography at visit 5 and post-visit 5 incident HF, HF with preserved ejection fraction, and reduced ejection fraction. Higher cumulative SBP was associated with greater left ventricular mass and worse diastolic measures (all <0.001), associations that were stronger with underlying compared with cumulative SBP (all <0.05). At 5.6±1.2 years follow-up post-visit 5, higher cumulative measured and underlying SBP were associated with incident HF (hazard ratio per 10 mm Hg for measured: 1.12 [1.01-1.24]; underlying: 1.19 [95% CI, 1.10-1.30]) and HF with preserved ejection fraction (measured: 1.15 [1.00-1.33]; underlying: 1.28 [1.14-1.45]), but not HF with reduced ejection fraction (measured: 1.11 [0.94-1.32]; underlying: 1.11 [0.96-1.24]). Associations with HF and HF with preserved ejection fraction were more robust with cumulative underlying compared with measured SBP (all <0.05). Time-averaged cumulative SBP in mid to late life is associated with worse cardiac function and risk of incident HF, especially HF with preserved ejection fraction, in late life. These associations were stronger considering underlying as opposed to measured SBP, highlighting the importance of prevention and effective treatment of hypertension to prevent late-life cardiac dysfunction and HF.



Hypertension: 14 Jun 2020:HYPERTENSIONAHA12014833; epub ahead of print
Teramoto K, Nadruz Junior W, Matsushita K, Claggett B, ... Cheng S, Shah AM
Hypertension: 14 Jun 2020:HYPERTENSIONAHA12014833; epub ahead of print | PMID: 32536273
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Abstract

Spending and quality after three years of Medicare\'s bundled payments for medical conditions: quasi-experimental difference-in-differences study.

Rolnick JA, Liao JM, Emanuel EJ, Huang Q, ... Cousins D, Navathe AS
Objective
To evaluate whether longer term participation in the bundled payments for care initiative (BPCI) for medical conditions in the United States, which held hospitals financially accountable for all spending during an episode of care from hospital admission to 90 days after discharge, was associated with changes in spending, mortality, or health service use.
Design
Quasi-experimental difference-in-differences analysis.
Setting
US hospitals participating in bundled payments for acute myocardial infarction, congestive heart failure, chronic obstructive pulmonary disease (COPD), or pneumonia, and propensity score matched to non-participating hospitals.
Participants
238 hospitals participating in the Bundled Payments for Care Improvement initiative (BPCI) and 1415 non-BPCI hospitals. 226 BPCI hospitals were matched to 700 non-BPCI hospitals.
Main outcome measures
Primary outcomes were total spending on episodes and death 90 days after discharge. Secondary outcomes included spending and use by type of post-acute care. BPCI and non-BPCI hospitals were compared by patient, hospital, and hospital market characteristics. Market characteristics included population size, competitiveness, and post-acute bed supply.
Results
In the 226 BPCI hospitals, episodes of care totaled 261 163 in the baseline period and 93 562 in the treatment period compared with 211 208 and 78 643 in the 700 matched non-BPCI hospitals, respectively, with small differences in hospital and market characteristics after matching. Differing trends were seen for some patient characteristics (eg, mean age change -0.3 years at BPCI hospitalsnon- BPCI hospitals, P<0.001). In the adjusted analysis, participation in BPCI was associated with a decrease in total episode spending (-1.2%, 95% confidence interval -2.3% to -0.2%). Spending on care at skilled nursing facilities decreased (-6.3%, -10.0% to -2.5%) owing to a reduced number of facility days (-6.2%, -9.8% to -2.6%), and home health spending increased (4.4%, 1.4% to 7.5%). Mortality at 90 days did not change (-0.1 percentage points, 95% confidence interval -0.5 to 0.2 percentage points).
Conclusions
In this longer term evaluation of a large national programme on medical bundled payments in the US, participation in bundles for four common medical conditions was associated with savings at three years. The savings were generated by practice changes that decreased use of high intensity care after hospital discharge without affecting quality, which also suggests that bundles for medical conditions could require multiple years before changes in savings and practice emerge.

© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

BMJ: 16 Jun 2020; 369:m1780
Rolnick JA, Liao JM, Emanuel EJ, Huang Q, ... Cousins D, Navathe AS
BMJ: 16 Jun 2020; 369:m1780 | PMID: 32554705
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Abstract

Age and Multimorbidity Predict Death Among COVID-19 Patients: Results of the SARS-RAS Study of the Italian Society of Hypertension.

Iaccarino G, Grassi G, Borghi C, Ferri C, ... Volpe M,

Several factors have been proposed to explain the high death rate of the coronavirus disease 2019 (COVID-19) outbreak, including hypertension and hypertension-related treatment with Renin Angiotensin System inhibitors. Also, age and multimorbidity might be confounders. No sufficient data are available to demonstrate their independent role. We designed a cross-sectional, observational, multicenter, nationwide survey in Italy to verify whether renin-angiotensin system inhibitors are related to COVID-19 severe outcomes. We analyzed information from Italian patients diagnosed with COVID-19, admitted in 26 hospitals. One thousand five hundred ninety-one charts (male, 64.1%; 66±0.4 years) were recorded. At least 1 preexisting condition was observed in 73.4% of patients, with hypertension being the most represented (54.9%). One hundred eighty-eight deaths were recorded (11.8%; mean age, 79.6±0.9 years). In nonsurvivors, older age, hypertension, diabetes mellitus, chronic obstructive pulmonary disease, chronic kidney disease, coronary artery diseases, and heart failure were more represented than in survivors. The Charlson Comorbidity Index was significantly higher in nonsurvivors compared with survivors (4.3±0.15 versus 2.6±0.05; <0.001). ACE (angiotensin-converting enzyme) inhibitors, diuretics, and β-blockers were more frequently used in nonsurvivors than in survivors. After correction by multivariate analysis, only age (=0.0001), diabetes mellitus (=0.004), chronic obstructive pulmonary disease (=0.011), and chronic kidney disease (=0.004) but not hypertension predicted mortality. Charlson Comorbidity Index, which cumulates age and comorbidities, predicts mortality with an exponential increase in the odds ratio by each point of score. In the COVID-19 outbreak, mortality is predicted by age and the presence of comorbidities. Our data do not support a significant interference of hypertension and antihypertensive therapy on COVID-19 lethality. Registration- URL: https://www.clinicaltrials.gov; Unique identifier: NCT04331574.



Hypertension: 21 Jun 2020:HYPERTENSIONAHA12015324; epub ahead of print
Iaccarino G, Grassi G, Borghi C, Ferri C, ... Volpe M,
Hypertension: 21 Jun 2020:HYPERTENSIONAHA12015324; epub ahead of print | PMID: 32564693
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Abstract

Machine Learning Clustering for Blood Pressure Variability Applied to Systolic Blood Pressure Intervention Trial (SPRINT) and the Hong Kong Community Cohort.

Tsoi KKF, Chan NB, Yiu KKL, Poon SKS, Lin B, Ho K

Visit-to-visit blood pressure variability (BPV) has been shown to be a predictor of cardiovascular disease. We aimed to classify the BPV levels using different machine learning algorithms. Visit-to-visit blood pressure readings were extracted from the SPRINT study in the United States and eHealth cohort in Hong Kong (HK cohort). Patients were clustered into low, medium, and high BPV levels with the traditional quantile clustering and 5 machine learning algorithms including K-means. Clustering methods were assessed by Stability Index. Similarities were assessed by Davies-Bouldin Index and Silhouette Index. Cox proportional hazard regression models were fitted to compare the risk of myocardial infarction, stroke, and heart failure. A total of 8133 participants had average blood pressure measurement 14.7 times in 3.28 years in SPRINT and 1094 participants who had average blood pressure measurement 165.4 times in 1.37 years in HK cohort. Quantile clustering assigned one-third participants as high BPV level, but machine learning methods only assigned 10% to 27%. Quantile clustering is the most stable method (stability index: 0.982 in the SPRINT and 0.948 in the HK cohort) with some levels of clustering similarities (Davies-Bouldin Index: 0.752 and 0.764, respectively). K-means clustering is the most stable across the machine learning algorithms (stability index: 0.975 and 0.911, respectively) with the lowest clustering similarities (Davies-Bouldin Index: 0.653 and 0.680, respectively). One out of 7 in the population was classified with high BPV level, who showed to have higher risk of stroke and heart failure. Machine learning methods can improve BPV classification for better prediction of cardiovascular diseases.



Hypertension: 28 Jun 2020:HYPERTENSIONAHA11914213; epub ahead of print
Tsoi KKF, Chan NB, Yiu KKL, Poon SKS, Lin B, Ho K
Hypertension: 28 Jun 2020:HYPERTENSIONAHA11914213; epub ahead of print | PMID: 32594794
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Abstract

Comparative Effectiveness of Glucose-Lowering Drugs for Type 2 Diabetes: A Systematic Review and Network Meta-analysis.

Tsapas A, Avgerinos I, Karagiannis T, Malandris K, ... Matthews DR, Bekiari E
Background
Several pharmacologic options for type 2 diabetes are available.
Purpose
To compare benefits and harms of glucose-lowering drugs in adults with type 2 diabetes.
Data sources
Several databases from inception through 18 December 2019 and ClinicalTrials.gov on 10 April 2020.
Study selection
English-language randomized trials that had at least 24 weeks of intervention and assessed the effects of glucose-lowering drugs on mortality, glycemic, and vascular outcomes.
Data extraction
Pairs of reviewers extracted data and appraised risk of bias.
Data synthesis
453 trials assessing 21 antidiabetic interventions from 9 drug classes were included. Interventions included monotherapies (134 trials), add-on to metformin-based therapies (296 trials), and monotherapies versus add-on to metformin therapies (23 trials). There were no differences between treatments in drug-naive patients at low cardiovascular risk. Insulin regimens and specific glucagon-like peptide-1 receptor agonists (GLP-1 RAs) added to metformin-based background therapy produced the greatest reductions in hemoglobin A level. In patients at low cardiovascular risk receiving metformin-based background treatment (298 trials), there were no clinically meaningful differences between treatments for mortality and vascular outcomes. In patients at increased cardiovascular risk receiving metformin-based background treatment (21 trials), oral semaglutide, empagliflozin, liraglutide, extended-release exenatide, and dapagliflozin reduced all-cause mortality. Oral semaglutide, empagliflozin, and liraglutide also reduced cardiovascular death. Odds of stroke were lower with subcutaneous semaglutide and dulaglutide. Sodium-glucose cotransporter-2 (SGLT-2) inhibitors reduced heart failure hospitalization and end-stage renal disease. Subcutaneous semaglutide and canagliflozin increased diabetic retinopathy and amputation, respectively.
Limitation
Inconsistent definitions of cardiovascular risk and low-level confidence in some estimates for patients at low cardiovascular risk.
Conclusion
In diabetic patients at low cardiovascular risk, no treatment differs from placebo for vascular outcomes. In patients at increased cardiovascular risk receiving metformin-based background therapy, specific GLP-1 RAs and SGLT-2 inhibitors have a favorable effect on certain cardiovascular outcomes.
Primary funding source
European Foundation for the Study of Diabetes, supported by an unrestricted educational grant from AstraZeneca. (PROSPERO: CRD42019122043).



Ann Intern Med: 29 Jun 2020; epub ahead of print
Tsapas A, Avgerinos I, Karagiannis T, Malandris K, ... Matthews DR, Bekiari E
Ann Intern Med: 29 Jun 2020; epub ahead of print | PMID: 32598218
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Abstract

Prior Beta-Blocker Therapy for Hypertension and Sex-Based Differences in Heart Failure Among Patients With Incident Coronary Heart Disease.

Bugiardini R, Yoon J, Kedev S, Stankovic G, ... Badimon L, Cenko E

The usefulness of β-blockers has been questioned for patients who have hypertension without a prior manifestation of coronary heart disease or heart failure. In addition, sex-based differences in the efficacy of β-blockers for prevention of heart failure during acute myocardial ischemia have never been evaluated. We explored whether the effect of β-blocker therapy varied according to the sex among patients with hypertension who have no prior history of cardiovascular disease. Data were drawn from the ISACS (International Survey of Acute Coronary Syndromes)-Archives. The study population consisted of 13 764 patients presenting with acute coronary syndromes. There were 2590 patients in whom hypertension was treated previously with β-blocker (954 women and 1636 men). Primary outcome measure was the incidence of heart failure according to Killip class classification. Subsidiary analyses were conducted to estimate the association between heart failure and all-cause mortality at 30 days. Outcome rates were assessed using the inverse probability of treatment weighting and logistic regression models. Estimates were compared by test of interaction on the log scale. Among patients taking β-blockers before admission, there was an absolute difference of 4.6% between women and men in the rate of heart failure (Killip ≥2) at hospital presentation (21.3% versus 16.7%; relative risk ratio, 1.35 [95% CI, 1.10-1.65]). On the opposite, the rate of heart failure was approximately similar among women and men who did not receive β-blockers (17.2% versus 16.1%; relative risk ratio, 1.09 [95% CI, 0.97-1.21]). The test of interaction identified a significant (=0.034) association between sex and β-blocker therapy. Heart failure was predictive of mortality at 30-day either in women (odds ratio, 7.54 [95% CI, 5.78-9.83]) or men (odds ratio, 9.62 [95% CI, 7.67-12.07]). In conclusion, β-blockers use may be an acute precipitant of heart failure in new-onset coronary heart disease among women, but not men. Heart failure increases the risk of death. Registration- URL: https://www.clinicaltrials.gov. Unique identifier: NCT04008173.



Hypertension: 12 Jul 2020:HYPERTENSIONAHA12015323; epub ahead of print
Bugiardini R, Yoon J, Kedev S, Stankovic G, ... Badimon L, Cenko E
Hypertension: 12 Jul 2020:HYPERTENSIONAHA12015323; epub ahead of print | PMID: 32654558
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Abstract

Estimated 24-Hour Urinary Sodium Excretion and Incident Cardiovascular Disease and Mortality Among 398 628 Individuals in UK Biobank.

Elliott P, Muller DC, Schneider-Luftman D, Pazoki R, ... Neal B, Tzoulaki I

We report on an analysis to explore the association between estimated 24-hour urinary sodium excretion (surrogate for sodium intake) and incident cardiovascular disease (CVD) and mortality. Data were obtained from 398 628 UK Biobank prospective cohort study participants (40-69 years) recruited between 2006 and 2010, with no history of CVD, renal disease, diabetes mellitus or cancer, and cardiovascular events and mortality recorded during follow-up. Hazard ratios between 24-hour sodium excretion were estimated from spot urinary sodium concentrations across incident CVD and its components and all-cause and cause-specific mortality. In restricted cubic splines analyses, there was little evidence for an association between estimated 24-hour sodium excretion and CVD, coronary heart disease, or stroke; hazard ratios for CVD (95% CIs) for the 15th and 85th percentiles (2.5 and 4.2 g/day, respectively) compared with the 50th percentile of estimated sodium excretion (3.2 g/day) were 1.05 (1.01-1.10) and 0.96 (0.92-1.00), respectively. An inverse association was observed with heart failure, but that was no longer apparent in sensitivity analysis. A J-shaped association was observed between estimated sodium excretion and mortality. Our findings do not support a J-shaped association of estimated sodium excretion with CVD, although such an association was apparent for all-cause and cause-specific mortality across a wide range of diseases. Reasons for these differences are unclear; methodological limitations, including the use of estimating equations based on spot urinary data, need to be considered in interpreting our findings.



Hypertension: 05 Jul 2020:HYPERTENSIONAHA11914302; epub ahead of print
Elliott P, Muller DC, Schneider-Luftman D, Pazoki R, ... Neal B, Tzoulaki I
Hypertension: 05 Jul 2020:HYPERTENSIONAHA11914302; epub ahead of print | PMID: 32623924
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Abstract

Nonalcoholic Fatty Liver Disease and Advanced Fibrosis in US Adults Across Blood Pressure Categories.

Ciardullo S, Monti T, Sala I, Grassi G, Mancia G, Perseghin G

Nonalcoholic fatty liver disease (NAFLD) is common in patients with hypertension but controversy exists as to whether screening for this condition should be performed. Here, we evaluate the prevalence of NAFLD and advanced fibrosis in US adults across blood pressure categories and estimate the number of patients who require referral to hepatologists. In this cross-sectional analysis of 11 489 adults from the 2005 to 2016 National Health and Nutrition Examination Survey, participants were segregated as having optimal, normal, high normal, and elevated blood pressure according to the 2018 European Society of Cardiology/Hypertension guidelines. NAFLD was defined using the US fatty liver index, whereas fibrosis was assessed using the NAFLD fibrosis score, fibrosis-4, and Hepamet Fibrosis Score. NAFLD prevalence increased progressively from optimal (16.5%) to normal (34.5%), high normal (39.9%), and elevated blood pressure (50.2%, <0.001). Patients with hypertension also showed a higher prevalence of advanced fibrosis (3%-9%, based on the specific biomarker used). When the screening flowchart from the European Association for the Study of the Liver, Diabetes, and Obesity guidelines was applied to patients with hypertension, 26.7% needed referral to hepatologists. Risk of referral was higher in Hispanic patients and those with diabetes mellitus, heart failure, and an altered urinary albumin excretion. NAFLD is highly prevalent in US adults with hypertension and a quarter of them would need to be referred to hepatologists because of a high risk of advanced fibrosis. While future studies on cost-effectiveness are needed, screening for NAFLD in these patients could be beneficial.



Hypertension: 28 Jun 2020:HYPERTENSIONAHA12015220; epub ahead of print
Ciardullo S, Monti T, Sala I, Grassi G, Mancia G, Perseghin G
Hypertension: 28 Jun 2020:HYPERTENSIONAHA12015220; epub ahead of print | PMID: 32594797
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Abstract

Ca-Dependent NOX5 (NADPH Oxidase 5) Exaggerates Cardiac Hypertrophy Through Reactive Oxygen Species Production.

Zhao GJ, Zhao CL, Ouyang S, Deng KQ, ... Touyz RM, Li H

NOX5 (NADPH oxidase 5) is a homolog of the gp91 subunit of the phagocyte NOX, which generates reactive oxygen species. NOX5 is involved in sperm motility and vascular contraction and has been implicated in diabetic nephropathy, atherosclerosis, and stroke. The function of NOX5 in the cardiac hypertrophy is unknown. Because NOX5 is a Ca-sensitive, procontractile NOX isoform, we questioned whether it plays a role in cardiac hypertrophy. Studies were performed in (1) cardiac tissue from patients undergoing heart transplant for cardiomyopathy and heart failure, (2) NOX5-expressing rat cardiomyocytes, and (3) mice expressing human NOX5 in a cardiomyocyte-specific manner. Cardiac hypertrophy was induced in mice by transverse aorta coarctation and Ang II (angiotensin II) infusion. NOX5 expression was increased in human failing hearts. Rat cardiomyocytes infected with adenoviral vector encoding human NOX5 cDNA exhibited elevated reactive oxygen species levels with significant enlargement and associated increased expression of ANP (atrial natriuretic peptides) and β-MHC (β-myosin heavy chain) and prohypertrophic genes (, , and ) under Ang II stimulation. These effects were reduced by N-acetylcysteine and diltiazem. Pressure overload and Ang II infusion induced left ventricular hypertrophy, interstitial fibrosis, and contractile dysfunction, responses that were exaggerated in cardiac-specifictrangenic mice. These phenomena were associated with increased reactive oxygen species levels and activation of redox-sensitive MAPK (mitogen-activated protein kinase). N-acetylcysteine treatment reduced cardiac oxidative stress and attenuated cardiac hypertrophy intrangenic. Our study defines Ca-regulated NOX5 as an important NOX isoform involved in oxidative stress- and MAPK-mediated cardiac hypertrophy and contractile dysfunction.



Hypertension: 19 Jul 2020:HYPERTENSIONAHA12015558; epub ahead of print
Zhao GJ, Zhao CL, Ouyang S, Deng KQ, ... Touyz RM, Li H
Hypertension: 19 Jul 2020:HYPERTENSIONAHA12015558; epub ahead of print | PMID: 32683902
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Abstract

Association Between Oral Corticosteroid Bursts and Severe Adverse Events: A Nationwide Population-Based Cohort Study.

Yao TC, Huang YW, Chang SM, Tsai SY, Wu AC, Tsai HJ
Background
Long-term use of oral corticosteroids has known adverse effects, but the risk from brief oral steroid bursts (≤14 days) is largely unknown.
Objective
To examine the associations between steroid bursts and severe adverse events, specifically gastrointestinal (GI) bleeding, sepsis, and heart failure.
Design
Self-controlled case series.
Setting
Entire National Health Insurance Research Database of medical claims records in Taiwan.
Participants
Adults aged 20 to 64 years with continuous enrollment in the National Health Insurance program from 1 January 2013 to 31 December 2015.
Measurements
Incidence rates of severe adverse events in steroid burst users and non-steroid users, as well as incidence rate ratios (IRRs) for severe adverse events within 5 to 30 and 31 to 90 days after initiation of steroid therapy.
Results
Of 15 859 129 adult participants, 2 623 327 who received a single steroid burst were included. The most common indications were skin disorders and respiratory tract infections. The incidence rates per 1000 person-years in steroid bursts were 27.1 (95% CI, 26.7 to 27.5) for GI bleeding, 1.5 (CI, 1.4 to 1.6) for sepsis, and 1.3 (CI, 1.2 to 1.4) for heart failure. Rates of GI bleeding (IRR, 1.80 [CI, 1.75 to 1.84]), sepsis (IRR, 1.99 [CI, 1.70 to 2.32]), and heart failure (IRR, 2.37 [CI, 2.13 to 2.63]) significantly increased within 5 to 30 days after steroid therapy initiation and attenuated during the subsequent 31 to 90 days.
Limitation
Persons younger than 20 years or older than 64 years were not included.
Conclusion
Oral corticosteroid bursts are frequently prescribed in the general adult population in Taiwan. The highest rates of GI bleeding, sepsis, and heart failure occurred within the first month after initiation of steroid therapy.
Primary funding source
National Health Research Institutes, Ministry of Science and Technology of Taiwan, Chang Gung Medical Foundation, and Eunice Kennedy Shriver National Institute of Child Health and Human Development.



Ann Intern Med: 06 Jul 2020; epub ahead of print
Yao TC, Huang YW, Chang SM, Tsai SY, Wu AC, Tsai HJ
Ann Intern Med: 06 Jul 2020; epub ahead of print | PMID: 32628532
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Abstract

Adult congenital heart disease and the COVID-19 pandemic.

Radke RM, Frenzel T, Baumgartner H, Diller GP

Adults with congenital heart disease (ACHD) may be at high risk in the case of COVID-19. Due to the heterogeneity of ACHD and secondary complications, risk profiles are, however, not uniform. This document aims to give an overview of relevant data and outline our pragmatic approach to disease prevention and management. Based on anatomy and additional physiological factors including symptoms, exercise capacity, heart failure, pulmonary hypertension and cyanosis, we propose a pragmatic approach to categorising patients into low-risk, intermediate-risk and high-risk groups. We regard especially patients with complex cyanotic conditions, those with palliated univentricular hearts, heart failure, severe valvular disease or pulmonary hypertension as high-risk patients. To avoid infection, we recommend self-isolation and exemption from work for these cohorts. Infected ACHD patients with low or moderate risk and without signs of deterioration may be remotely followed and cared for at home while in self isolation. High-risk patients or those with signs of respiratory or cardiovascular impairment require admission ideally at a tertiary ACHD centre. Especially patients with complex, cyanotic disease, heart failure and arrhythmias require particular attention. Treatment in patients with cyanotic heart disease should be guided by the relative degree of desaturation compared with baseline and lactate levels rather than absolute oxygen saturation levels. Patients with right heart dilatation or dysfunction are potentially at increased risk of right heart failure as mechanical ventilation and acute respiratory distress syndrome can lead to increase in pulmonary arterial pressures.

© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Heart: 09 Jun 2020; epub ahead of print
Radke RM, Frenzel T, Baumgartner H, Diller GP
Heart: 09 Jun 2020; epub ahead of print | PMID: 32522822
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Abstract

Basic Mechanisms of Diabetic Heart Disease.

Ritchie RH, Abel ED

Diabetes mellitus predisposes affected individuals to a significant spectrum of cardiovascular complications, one of the most debilitating in terms of prognosis is heart failure. Indeed, the increasing global prevalence of diabetes mellitus and an aging population has given rise to an epidemic of diabetes mellitus-induced heart failure. Despite the significant research attention this phenomenon, termed diabetic cardiomyopathy, has received over several decades, understanding of the full spectrum of potential contributing mechanisms, and their relative contribution to this heart failure phenotype in the specific context of diabetes mellitus, has not yet been fully resolved. Key recent preclinical discoveries that comprise the current state-of-the-art understanding of the basic mechanisms of the complex phenotype, that is, the diabetic heart, form the basis of this review. Abnormalities in each of cardiac metabolism, physiological and pathophysiological signaling, and the mitochondrial compartment, in addition to oxidative stress, inflammation, myocardial cell death pathways, and neurohumoral mechanisms, are addressed. Further, the interactions between each of these contributing mechanisms and how they align to the functional, morphological, and structural impairments that characterize the diabetic heart are considered in light of the clinical context: from the disease burden, its current management in the clinic, and where the knowledge gaps remain. The need for continued interrogation of these mechanisms (both known and those yet to be identified) is essential to not only decipher the how and why of diabetes mellitus-induced heart failure but also to facilitate improved inroads into the clinical management of this pervasive clinical challenge.



Circ Res: 21 May 2020; 126:1501-1525
Ritchie RH, Abel ED
Circ Res: 21 May 2020; 126:1501-1525 | PMID: 32437308
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Abstract

CITED4 Protects Against Adverse Remodeling in Response to Physiological and Pathological Stress.

Lerchenmüller C, Rabolli CP, Yeri AS, Kitchen R, ... Das S, Rosenzweig A

Cardiac CITED4 is induced by exercise and is sufficient to cause physiological hypertrophy and mitigate adverse ventricular remodeling after ischemic injury. However, the role of endogenous CITED4 in response to physiological or pathological stress is unknown.To investigate the role of CITED4 in murine models of exercise and pressure overload.We generated cardiomyocyte-specific CITED4 knockout mice (C4KO) and subjected them to an intensive swim exercise protocol as well as transverse aortic constriction (TAC). Echocardiography, western blotting, qPCR, immunohistochemistry, immunofluorescence, and transcriptional profiling for mRNA and miRNA expression were performed. Cellular crosstalk was investigated in vitro. CITED4 deletion in cardiomyocytes did not affect baseline cardiac size or function in young adult mice. C4KO mice developed modest cardiac dysfunction and dilation in response to exercise. After TAC, C4KOs developed severe heart failure with left ventricular dilation, impaired cardiomyocyte growth accompanied by reduced mammalian target of rapamycin (mTOR) activity and maladaptive cardiac remodeling with increased apoptosis, autophagy, and impaired mitochondrial signaling. Interstitial fibrosis was markedly increased in C4KO hearts after TAC. RNAseq revealed induction of a pro-fibrotic miRNA network. miR30d was decreased in C4KO hearts after TAC and mediated crosstalk between cardiomyocytes and fibroblasts to modulate fibrosis. miR30d inhibition was sufficient to increase cardiac dysfunction and fibrosis after TAC.CITED4 protects against pathological cardiac remodeling by regulating mTOR activity and a network of miRNAs mediating cardiomyocyte to fibroblast crosstalk. Our findings highlight the importance of CITED4 in response to both physiological and pathological stimuli.



Circ Res: 17 May 2020; epub ahead of print
Lerchenmüller C, Rabolli CP, Yeri AS, Kitchen R, ... Das S, Rosenzweig A
Circ Res: 17 May 2020; epub ahead of print | PMID: 32418505
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Abstract

Opportunistic screening for atrial fibrillation by clinical pharmacists in UK general practice during the influenza vaccination season: A cross-sectional feasibility study.

Savickas V, Stewart AJ, Rees-Roberts M, Short V, ... Mathie A, Veale EL
Background
Growing prevalence of atrial fibrillation (AF) in the ageing population and its associated life-changing health and resource implications have led to a need to improve its early detection. Primary care is an ideal place to screen for AF; however, this is limited by shortages in general practitioner (GP) resources. Recent increases in the number of clinical pharmacists within primary care makes them ideally placed to conduct AF screening. This study aimed to determine the feasibility of GP practice-based clinical pharmacists to screen the over-65s for AF, using digital technology and pulse palpation during the influenza vaccination season.
Methods and findings
Screening was conducted over two influenza vaccination seasons, 2017-2018 and 2018-2019, in four GP practices in Kent, United Kingdom. Pharmacists were trained by a cardiologist to pulse palpate, record, and interpret a single-lead ECG (SLECG). Eligible persons aged ≥65 years (y) attending an influenza vaccination clinic were offered a free heart rhythm check. Six hundred four participants were screened (median age 73 y, 42.7% male). Total prevalence of AF was 4.3%. All participants with AF qualified for anticoagulation and were more likely to be male (57.7%); be older; have an increased body mass index (BMI); and have a CHA2DS2-VASc (Congestive heart failure, Hypertension, Age ≥ 75 years, Diabetes, previous Stroke, Vascular disease, Age 65-74 years, Sex category) score ≥ 3. The sensitivity and specificity of clinical pharmacists diagnosing AF using pulse palpation was 76.9% (95% confidence interval [CI] 56.4-91.0) and 92.2% (95% CI 89.7-94.3), respectively. This rose to 88.5% (95% CI 69.9-97.6) and 97.2% (95% CI 95.5-98.4) with an SLECG. At follow-up, four participants (0.7%) were diagnosed with new AF and three (0.5%) were initiated on anticoagulation. Screening with SLECG also helped identify new non-AF cardiovascular diagnoses, such as left ventricular hypertrophy, in 28 participants (4.6%). The screening strategy was cost-effective in 71.8% and 64.3% of the estimates for SLECG or pulse palpation, respectively. Feedback from participants (422/604) was generally positive. Key limitations of the study were that the intervention did not reach individuals who did not attend the practice for an influenza vaccination and there was a limited representation of UK ethnic minority groups in the study cohort.
Conclusions
This study demonstrates that AF screening performed by GP practice-based pharmacists was feasible, economically viable, and positively endorsed by participants. Furthermore, diagnosis of AF by the clinical pharmacist using an SLECG was more sensitive and more specific than the use of pulse palpation alone. Future research should explore the key barriers preventing the adoption of national screening programmes.



PLoS Med: 29 Jun 2020; 17:e1003197
Savickas V, Stewart AJ, Rees-Roberts M, Short V, ... Mathie A, Veale EL
PLoS Med: 29 Jun 2020; 17:e1003197 | PMID: 32678820
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Abstract

Systems Genetics for Mechanistic Discovery in Heart Diseases.

Rau CD, Lusis AJ, Wang Y

Cardiovascular diseases are the leading cause of death worldwide. Complex diseases with highly heterogenous disease progression among patient populations, cardiovascular diseases feature multifactorial contributions from both genetic and environmental stressors. Despite significant effort utilizing multiple approaches from molecular biology to genome-wide association studies, the genetic landscape of cardiovascular diseases, particularly for the nonfamilial forms of heart failure, is still poorly understood. In the past decade, systems-level approaches based on omics technologies have become an important approach for the study of complex traits in large populations. These advances create opportunities to integrate genetic variation with other biological layers to identify and prioritize candidate genes, understand pathogenic pathways, and elucidate gene-gene and gene-environment interactions. In this review, we will highlight some of the recent progress made using systems genetics approaches to uncover novel mechanisms and molecular bases of cardiovascular pathophysiological manifestations. The key technology and data analysis platforms necessary to implement systems genetics will be described, and the current major challenges and future directions will also be discussed. For complex cardiovascular diseases, such as heart failure, systems genetics represents a powerful strategy to obtain mechanistic insights and to develop individualized diagnostic and therapeutic regiments, paving the way for precision cardiovascular medicine.



Circ Res: 04 Jun 2020; 126:1795-1815
Rau CD, Lusis AJ, Wang Y
Circ Res: 04 Jun 2020; 126:1795-1815 | PMID: 32496909
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Abstract

Positron emission tomography imaging in cardiovascular disease.

Tarkin JM, Ćorović A, Wall C, Gopalan D, Rudd JH

Positron emission tomography (PET) imaging is useful in cardiovascular disease across several areas, from assessment of myocardial perfusion and viability, to highlighting atherosclerotic plaque activity and measuring the extent of cardiac innervation in heart failure. Other important roles of PET have emerged in prosthetic valve endocarditis, implanted device infection, infiltrative cardiomyopathies, aortic stenosis and cardio-oncology. Advances in scanner technology, including hybrid PET/MRI and total body PET imaging, as well as the development of novel PET tracers and cardiac-specific postprocessing techniques using artificial intelligence will undoubtedly continue to progress the field.

© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.

Heart: 21 Jun 2020; epub ahead of print
Tarkin JM, Ćorović A, Wall C, Gopalan D, Rudd JH
Heart: 21 Jun 2020; epub ahead of print | PMID: 32571959
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Abstract

Self-Maintenance of Cardiac Resident Reparative Macrophages Attenuates Doxorubicin-induced Cardiomyopathy Through the SR-A1-c-Myc Axis.

Zhang H, Xu A, Sun X, Yang Y, ... Xu Y, Chen Q

Doxorubicin-induced cardiomyopathy (DiCM) is a primary cause of heart failure and mortality in cancer patients, in which macrophage-orchestrated inflammation serves as an essential pathological mechanism. However, the specific roles of tissue-resident and monocyte-derived macrophages in DiCM remain poorly understood.Uncovering the origins, phenotypes, and functions of proliferative cardiac resident macrophages and mechanistic insights into the self-maintenance of cardiac macrophage during DiCM progression.Mice were administrated with doxorubicin to induce cardiomyopathy. Dynamic changes of resident and monocyte-derived macrophages were examined by lineage tracing, parabiosis, and bone marrow transplantation. We found that the monocyte-derived macrophages primarily exhibited a pro-inflammatory phenotype that dominated the whole DiCM pathological process and impaired cardiac function. In contrast, cardiac resident macrophages were vulnerable to doxorubicin insult. The survived resident macrophages exhibited enhanced proliferation and conferred a reparative role. Global or myeloid specifically ablation of class A1 scavenger receptor (SR-A1) inhibited proliferation of cardiac resident reparative macrophages and therefore exacerbated cardiomyopathy in DiCM mice. Importantly, the detrimental effect of macrophage SR-A1 deficiency was confirmed by transplantation of bone marrow. At the mechanistic level, we show that c-Myc, a key transcriptional factor for the SR-A1-P38-SIRT1 pathway, mediated the effect of SR-A1 in reparative macrophage proliferation in DiCM.The SR-A1-c-Myc axis may represent a promising target to treat DiCM through augmentation of cardiac resident reparative macrophage proliferation.



Circ Res: 28 May 2020; epub ahead of print
Zhang H, Xu A, Sun X, Yang Y, ... Xu Y, Chen Q
Circ Res: 28 May 2020; epub ahead of print | PMID: 32466726
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Abstract

Epigenomes of Human Hearts Reveal New Genetic Variants Relevant for Cardiac Disease and Phenotype.

Tan WLW, Anene-Nzelu CG, Wong E, Lee M, ... Prabhakar S, Foo RS

Identifying genetic markers for heterogeneous complex diseases such as heart failure is challenging, and requires prohibitively large cohort sizes in genome-wide association studies (GWAS) in order to meet the stringent threshold of genome-wide statistical significance. On the other hand, chromatin quantitative trait loci (QTL), elucidated by direct epigenetic profiling of specific human tissues, may contribute towards prioritising sub-threshold variants for disease-association.Here, we captured non-coding genetic variants by performing epigenetic profiling for enhancer H3K27ac ChIP-seq in 70 human control and end-stage failing hearts.We have mapped a comprehensive catalogue of 47,321 putative human heart enhancers and promoters. 3,897 differential acetylation peaks (FDR 5%) pointed to pathways altered in heart failure (HF). To identify cardiac histone acetylation QTLs (haQTLs), we regressed out confounding factors including HF disease status, and employed the G-SCI test1 to call out 1,680 haQTLs (FDR 10%). RNA-seq performed on the same heart samples proved a subset of haQTLs to have significant association also to gene expression (expression QTLs), either in cis (180), or through long range interactions (81), identified by Hi-C and HiChIP performed on a subset of hearts. Furthermore, a concordant relationship between the gain or disruption of transcription factor (TF) binding motifs, inferred from alternative alleles at the haQTLs, implied a surprising direct association between these specific TF and local histone acetylation in human hearts. Finally, 62 unique loci were identified by colocalisation of haQTLs with the sub-threshold loci of heart-related GWAS datasets.Disease and phenotype-association for 62 unique loci are now implicated. These loci may indeed mediated their effect through modification of enhancer H3K27-acetylation enrichment and their corresponding gene expression differences.



Circ Res: 11 Jun 2020; epub ahead of print
Tan WLW, Anene-Nzelu CG, Wong E, Lee M, ... Prabhakar S, Foo RS
Circ Res: 11 Jun 2020; epub ahead of print | PMID: 32529949
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Abstract

GRK5 Controls SAP97-Dependent Cardiotoxic β1 Adrenergic Receptor-CaMKII Signaling in Heart Failureβ.

Xu B, Li M, Wang Y, Zhao M, ... Nieves-Cintrón M, Xiang YK

Cardiotoxic β1 adrenergic receptor (β1AR)-CaMKII signaling is a major and critical feature associated with development of heart failure. Synapse-associated protein 97 (SAP97) is a multi-functional scaffold protein that binds directly to the C-terminus of β1AR and organizes a receptor signalosome.We aim to elucidate the dynamics of β1AR-SAP97 signalosome and its potential role in chronic cardiotoxic β1AR-CaMKII signaling that contributes to development of heart failure. The integrity of cardiac β1AR-SAP97 complex was examined in heart failure. Cardiac specific deletion of SAP97 was developed to examine β1AR signaling in ageing mice, after chronic adrenergic stimulation, and in pressure overload hypertrophic heart failure. We show that the β1AR-SAP97 signaling complex is reduced in heart failure. Cardiac specific deletion of SAP97 yields an ageing-dependent cardiomyopathy and exacerbates cardiac dysfunction induced by chronic adrenergic stimulation and pressure overload, which are associated with elevated CaMKII activity. Loss of SAP97 promotes PKA-dependent association of β1AR with arrestin2 and CaMKII and turns on an Epac-dependent activation of CaMKII, which drives detrimental functional and structural remodeling in myocardium. Moreover, we have identified that GRK5 is necessary to promote agonist-induced dissociation of SAP97 from β1AR. Cardiac deletion of GRK5 prevents adrenergic-induced dissociation of β1AR-SAP97 complex and increases in CaMKII activity in hearts. These data reveal a critical role of SAP97 in maintaining the integrity of cardiac β1AR signaling and a detrimental cardiac GRK5-CaMKII axis that can be potentially targeted in heart failure therapy.



Circ Res: 07 Jun 2020; epub ahead of print
Xu B, Li M, Wang Y, Zhao M, ... Nieves-Cintrón M, Xiang YK
Circ Res: 07 Jun 2020; epub ahead of print | PMID: 32507058
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Abstract

Systemic Amyloidosis Recognition, Prognosis, and Therapy: A Systematic Review.

Gertz MA, Dispenzieri A
Importance
Many patients with systemic amyloidosis are underdiagnosed. Overall, 25% of patients with immunoglobulin light chain (AL) amyloidosis die within 6 months of diagnosis and 25% of patients with amyloid transthyretin (ATTR) amyloidosis die within 24 months of diagnosis. Effective therapy exists but is ineffective if end-organ damage is severe.
Objective
To provide evidence-based recommendations that could allow clinicians to diagnose this rare set of diseases earlier and enable accurate staging and counseling about prognosis.
Evidence review
A comprehensive literature search was conducted by a reference librarian with publication dates from January 1, 2000, to December 31, 2019. Key search terms included amyloid, amyloidosis, nephrotic syndrome, heart failure preserved ejection fraction, and peripheral neuropathy. Exclusion criteria included case reports, non-English-language text, and case series of fewer than 10 patients. The authors independently selected and appraised relevant literature.
Findings
There was a total of 1769 studies in the final data set. Eighty-one articles were included in this review, of which 12 were randomized clinical trials of therapy that included 3074 patients, 9 were case series, and 3 were cohort studies. The incidence of AL amyloidosis is approximately 12 cases per million persons per year and there is an estimated prevalence of 30 000 to 45 000 cases in the US and European Union. The incidence of variant ATTR amyloidosis is estimated to be 0.3 cases per year per million persons with a prevalence estimate of 5.2 cases per million persons. Wild-type ATTR is estimated to have a prevalence of 155 to 191 cases per million persons. Amyloidosis should be considered in the differential diagnosis of adult nondiabetic nephrotic syndrome; heart failure with preserved ejection fraction, particularly if restrictive features are present; unexplained hepatomegaly without imaging abnormalities; peripheral neuropathy with distal sensory symptoms, such as numbness, paresthesia, and dysesthesias (although the autonomic manifestations occasionally may be the presenting feature); and monoclonal gammopathy of undetermined significance with atypical clinical features. Staging can be performed using blood testing only. Therapeutic decision-making for AL amyloidosis involves choosing between high-dose chemotherapy and stem cell transplant or bortezomib-based chemotherapy. There are 3 therapies approved by the US Food and Drug Administration for managing ATTR amyloidosis, depending on clinical phenotype.
Conclusions and relevance
All forms of amyloidosis are underdiagnosed. All forms now have approved therapies that have been demonstrated to improve either survival or disability and quality of life. The diagnosis should be considered in patients that have a multisystem disorder involving the heart, kidney, liver, or nervous system.



JAMA: 06 Jul 2020; 324:79-89
Gertz MA, Dispenzieri A
JAMA: 06 Jul 2020; 324:79-89 | PMID: 32633805
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Abstract

Digital arterial pressure pulse wave analysis and cardiovascular events in the general population: the Prevention of Renal and Vascular End-stage Disease study.

De Jong MA, Van Roon AM, Bakker JT, Bijen HTJ, ... Bakker SJL, De Borst MH
Background
Arterial stiffness influences the contour of the digital pressure pulse wave.
Method
Here, we investigated whether the digital pulse propagation index (DPPI), based on the digital pressure pulse wave, DPPI is associated with cardiovascular events, heart failure, and mortality in a large population-based cohort. Between 2001 and 2003, DPPI was measured with a PortaPres noninvasive hemodynamic monitoring device (FinaPres Medical Systems, Amsterdam, The Netherlands) in participants of the Prevention of Renal and Vascular End-stage Disease study, a community-based cohort. We assessed the main determinants of the DPPI and investigated associations of DPPI with cardiovascular events and mortality.
Results
The study included 5474 individuals. Mean age was 52.3 ± 11.8 years and 50.5% was male. Median baseline DPPI was 5.81 m/s (interquartile range 5.47-6.20). Higher age, mean arterial blood pressure, body height, heart rate, current smoking, and lower HDL cholesterol levels and waist circumference were independent determinants of the DPPI (r = 0.43). After adjustment for heart rate, highlogDPPI was associated with all-cause mortality [hazard ratio: 1.67, 95% confidence interval (1.55-1.81) per SD; P < 0.001], cardiovascular mortality [hazard ratio 1.95 (1.72-2.22); P < 0.001], and incident heart failure with reduced ejection fraction [hazard ratio 1.81 (1.60-2.06); P < 0.001]. These associations remained independent upon further adjustment for confounders. Optimal cutoff values for DPPI ranged between 6.1 and 6.3 m/s for all endpoints. After multivariable adjustment, DPPI was no longer associated with coronary artery disease events or cerebrovascular events.
Conclusion
The DPPI is associated with an increased risk of development of new onset heart failure with reduced ejection fraction and all-cause and cardiovascular mortality, but not with coronary artery events or cerebrovascular events.



J Hypertens: 30 May 2020; 38:1064-1071
De Jong MA, Van Roon AM, Bakker JT, Bijen HTJ, ... Bakker SJL, De Borst MH
J Hypertens: 30 May 2020; 38:1064-1071 | PMID: 32371796
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Abstract

Dilated Cardiomyopathy (DCM)-linked Heat shock protein Family D Member 1 (HSPD1) mutations cause upregulation of ROS and autophagy through mitochondrial dysfunction.

Enomoto H, Mittal N, Inomata T, Arimura T, ... Fukuda K, Makino S
Background
During heart failure, the levels of circulatory HSPD1 (HSP60) increase. However, its underlying mechanism is still unknown. The apical domain of HSPD1 is conserved throughout evolution. We found a point mutation in HSPD1 in a familial dilated cardiomyopathy (DCM) patient. A similar point mutation in HSPD1 in the zebrafish mutant, nbl, led to loss of its regenerative capacity and development of pericardial edema under heat stress condition. In this study, we aimed to determine the direct involvement of HSPD1 in the development of DCM.
Methods and results
By Sanger method, we found a point mutation (Thr320Ala) in the apical domain of HSPD1, in one familial DCM patient, which was four amino acids away from the point mutation (Val324Glu) in the nbl mutant zebrafish. The nbl mutants showed atrioventricular block and sudden death at eight months post-fertilization. Histological and microscopic analysis of the nbl mutant hearts showed decreased ventricular wall thickness, elevated level of reactive oxygen species (ROS), increased fibrosis, mitochondrial damage, and increased autophagosomes. mRNA and protein expression of autophagy-related genes significantly increased in nbl mutants. We established HEK293 stable cell lines of WT, nbl-type, and DCM-type HSPD1, with tetracycline-dependent expression. Compared to WT, both nbl- and DCM-type cells showed decreased cell growth, increased expression of ROS and autophagy-related genes, inhibition of the activity of mitochondrial electron transport chain complexes III and IV, and decreased mitochondrial fission and fusion.
Conclusions
Mutations in HSPD1 caused mitochondrial dysfunction and induced mitophagy. Mitochondrial dysfunction caused increased ROS and cardiac atrophy.
Translational perspective
The aged heart is more susceptible to stress despite the increased compensatory chaperones/co-chaperones activity. Here, we identified a point mutation in HSPD1 in a human DCM family. Using zebrafish, we demonstrated that functional inactivation of HSPD1 resulted in increased ROS level and mitophagy, thereby resulting in heart failure at a relatively early age. Inhibition of ROS activity by antioxidants decreased cell death and mitophagy. This work identifies the key role of HSPD1 in cardiac muscle protection and suggests the supplementation of antioxidants may improve the cardiac function through the mitochondrial ROS pathway in patients with chronic heart failure.

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

Cardiovasc Res: 09 Jun 2020; epub ahead of print
Enomoto H, Mittal N, Inomata T, Arimura T, ... Fukuda K, Makino S
Cardiovasc Res: 09 Jun 2020; epub ahead of print | PMID: 32520982
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Abstract

Stretch-induced sarcoplasmic reticulum calcium leak is causatively associated with atrial fibrillation in pressure-overloaded hearts.

Zhang Y, Qi Y, Li JJ, He WJ, ... Du XJ, Xie W
Aims
Despite numerous reports documenting an important role of hypertension in the development of atrial fibrillation (AF), the detailed mechanism underlying the pathological process remains incompletely understood. Here, we aim to test the hypothesis that diastolic sarcoplasmic reticulum (SR) Ca2+ leak in atrial myocytes, induced by mechanical stretch due to elevated pressure in the left atrium (LA), plays an essential role in the AF development in pressure-overloaded hearts.
Methods and results
Isolated mouse atrial myocytes subjected to acute axial stretch displayed an immediate elevation of SR Ca2+ leak. Using a mouse model of transverse aortic constriction (TAC), the relation between stretch, SR Ca2+ leak and AF susceptibility was further tested. At 36 hours post TAC, SR Ca2+ leak in cardiomyocytes from the LA (with hemodynamic stress), but not right atrium (without hemodynamic stress), significantly increased, which was further elevated at 4 weeks post TAC. Accordingly, AF susceptibility to atrial burst pacing in the 4-week TAC mice were also significantly increased, which was unaffected by inhibition of atrial fibrosis or inflammation via deletion of galectin-3. Western blotting revealed that type 2 ryanodine receptor (RyR2) in LA myocytes of TAC mice was oxidized due to activation and upregulation of Nox2 and Nox4. Direct rescue of dysfunctional RyR2 with dantrolene or rycal S107 reduced diastolic SR Ca2+ leak in LA myocytes and prevented atrial burst pacing stimulated AF.
Conclusion
Our study demonstrated for the first time the increased SR Ca2+ leak mediated by enhanced oxidative stress in LA myocytes that is causatively associated with higher AF susceptibility in pressure-overloaded hearts.
Translational perspective
RyR2 is the major Ca2+ channel in cardiac myocytes, strongly affecting cellular activities. Several types of heart diseases, including heart failure and ventricular arrhythmias, are related to RyR2 dysfunction in ventricular myocytes. The present study expands RyR2 dysfunction as a critical contributor in pressure-overload associated AF. As AF is usually accompanied with cardiac remodeling and dysfunction in the setting of hypertension, which is a common risk factor for different cardiovascular diseases, the convergence of several pathological processes on the dysfunctional RyR2 makes it a common therapeutic target in these diseased settings.

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

Cardiovasc Res: 11 Jun 2020; epub ahead of print
Zhang Y, Qi Y, Li JJ, He WJ, ... Du XJ, Xie W
Cardiovasc Res: 11 Jun 2020; epub ahead of print | PMID: 32531044
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Abstract

Prediction of adverse cardiac events in pregnant women with valvular rheumatic heart disease.

Baghel J, Keepanasseril A, Pillai AA, Mondal N, Jeganathan Y, Kundra P
Objective
To assess the incidence of adverse cardiac events in pregnant women with rheumatic valvular heart disease (RHD) and to derive a clinical risk scoring for predicting it.
Methods
This is an observational study involving pregnant women with RHD, attending a tertiary centre in south India. Data regarding obstetric history, medical history, maternal complications and perinatal outcome till discharge were collected. Eight-hundred and twenty pregnancies among 681 women were included in the analysis. Primary outcome was composite adverse cardiac event defined as occurrence of one or more of complications such as death, cardiac arrest, heart failure, cerebrovascular accident from thromboembolism and new-onset arrhythmias.
Results
Of the 681 women with RHD, 180 (26.3%) were diagnosed during pregnancy. Composite adverse cardiac outcome during pregnancy/post partum occurred in 122 (14.9%) pregnancies, with 12 of them succumbed to the disease. In multivariate analysis, prior adverse cardiac events (OR=8.35, 95% CI 3.54 to 19.71), cardiac medications at booking (OR=0.53, 95% CI 0.32 to 0.86), mitral stenosis (mild OR=2.48, 95% CI 1.08 to 5.69; moderate OR=2.23, 95% CI 1.19 to 4.18; severe OR=7.72,95% 4.05 to 12.89), valve replacement (OR=2.53, 95% CI 1.28 to 5.02) and pulmonary hypertension (OR=6.90, 3.81 to 12.46) were predictive of composite adverse cardiac events with a good discrimination (area under the curve=0.803) and acceptable calibration. A predictive score combining these factors is proposed for clinical utility.
Conclusion
Heart failure remains the most common adverse cardiac event during pregnancy or puerperium. Combining the lesion-specific characteristics and clinical information into a predictive score, which is simple and effective, could be used in routine clinical practice.

© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.

Heart: 28 Jun 2020; epub ahead of print
Baghel J, Keepanasseril A, Pillai AA, Mondal N, Jeganathan Y, Kundra P
Heart: 28 Jun 2020; epub ahead of print | PMID: 32601124
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Abstract

Lung ultrasound-guided therapy reduces acute decompensation events in chronic heart failure.

Marini C, Fragasso G, Italia L, Sisakian H, ... Margonato A, Agricola E
Objective
Pulmonary congestion is the main cause of hospital admission in patients with heart failure (HF). Lung ultrasound (LUS) is a useful tool to identify subclinical pulmonary congestion. We evaluated the usefulness of LUS in addition to physical examination (PE) in the management of outpatients with HF.
Methods
In this randomised multicentre unblinded study, patients with chronic HF and optimised medical therapy were randomised in two groups: \'PE+LUS\' group undergoing PE and LUS and \'PE only\' group. Diuretic therapy was modified according to LUS findings and PE, respectively. The primary endpoint was the reduction in hospitalisation rate for acute decompensated heart failure (ADHF) at 90-day follow-up. Secondary endpoints were reduction in NT-proBNP, quality-of-life test (QLT) and cardiac mortality at 90-day follow-up.
Results
A total of 244 patients with chronic HF and optimised medical therapy were enrolled and randomised in \'PE+LUS\' group undergoing PE and LUS, and in \'PE only\' group. Thirty-seven primary outcome events occurred. The hospitalisation for ADHF at 90 day was significantly reduced in \'PE+LUS\' group (9.4% vs 21.4% in \'PE only\' group; relative risk=0.44; 95% CI 0.23 to 0.84; p=0.01), with a reduction of risk for hospitalisation for ADHF by 56% (p=0.01) and a number needed to treat of 8.4 patients (95% CI 4.8 to 34.3). At day 90, NT-proBNP and QLT score were significantly reduced in \'PE+LUS\' group, whereas in \'PE only\' group both were increased. There were no differences in mortality between the two groups.
Conclusions
LUS-guided management reduces hospitalisation for ADHF at mid-term follow-up in outpatients with chronic HF.

© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.

Heart: 21 Jun 2020; epub ahead of print
Marini C, Fragasso G, Italia L, Sisakian H, ... Margonato A, Agricola E
Heart: 21 Jun 2020; epub ahead of print | PMID: 32571960
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Abstract

Home monitoring with technology-supported management in chronic heart failure: a randomised trial.

Rahimi K, Nazarzadeh M, Pinho-Gomes AC, Woodward M, ... Cleland J,
Objectives
We aimed to investigate whether digital home monitoring with centralised specialist support for remote management of heart failure (HF) is more effective in improving medical therapy and patients\' quality of life than digital home monitoring alone.
Methods
In a two-armed partially blinded parallel randomised controlled trial, seven sites in the UK recruited a total of 202 high-risk patients with HF (71.3 years SD 11.1; left ventricular ejection fraction 32.9% SD 15.4). Participants in both study arms were given a tablet computer, Bluetooth-enabled blood pressure monitor and weighing scales for health monitoring. Participants randomised to intervention received additional regular feedback to support self-management and their primary care doctors received instructions on blood investigations and pharmacological treatment. The primary outcome was the use of guideline-recommended medical therapy for chronic HF and major comorbidities, measured as a composite opportunity score (total number of recommended treatment given divided by the total number of opportunities the treatment should have been given, with a score 1 indicating 100% adherence to recommendations). Co-primary outcome was change in physical score of Minnesota Living with Heart Failure questionnaire.
Results
101 patients were randomised to \'enhanced self-management\' and 101 to \'supported medical management\'. At the end of follow-up, the opportunity score was 0.54 (95% CI 0.46 to 0.62) in the control arm and 0.61 (95% CI 0.52 to 0.70) in the intervention arm (p=0.25). Physical well-being of participants also did not differ significantly between the groups (17.4 (12.4) mean (SD) for control arm vs 16.5 (12.1) in treatment arm; p for change=0.84).
Conclusions
Central provision of tailored specialist management in a multi-morbid HF population was feasible. However, there was no strong evidence for improvement in use of evidence-based treatment nor health-related quality of life.
Trial registration number
ISRCTN86212709.

© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.

Heart: 23 Jun 2020; epub ahead of print
Rahimi K, Nazarzadeh M, Pinho-Gomes AC, Woodward M, ... Cleland J,
Heart: 23 Jun 2020; epub ahead of print | PMID: 32580977
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Abstract

COVID-19 and Decompressive Hemicraniectomy for Acute Ischemic Stroke.

Liang JW, Reynolds AS, Reilly K, Lay C, ... Dangayach NS,
Background and purpose
Young patients with malignant cerebral edema have been shown to benefit from early decompressive hemicraniectomy. The impact of concomitant infection with coronavirus disease 2019 (COVID-19) and how this should weigh in on the decision for surgery is unclear.
Methods
We retrospectively reviewed all COVID-19-positive patients admitted to the neuroscience intensive care unit for malignant edema monitoring. Patients with >50% of middle cerebral artery involvement on computed tomography imaging were considered at risk for malignant edema.
Results
Seven patients were admitted for monitoring of whom 4 died. Cause of death was related to COVID-19 complications, and these were either seen both very early and several days into the intensive care unit course after the typical window of malignant cerebral swelling. Three cases underwent surgery, and 1 patient died postoperatively from cardiac failure. A good outcome was attained in the other 2 cases.
Conclusions
COVID-19-positive patients with large hemispheric stroke can have a good outcome with decompressive hemicraniectomy. A positive test for COVID-19 should not be used in isolation to exclude patients from a potentially lifesaving procedure.



Stroke: 07 Jul 2020:STROKEAHA120030804; epub ahead of print
Liang JW, Reynolds AS, Reilly K, Lay C, ... Dangayach NS,
Stroke: 07 Jul 2020:STROKEAHA120030804; epub ahead of print | PMID: 32639861
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Abstract

Characteristics and outcomes of patients with suspected heart failure referred in line with National Institute for Health and Care Excellence guidance.

Zheng A, Cowan E, Mach L, Adam RD, ... Flett A, Morton G
Objective
To describe the population, heart failure (HF) diagnosis rate, and 1-year hospitalisation and mortality of patients with suspected HF and elevated N-terminal pro B-type natriuretic peptide (NTproBNP) investigated according to UK National Institute for Health and Care Excellence (NICE) guidelines.
Methods
NICE recommends patients with suspected HF, based on clinical presentation and elevated NTproBNP, are referred for specialist assessment and echocardiography. Patients should be seen within 2 weeks when NTproBNP is >2000 pg/mL (2-week pathway: 2WP) or within 6 weeks when NTproBNP is 400-2000 pg/mL (6-week pathway: 6WP). This is a retrospective, multicentre, observational study of consecutive patients with suspected HF referred from primary care between 2014 and 2016 to dedicated secondary care HF clinics based on the NICE 2WP and 6WP. Data were obtained from hospital records and episode statistics. Mortality and hospitalisation rates were calculated 1 year from NTproBNP measurement.
Results
1271 patients (median age 80; IQR 73-85) were assessed, 680 (53%) of whom were female. 667 (53%) were referred on the 2WP and 604 (47%) on the 6WP. 698 (55%) were diagnosed with HF (369 HF with reduced ejection fraction) and 566 (45%) as not HF (NHF). 1-year mortality was 10% (n=129) and hospitalisation was 33% (n=413). Patients on the 2WP had higher mortality and hospitalisation rates than those on the 6WP, 14% vs 6% (p<0.001) and 38% vs 27% (p<0.001), respectively. All-cause mortality (11% vs 9%; p=0.306) and hospitalisation rates (35% vs 29%; p=0.128) did not differ between HF and NHF patients, respectively.
Conclusions
Outcomes using the NICE approach of short waiting time targets for specialist assessment of patients with suspected HF and raised NTproBNP are not known. The model identifies an elderly population a high proportion of whom have HF. Irrespective of diagnosis, patients have high rates of adverse outcomes. These contemporary real-world data provide a platform for discussions with patients and shaping HF services.

© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Heart: 19 Jul 2020; epub ahead of print
Zheng A, Cowan E, Mach L, Adam RD, ... Flett A, Morton G
Heart: 19 Jul 2020; epub ahead of print | PMID: 32690621
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Abstract

Eisenmenger syndrome: diagnosis, prognosis and clinical management.

Arvanitaki A, Giannakoulas G, Baumgartner H, Lammers AE

Eisenmenger syndrome (ES) represents the most severe phenotype of pulmonary arterial hypertension (PAH) associated with congenital heart disease (CHD) and occurs in patients with large unrepaired shunts. Despite early detection of CHD and major advances in paediatric cardiac surgery, ES is still prevalent and requires a multidisciplinary approach by adult CHD experts in tertiary centres. Central cyanosis is the primary clinical manifestation leading to secondary erythrocytosis and various multiorgan complications that increase morbidity and affect quality of life. Close follow-up is needed to early diagnose and timely manage these complications. The primary goal of care is to maintain patients\' fragile stability. Although the recent use of advanced PAH therapies has substantially improved functional capacity and increased life expectancy, long-term survival remains poor. Progressive heart failure, infectious diseases and sudden cardiac death comprise the main causes of death in patients with ES. Impaired exercise tolerance, decreased arterial oxygen saturation, iron deficiency, pre-tricuspid shunts, arrhythmias, increased brain natriuretic peptide, echocardiographic indices of right ventricular dysfunction and hospitalisation for heart failure predict mortality. Endothelin receptor antagonists are used as first-line treatment in symptomatic patients, while phosphodiesterase-5 inhibitors may be added. Due to the lack of evidence, current guidelines do not provide a clear therapeutic strategy regarding treatment escalation. Additional well-designed trials are required to assess the comparative efficacy of various PAH agents and the benefit of combination therapy. Finally, the development of a risk score is of utmost importance to guide clinical therapy.

© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.

Heart: 19 Jul 2020; epub ahead of print
Arvanitaki A, Giannakoulas G, Baumgartner H, Lammers AE
Heart: 19 Jul 2020; epub ahead of print | PMID: 32690623
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Abstract

Myofibroblasts and Fibrosis: Mitochondrial and Metabolic Control of Cellular Differentiation.

Gibb AA, Lazaropoulos MP, Elrod JW

Cardiac fibrosis is mediated by the activation of resident cardiac fibroblasts, which differentiate into myofibroblasts in response to injury or stress. Although myofibroblast formation is a physiological response to acute injury, such as myocardial infarction, myofibroblast persistence, as occurs in heart failure, contributes to maladaptive remodeling and progressive functional decline. Although traditional pathways of activation, such as TGFβ (transforming growth factor β) and AngII (angiotensin II), have been well characterized, less understood are the alterations in mitochondrial function and cellular metabolism that are necessary to initiate and sustain myofibroblast formation and function. In this review, we highlight recent reports detailing the mitochondrial and metabolic mechanisms that contribute to myofibroblast differentiation, persistence, and function with the hope of identifying novel therapeutic targets to treat, and potentially reverse, tissue organ fibrosis.



Circ Res: 16 Jul 2020; 127:427-447
Gibb AA, Lazaropoulos MP, Elrod JW
Circ Res: 16 Jul 2020; 127:427-447 | PMID: 32673537
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Abstract

Glutamyl-Prolyl-tRNA Synthetase Regulates Proline-Rich Pro-fibrotic Protein Synthesis During Cardiac Fibrosis.

Wu J, Subbaiah KCV, Xie LH, Jiang F, ... Tang WW, Yao P

Increased protein synthesis of pro-fibrotic genes is a common feature in cardiac fibrosis and heart failure. Despite this observation, critical factors and molecular mechanisms for translational control of pro-fibrotic genes during cardiac fibrosis remain unclear.To investigate the role of a bifunctional aminoacyl-tRNA synthetase (ARS), glutamyl-prolyl-tRNA synthetase (EPRS) in translational control of cardiac fibrosis.Results from re-analyses of multiple publicly available datasets of human and mouse heart failure, demonstrated that EPRS acted as an integrated node among the ARSs in various cardiac pathogenic processes. We confirmed that EPRS was induced at mRNA and protein levels (~1.5-2.5 fold increase) in failing hearts compared with non-failing hearts using our cohort of human and mouse heart samples. Genetic knockout of one allele ofglobally () using CRISPR-Cas9 technology or in a Postn-Cre-dependent manner () strongly reduces cardiac fibrosis (~50% reduction) in isoproterenol-, transverse aortic constriction-, and myocardial infarction-induced heart failure mouse models. Inhibition of EPRS using a prolyl-tRNA synthetase (PRS)-specific inhibitor, halofuginone (Halo), significantly decreases translation efficiency of proline-rich collagens in cardiac fibroblasts as well as TGF-beta-activated myofibroblasts. Overexpression of EPRS increases collagen protein expression in primary cardiac fibroblasts under TGF-beta stimulation. Using transcriptome-wide RNA-Seq and polysome profiling-Seq in Halo treated fibroblasts, we identified multiple novel Pro-rich genes in addition to collagens, such as Ltbp2 and Sulf1, which are translationally regulated by EPRS. SULF1 is highly enriched in human and mouse myofibroblasts. In the primary cardiac fibroblast culture system, siRNA-mediated knockdown of SULF1 attenuates cardiac myofibroblast activation and collagen deposition. Overexpression of SULF1 promotes TGF-beta-induced myofibroblast activation and partially antagonizes anti-fibrotic effects of Halo treatment.Our results indicate that EPRS preferentially controls translational activation of proline codon rich pro-fibrotic genes in cardiac fibroblasts and augments pathological cardiac remodeling.



Circ Res: 30 Jun 2020; epub ahead of print
Wu J, Subbaiah KCV, Xie LH, Jiang F, ... Tang WW, Yao P
Circ Res: 30 Jun 2020; epub ahead of print | PMID: 32611237
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Abstract

Cardiac dysfunction in cancer patients: beyond direct cardiomyocyte damage of anticancer drugs. Novel cardio-oncology insights from the joint 2019 meeting of the ESC Working Groups of Myocardial Function and Cellular Biology of the Heart.

Tocchetti CG, Ameri P, de Boer RA, D\'Alessandra Y, ... Heymans S, Thum T

In the Western countries cardiovascular disease and cancer are the leading causes of death in the ageing population. Recent epidemiological data suggest that cancer is more frequent in patients with prevalent or incident cardiovascular disease, in particular heart failure. Indeed, there is a tight link in terms of shared risk factors and mechanisms between heart failure and cancer. Heart failure induced by anticancer therapies has been extensively studied, primarily focusing on the toxic effects that antitumor treatments exert on cardiomyocytes. In this Cardio-Oncology update, members of the ESC WGs of Myocardial Function and of Cellular Biology of the Heart discuss novel evidence interconnecting cardiac dysfunction and cancer via pathways in which cardiomyocytes may be involved, but are not central. In particular, the multiple roles of cardiac stromal cells (endothelial cells, fibroblasts) and inflammatory cells are highlighted. Also, the gut microbiota is depicted as a new player at the crossroads between heart failure and cancer. Finally, the role of non-coding RNAs in Cardio-Oncology is also addressed. All these insights are expected to fuel additional research efforts in the field of Cardio-Oncology.

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

Cardiovasc Res: 18 Jul 2020; epub ahead of print
Tocchetti CG, Ameri P, de Boer RA, D'Alessandra Y, ... Heymans S, Thum T
Cardiovasc Res: 18 Jul 2020; epub ahead of print | PMID: 32683451
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Impact:
Abstract

Extreme Acetylation of the Cardiac Mitochondrial Proteome Does Not Promote Heart Failure.

Davidson MT, Grimsrud P, Lai L, Draper J, ... Kelly DP, Muoio DM

Circumstantial evidence links the development of heart failure to post-translational modifications of mitochondrial proteins, including lysine acetylation (Kac). Nonetheless, direct evidence that Kac compromises mitochondrial performance remains sparse.This study sought to explore the premise that mitochondrial Kac contributes to heart failure by disrupting oxidative metabolism. A dual knockout (DKO) mouse line with deficiencies in carnitine acetyltransferase (CrAT) and sirtuin 3 (Sirt3), enzymes that oppose Kac by buffering the acetyl group pool and catalyzing lysine deacetylation, respectively, was developed to model extreme mitochondrial Kac in cardiac muscle, as confirmed by quantitative acetyl-proteomics. The resulting impact on mitochondrial bioenergetics was evaluated using a respiratory diagnostics platform that permits comprehensive assessment of mitochondrial function and energy transduction. Susceptibility of DKO mice to heart failure was investigated using transaortic constriction (TAC) as a model of cardiac pressure overload. The mitochondrial acetyl-lysine landscape of DKO hearts was elevated well beyond that observed in response to pressure overload or Sirt3 deficiency alone. Relative changes in the abundance of specific acetylated lysine peptides measured in DKO versus Sirt3 KO hearts were strongly correlated. A proteomics comparison across multiple settings of hyperacetylation revealed ∼86% overlap between the populations of Kac peptides affected by the DKO manipulation as compared to experimental heart failure. Despite the severity of cardiac Kac in DKO mice relative to other conditions, deep phenotyping of mitochondrial function revealed a surprisingly normal bioenergetics profile. Thus, of the >120 mitochondrial energy fluxes evaluated, including substrate-specific dehydrogenase activities, respiratory responses, redox charge, mitochondrial membrane potential and electron leak, we found minimal evidence of oxidative insufficiencies. Similarly, DKO hearts were not more vulnerable to dysfunction caused by TAC-induced pressure overload. The findings challenge the premise that hyperacetylation per se threatens metabolic resilience in the myocardium by causing broad-ranging disruption to mitochondrial oxidative machinery.



Circ Res: 13 Jul 2020; epub ahead of print
Davidson MT, Grimsrud P, Lai L, Draper J, ... Kelly DP, Muoio DM
Circ Res: 13 Jul 2020; epub ahead of print | PMID: 32660330
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Abstract

Proportionate or disproportionate secondary mitral regurgitation: how to untangle the Gordian knot?

Kamoen V, Calle S, De Buyzere M, Timmermans F

Recent randomised percutaneous mitral intervention trials in patients with heart failure with secondary mitral regurgitation (SMR) have yielded contrasting results. A \'relative load\' or \'proportionality\' conceptual framework for SMR has been proposed to partly explain the disparate results. The rationale behind the framework is that SMR depends on the left ventricular dimension and not vice versa. In this review, we provide an in-depth analysis of the proportionality parameters used in this framework and also discuss the regurgitant fraction. We also consider haemodynamic observations in SMR that may affect the interpretation and comparisons among proportionality parameters. The conclusion is that the proportionality concept remains hypothetical and requires prospective validation before envisaging its use at individual patient level for risk stratification or therapeutic decision-making.

© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.

Heart: 29 Jul 2020; epub ahead of print
Kamoen V, Calle S, De Buyzere M, Timmermans F
Heart: 29 Jul 2020; epub ahead of print | PMID: 32732437
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Abstract

Performance and Interpretation of Invasive Hemodynamic Exercise Testing.

Jain CC, Borlaug BA

Exertional dyspnea is a common complaint for patients seen in pulmonary, cardiac and general medicine clinics, and elucidating the cause is often challenging, particularly when physical examination, echocardiography, radiography and pulmonary function test results are inconclusive. Invasive cardiopulmonary exercise testing (CPET) has emerged as the gold standard test to define causes of dyspnea and exertional limitation in this population. In this review, we describe the methods for performing and interpreting invasive CPET, with particular attention to the hemodynamic and blood sampling data as they apply to patients being evaluated for heart failure and pulmonary hypertension.

Copyright © 2020. Published by Elsevier Inc.

Chest: 27 May 2020; epub ahead of print
Jain CC, Borlaug BA
Chest: 27 May 2020; epub ahead of print | PMID: 32473950
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Abstract

Heart Failure with Preserved Ejection Fraction: Insights into Diagnosis and Pathophysiology.

Nagueh SF

Heart failure with preserved ejection fraction (HFpEF) accounts for at least half the cases of heart failure, currently diagnosed. There are several cardiac and non-cardiac manifestations of the syndrome. Structure and function abnormalities can include all four cardiac chambers. The left ventricle (LV) has abnormal systolic and diastolic functions which can be examined by invasive and noninvasive measurements. In addition, the left atrium (LA) enlarges with abnormal LA function, pulmonary hypertension occurs, and the right ventricle can develop hypertrophy, enlargement, and systolic dysfunction. There are a paucity of data on calcium handling in HFpEF patients. Growing literature supports the presence of abnormalities in titin and its phosphorylation, and increased interstitial fibrosis contributing to increased chamber stiffness. A systemic inflammatory state causing reduced myocardial c-GMP along with defects in the unfolded protein response have been recently reported. Diagnosis relies on signs and symptoms of heart failure, preserved EF, and detection of diastolic function abnormalities based on echocardiographic findings and abnormally elevated natriuretic peptide levels or invasive measurements of wedge pressure at rest or with exercise. There are currently two diagnostic algorithms: H2FPEF, and HFA-PEFF with limited data comparing their performance head to head in the same patient population. Despite the growing understanding of the syndrome\'s pathophysiology, there have been little success in developing specific treatment for patients with HFpEF.

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

Cardiovasc Res: 26 Jul 2020; epub ahead of print
Nagueh SF
Cardiovasc Res: 26 Jul 2020; epub ahead of print | PMID: 32717061
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Abstract

Disruption of Actin Dynamics Regulated by Rho Effector mDia1 Attenuates Pressure Overload-Induced Cardiac Hypertrophic Responses and Exacerbates Dysfunction.

Abe I, Terabayashi T, Hanada K, Kondo H, ... Takahashi N, Ishizaki T
Aims
Cardiac hypertrophy is a compensatory response to pressure overload, leading to heart failure. Recent studies have demonstrated that Rho is immediately activated in left ventricles after pressure overload, and that Rho signalling plays crucial regulatory roles in actin cytoskeleton rearrangement during cardiac hypertrophic responses. However, the mechanisms by which Rho and its downstream proteins control actin dynamics during hypertrophic responses remain not fully understood. In this study, we identified the pivotal roles of mammalian homologue of Drosophila diaphanous (mDia) 1, a Rho-effector molecule, in pressure overload-induced ventricular hypertrophy.
Methods and results
Male wild-type (WT) and mDia1-knockout (mDia1KO) mice (10-12 weeks old) were subjected to a transverse aortic constriction (TAC) or sham operation. The heart weight/tibia length ratio, cardiomyocyte cross-sectional area, left ventricular wall thickness, and expression of hypertrophy-specific genes were significantly decreased in mDia1KO mice 3 weeks after TAC, and the mortality rate was higher at 12 weeks. Echocardiography indicated that mDia1 deletion increased the severity of heart failure 8 weeks after TAC. Importantly, we could not observe apparent defects in cardiac hypertrophic responses in mDia3-knockout mice. Microarray analysis revealed that mDia1 was involved in the induction of hypertrophy related genes, including immediate early genes, in pressure overloaded hearts. Loss of mDia1 attenuated activation of the mechanotransduction pathway in TAC-operated mice hearts. We also found that mDia1 was involved in stretch-induced activation of the mechanotransduction pathway and gene expression of c-fos in neonatal rat ventricular cardiomyocytes (NRVMs). mDia1 regulated the filamentous/globular (F/G)-actin ratio in response to pressure overload in mice. Additionally, increases in nuclear myocardin-related transcription factors and serum response factor were perturbed in response to pressure overload in mDia1KO mice and to mechanical stretch in mDia1 depleted NRVMs.
Conclusions
mDia1, through actin dynamics, is involved in compensatory cardiac hypertrophy in response to pressure overload.
Translational perspective
Heart disease is associated with increased cardiac mass resulting from hypertrophic growth and remodelling in response to excessive mechanical stress. Although numerous signalling pathways have been shown to influence cardiac hypertrophy, the molecular mechanisms contributing to the pressure overload-induced cardiac hypertrophy have remained incompletely understood. Here, we present evidence that the cardioprotective functions of actin polymerization by mammalian homologue of Drosophila diaphanous 1, a Rho-effector molecule, in response to mechanical stress. Understanding this mechanotransduction pathway may provide new prospects for identifying a novel strategy for pressure overload-induced cardiovascular disease.

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

Cardiovasc Res: 08 Jul 2020; epub ahead of print
Abe I, Terabayashi T, Hanada K, Kondo H, ... Takahashi N, Ishizaki T
Cardiovasc Res: 08 Jul 2020; epub ahead of print | PMID: 32647865
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Abstract

Metabolic Inflammation in Heart Failure with Preserved Ejection Fraction.

Schiattarella GG, Rodolico D, Hill JA

One in ten persons in the world aged 40 years and older will develop the syndrome of HFpEF (heart failure with preserved ejection fraction), the most common form of chronic cardiovascular disease for which no effective therapies are currently available. Metabolic disturbance and inflammatory burden contribute importantly to HFpEF pathogenesis. The interplay within these two biological processes is complex; indeed, it is now becoming clear that the notion of metabolic inflammation - metainflammation - must be considered central to HFpEF pathophysiology. Inflammation and metabolism interact over the course of syndrome progression, and likely impact HFpEF treatment and prevention. Here, we discuss evidence in support of a causal, mechanistic role of metainflammation in shaping HFpEF, proposing a framework in which metabolic comorbidities profoundly impact cardiac metabolism and inflammatory pathways in the syndrome.

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

Cardiovasc Res: 13 Jul 2020; epub ahead of print
Schiattarella GG, Rodolico D, Hill JA
Cardiovasc Res: 13 Jul 2020; epub ahead of print | PMID: 32666082
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Abstract

Angiopoietin-1 enhanced myocyte mitosis, engraftment, and the reparability of hiPSC-CMs for treatment of myocardial infarction.

Tao Z, Loo S, Su L, Tan S, ... Chen X, Ye L
Aims
To examine whether transient over-expression of angiopoietin-1 (Ang-1) increases the potency of hiPSC-CMs for treatment of heart failure.
Methods and results
Atrial hiPSC-CMs (hiPSC-aCMs) were differentiated from hiPSCs and purified by lactic acid and were transfected with Ang-1 (Ang-1-hiPSC-aCMs) plasmid using lipoSTEM. Ang-1 gene transfection efficiency was characterized in vitro. Gene transfected CMs (1x106) were seeded into a fibrin/thrombin patch and implanted on the rat infarcted left ventricular anterior wall after myocardial infarction (MI). Echo function was determined at 1- and 6- weeks post-MI. Immunohistochemistry study was performed at week-6 post-MI. Ang-1 (20 and 40 ng/ml) protected hiPSC-aCMs from hypoxia through up-regulating pERK1/2 and inhibiting Bax protein expressions. Ang-1-hiPSC-aCMs transiently secreted Ang-1 protein up to 14 days, with peak level on day-2 post-transfection (24.39±13.02 ng/ml) in vitro. Animal study showed that transplantation of Ang-1-hiPSC-aCM seeded patch more effectively limited rat heart apoptosis at 1-day post-MI as compared with LipoSTEM-Ang-1 or hiPSC-aCMs transplantation. Ang-1-hiPSC-aCMs transplantation induced host (rat) and donor (human) CM mitosis and arteriole formation, improved cell engraftment rate, more effectively limited left ventricle (LV) dilation (EDV=460.7±96.1 μl and ESV=219.8±72.9 μl) and improved LV global pump function (EF = 53.1±9%) as compared with the MI (EDV=570.9±91.8 μl, p = 0.033; ESV=331.6±71.2 μl, p = 0.011; EF = 42.3±4.1%, p = 0.02) or the LipoSTEM-Ang-1 injected (EDV=491.4±100.4 μl, p = 0.854; ESV=280.9±71.5 μl, p = 0.287; EF = 43.2±4.6, p = 0.039) or hiPSC-CM transplanted (EDV=547.9±55.5 μl, p = 0.095; ESV=300.2±88.4 μl, p = 0.075; EF = 46±10.9%, p = 0.166) animal groups at 6 weeks post-MI and treatment.
Conclusions
Transient overexpression of Ang-1 enhanced hiPSC-aCM mitosis and engraftment and increased the reparability potency of hiPSC-aCMs for treatment of MI.
Translational perspective
Cellular cardiomyoplasty using hiPSC-CMs alone may be insufficient to recover the structure and function of infarcted myocardium in which blood vessels and perfusion are damaged. A combinational approach of myogenesis with vasculogenesis to repopulate CMs with functional neovascular network is necessary to recover LV structure and function post-MI. This is the first report showing evidence that transplantation of hiPSC-CM transiently overexpressing Ang-1 had better cell engraftment and improved heart structure and function post-MI. It highlights that transient genetic modification of hiPSC-CMs with Ang-1 using non-viral vectors offers a better CM based angiomyogenesis therapy for treatment of MI.

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

Cardiovasc Res: 13 Jul 2020; epub ahead of print
Tao Z, Loo S, Su L, Tan S, ... Chen X, Ye L
Cardiovasc Res: 13 Jul 2020; epub ahead of print | PMID: 32666104
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Abstract

Gene expression profiling of hypertrophic cardiomyocytes identifies new players in pathological remodeling.

Vigil-Garcia M, Demkes CJ, Eding JEC, Versteeg D, ... Boogerd CJ, van Rooij E
Aims
Pathological cardiac remodeling is characterized by cardiomyocyte hypertrophy and fibroblast activation, which can ultimately lead to maladaptive hypertrophy and heart failure (HF). Genome-wide expression analysis on heart tissue has been instrumental for the identification of molecular mechanisms at play. However, these data were based on signals derived from all cardiac cell types. Here we aimed for a more detailed view on molecular changes driving maladaptive cardiomyocyte hypertrophy to aid in the development of therapies to reverse pathological remodeling.
Methods and results
Utilizing cardiomyocyte-specific reporter mice exposed to pressure overload by transverse aortic banding and cardiomyocyte isolation by flow cytometry, we obtained gene expression profiles of hypertrophic cardiomyocytes in the more immediate phase after stress, and cardiomyocytes showing pathological hypertrophy. We identified subsets of genes differentially regulated and specific for either stage. Among the genes specifically upregulated in the cardiomyocytes during the maladaptive phase we found known stress markers, such as Nppb and Myh7, but additionally identified a set of genes with unknown roles in pathological hypertrophy, including the platelet isoform of phosphofructokinase (PFKP). Norepinephrine-angiotensin II treatment of cultured human cardiomyocytes induced secretion of NT pro-BNP and recapitulated the upregulation of these genes, indicating conservation of the upregulation in failing cardiomyocytes. Moreover, several genes induced during pathological hypertrophy were also found to be increased in human heart failure, with their expression positively correlating to the known stress markers NPPB and MYH7. Mechanistically, suppression of Pfkp in primary cardiomyocytes attenuated stress-induced gene expression and hypertrophy, indicating that Pfkp is an important novel player in pathological remodeling of cardiomyocytes.
Conclusions
Using cardiomyocyte-specific transcriptomic analysis we identified novel genes induced during pathological hypertrophy that are relevant for human HF, and we show that PFKP is a conserved failure-induced gene that can modulate the cardiomyocyte stress response.
Translational perspective
Maladaptive cardiac remodeling is a consequence of pathological hypertrophy which includes cardiomyocytes changes and a decline in contractility. Our cardiomyocyte-specific gene expression studies revealed a gene program specific for pathological hypertrophy that is conserved in diseased mouse and human cardiomyocytes. We identified PFKP as a novel gene actively involved in cardiomyocyte remodeling, indicating PFKP as a potential therapeutic target to block the progression of heart failure.

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

Cardiovasc Res: 26 Jul 2020; epub ahead of print
Vigil-Garcia M, Demkes CJ, Eding JEC, Versteeg D, ... Boogerd CJ, van Rooij E
Cardiovasc Res: 26 Jul 2020; epub ahead of print | PMID: 32717063
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Abstract

Heart Failure With Reduced Ejection Fraction: A Review.

Murphy SP, Ibrahim NE, Januzzi JL
Importance
Worldwide, the burden of heart failure has increased to an estimated 23 million people, and approximately 50% of cases are HF with reduced ejection fraction (HFrEF).
Observations
Heart failure is a clinical syndrome characterized by dyspnea or exertional limitation due to impairment of ventricular filling or ejection of blood or both. HFrEF occurs when the left ventricular ejection fraction (LVEF) is 40% or less and is accompanied by progressive left ventricular dilatation and adverse cardiac remodeling. Assessment for heart failure begins with obtaining a medical history and physical examination. Also central to diagnosis are elevated natriuretic peptides above age- and context-specific thresholds and identification of left ventricular systolic dysfunction with LVEF of 40% or less as measured by echocardiography. Treatment strategies include the use of diuretics to relieve symptoms and application of an expanding armamentarium of disease-modifying drug and device therapies. Unless there are specific contraindications, patients with HFrEF should be treated with a β-blocker and one of an angiotensin receptor-neprilysin inhibitor, angiotensin-converting enzyme inhibitor, or angiotensin receptor blocker as foundational therapy, with addition of a mineralocorticoid receptor antagonist in patients with persistent symptoms. Ivabradine and hydralazine/isosorbide dinitrate also have a role in the care of certain patients with HFrEF. More recently, sodium-glucose cotransporter 2 (SGLT2) inhibitors have further improved disease outcomes, significantly reducing cardiovascular and all-cause mortality irrespective of diabetes status, and vericiguat, a soluble guanylate cyclase stimulator, reduces heart failure hospitalization in high-risk patients with HFrEF. Device therapies may be beneficial in specific subpopulations, such as cardiac resynchronization therapy in patients with interventricular dyssynchrony, transcatheter mitral valve repair in patients with severe secondary mitral regurgitation, and implantable cardiac defibrillators in patients with more severe left ventricular dysfunction particularly of ischemic etiology.
Conclusions and relevance
HFrEF is a major public health concern with substantial morbidity and mortality. The management of HFrEF has seen significant scientific breakthrough in recent decades, and the ability to alter the natural history of the disease has never been better. Recent developments include SGLT2 inhibitors, vericiguat, and transcatheter mitral valve repair, all of which incrementally improve prognosis beyond foundational neurohormonal therapies. Disease morbidity and mortality remain high, with a 5-year survival rate of 25% after hospitalization for HFrEF.



JAMA: 03 Aug 2020; 324:488-504
Murphy SP, Ibrahim NE, Januzzi JL
JAMA: 03 Aug 2020; 324:488-504 | PMID: 32749493
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Abstract

Hypertensive emergencies and urgencies in emergency departments: a systematic review and meta-analysis.

Astarita A, Covella M, Vallelonga F, Cesareo M, ... Veglio F, Milan A
Objectives
The prevalence of hypertensive emergencies and urgencies and of acute hypertension-mediated organ damage (aHMOD) in emergency departments is unknown. Moreover, the predictive value of symptoms, blood pressure (BP) levels and cardiovascular risk factors to suspect the presence of aHMOD is still unclear. The aim of this study was to investigate the prevalence of hypertensive emergencies and hypertensive urgencies in emergency departments and of the relative frequency of subtypes of aHMOD, as well as to assess the clinical variables associated with aHMOD.
Methods
We conducted a systematic literature search on PubMed, OVID, and Web of Science from their inception to 22 August 2019. Two independent investigators extracted study-level data for a random-effects meta-analysis.
Results
Eight studies were analysed, including 1970 hypertensive emergencies and 4983 hypertensive urgencies. The prevalence of hypertensive emergencies and hypertensive urgencies was 0.3 and 0.9%, respectively [odds ratio for hypertensive urgencies vs. hypertensive emergencies 2.5 (1.4-4.3)]. Pulmonary oedema/heart failure was the most frequent subtype of aHMOD (32%), followed by ischemic stroke (29%), acute coronary syndrome (18%), haemorrhagic stroke (11%), acute aortic syndrome (2%) and hypertensive encephalopathy (2%). No clinically meaningful difference was found for BP levels at presentations. Hypertensive urgency patients were younger than hypertensive emergency patients by 5.4 years and more often complained of nonspecific symptoms and/or headache, whereas specific symptoms were more frequent among hypertensive emergency patients.
Conclusion
Hypertensive emergencies and hypertensive urgencies are a frequent cause of access to emergency departments, with hypertensive urgencies being significantly more common. BP levels alone do not reliably predict the presence of aHMOD, which should be suspected according to the presenting signs and symptoms.



J Hypertens: 29 Jun 2020; 38:1203-1210
Astarita A, Covella M, Vallelonga F, Cesareo M, ... Veglio F, Milan A
J Hypertens: 29 Jun 2020; 38:1203-1210 | PMID: 32510905
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Abstract

Association of Diagnosis Coding With Differences in Risk-Adjusted Short-term Mortality Between Critical Access and Non-Critical Access Hospitals.

Kosar CM, Loomer L, Thomas KS, White EM, Panagiotou OA, Rahman M
Importance
Critical access hospitals (CAHs) provide care to rural communities. Increasing mortality rates have been reported for CAHs relative to non-CAHs. Because Medicare reimburses CAHs at cost, CAHs may report fewer diagnoses than non-CAHs, which may affect risk-adjusted comparisons of outcomes.
Objective
To assess serial differences in risk-adjusted mortality rates between CAHs and non-CAHs after accounting for differences in diagnosis coding.
Design, setting, and participants
Serial cross-sectional study of rural Medicare Fee-for-Service beneficiaries admitted to US CAHs and non-CAHs for pneumonia, heart failure, chronic obstructive pulmonary disease, arrhythmia, urinary tract infection, septicemia, and stroke from 2007 to 2017. The final date of follow-up was December 31, 2017.
Exposure
Admission to a CAH vs non-CAH.
Main outcomes and measures
Discharge diagnosis count including trends from 2010 to 2011 when Medicare expanded the allowable number of billing codes for hospitalizations, and combined in-hospital and 30-day postdischarge mortality adjusted for demographics, primary diagnosis, preexisting conditions, and with vs without further adjustment for Hierarchical Condition Category (HCC) score to understand the contribution of in-hospital secondary diagnoses.
Results
There were 4 094 720 hospitalizations (17% CAH) for 2 850 194 unique Medicare beneficiaries (mean [SD] age, 76.3 [11.7] years; 55.5% women). Patients in CAHs were older (median age, 80.1 vs 76.8 years) and more likely to be female (58% vs 55%). In 2010, the adjusted mean discharge diagnosis count was 7.52 for CAHs vs 8.53 for non-CAHs (difference, -0.99 [95% CI, -1.08 to -0.90]; P < .001). In 2011, the CAH vs non-CAH difference in diagnoses coded increased (P < .001 for interaction between CAH and year) to 9.27 vs 12.23 (difference, -2.96 [95% CI, -3.19 to -2.73]; P < .001). Adjusted mortality rates from the model with HCC were 13.52% for CAHs vs 11.44% for non-CAHs (percentage point difference, 2.08 [95% CI, 1.74 to 2.42]; P < .001) in 2007 and increased to 15.97% vs 12.46% (difference, 3.52 [95% CI, 3.09 to 3.94]; P < .001) in 2017 (P < .001 for interaction). Adjusted mortality rates from the model without HCC were not significantly different between CAHs and non-CAHs in all years except 2007 (12.19% vs 11.74%; difference, 0.45 [95% CI, 0.12 to 0.79]; P = .008) and 2010 (12.71% vs 12.28%; difference, 0.42 [95% CI, 0.07 to 0.77]; P = .02).
Conclusions and relevance
For rural Medicare beneficiaries hospitalized from 2007 to 2017, CAHs submitted significantly fewer hospital diagnosis codes than non-CAHs, and short-term mortality rates adjusted for preexisting conditions but not in-hospital comorbidity measures were not significantly different by hospital type in most years. The findings suggest that short-term mortality outcomes at CAHs may not differ from those of non-CAHs after accounting for different coding practices for in-hospital comorbidities.



JAMA: 03 Aug 2020; 324:481-487
Kosar CM, Loomer L, Thomas KS, White EM, Panagiotou OA, Rahman M
JAMA: 03 Aug 2020; 324:481-487 | PMID: 32749490
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Impact:
Abstract

Inflammasomes and Proteostasis Novel Molecular Mechanisms Associated With Atrial Fibrillation.

Li N, Brundel BJJM

Atrial fibrillation (AF), the most common progressive and age-related cardiac arrhythmia, affects millions of people worldwide. AF is associated with common risk factors, including hypertension, diabetes mellitus, and obesity, and serious complications such as stroke and heart failure. Notably, AF is progressive in nature, and because current treatment options are mainly symptomatic, they have only a moderate effect on prevention of arrhythmia progression. Hereto, there is an urgent unmet need to develop mechanistic treatments directed at root causes of AF. Recent research findings indicate a key role for inflammasomes and derailed proteostasis as root causes of AF. Here, we elaborate on the molecular mechanisms of these 2 emerging key pathways driving the pathogenesis of AF. First the role of NLRP3 (NACHT, LRR, and PYD domains-containing protein 3) inflammasome on AF pathogenesis and cardiomyocyte remodeling is discussed. Then we highlight pathways of proteostasis derailment, including exhaustion of cardioprotective heat shock proteins, disruption of cytoskeletal proteins via histone deacetylases, and the recently discovered DNA damage-induced nicotinamide adenine dinucleotide depletion to underlie AF. Moreover, potential interactions between the inflammasomes and proteostasis pathways are discussed and possible therapeutic targets within these pathways indicated.



Circ Res: 18 Jun 2020; 127:73-90
Li N, Brundel BJJM
Circ Res: 18 Jun 2020; 127:73-90 | PMID: 32717176
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Impact:
Abstract

How Will Genetics Inform the Clinical Care of Atrial Fibrillation?

Shoemaker MB, Shah RL, Roden DM, Perez MV

Susceptibility to atrial fibrillation (AF) is determined by well-recognized risk factors such as diabetes mellitus or hypertension, emerging risk factors such as sleep apnea or inflammation, and increasingly well-defined genetic variants. As discussed in detail in a companion article in this series, studies in families and in large populations have identified multiple genetic loci, specific genes, and specific variants increasing susceptibility to AF. Since it is becoming increasingly inexpensive to obtain genotype data and indeed whole genome sequence data, the question then becomes to define whether using emerging new genetics knowledge can improve care for patients both before and after development of AF. Examples of improvements in care could include identifying patients at increased risk for AF (and thus deploying increased surveillance or even low-risk preventive therapies should these be available), identifying patient subsets in whom specific therapies are likely to be effective or ineffective or in whom the driving biology could motivate the development of new mechanism-based therapies or identifying an underlying susceptibility to comorbid cardiovascular disease. While current guidelines for the care of patients with AF do not recommend routine genetic testing, this rapidly increasing knowledge base suggests that testing may now or soon have a place in the management of select patients. The opportunity is to generate, validate, and deploy clinical predictors (including family history) of AF risk, to assess the utility of incorporating genomic variants into those predictors, and to identify and validate interventions such as wearable or implantable device-based monitoring ultimately to intervene in patients with AF before they present with catastrophic complications like heart failure or stroke.



Circ Res: 18 Jun 2020; 127:111-127
Shoemaker MB, Shah RL, Roden DM, Perez MV
Circ Res: 18 Jun 2020; 127:111-127 | PMID: 32716712
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Impact:
Abstract

Genetics of Atrial Fibrillation in 2020: GWAS, Genome Sequencing, Polygenic Risk, and Beyond.

Roselli C, Rienstra M, Ellinor PT

Atrial fibrillation is a common heart rhythm disorder that leads to an increased risk for stroke and heart failure. Atrial fibrillation is a complex disease with both environmental and genetic risk factors that contribute to the arrhythmia. Over the last decade, rapid progress has been made in identifying the genetic basis for this common condition. In this review, we provide an overview of the primary types of genetic analyses performed for atrial fibrillation, including linkage studies, genome-wide association studies, and studies of rare coding variation. With these results in mind, we aim to highlighting the existing knowledge gaps and future directions for atrial fibrillation genetics research.



Circ Res: 18 Jun 2020; 127:21-33
Roselli C, Rienstra M, Ellinor PT
Circ Res: 18 Jun 2020; 127:21-33 | PMID: 32716721
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Impact:
Abstract

Lower socioeconomic status predicts higher mortality and morbidity in patients with heart failure.

Schrage B, Lund LH, Benson L, Stolfo D, ... Ferreira JP, Savarese G
Objective
It is not fully understood whether and how socioeconomic status (SES) has a prognostic impact in patients with heart failure (HF). We assessed SES and its association with patient characteristics and outcomes in a contemporary and well-characterised HF cohort.
Methods
Socioeconomic risk factors (SERF) were defined in the Swedish HF Registry based on income (low vs high according to the annual median value), education level (no degree/compulsory school vs university/secondary school) and living arrangement (living alone vs cohabitating).
Results
Of 44 631 patients, 21% had no, 33% one, 30% two and 16% three SERF. Patient characteristics strongly and independently associated with lower SES were female sex and no specialist referral. Additional independent associations were older age, more severe HF, heavier comorbidity burden, use of diuretics and less use of HF devices. Lower SES was associated with higher risk of HF hospitalisation/mortality, and overall cardiovascular and non-cardiovascular events. These associations persisted after extensive adjustment for patient characteristics, treatments and care. The magnitude of the association increased linearly with the increasing number of coexistent SERF: HR (95% CI) 1.09 (1.05 to 1.13) for one, 1.16 (1.12 to 1.20) for two and 1.22 (1.18 to 1.28) for three SERF (p<0.01).
Conclusions
In a contemporary and well-characterised HF cohort and after comprehensive adjustment for confounders, lower SES was linked with multiple factors such as less use of HF devices and age, but most strongly with female sex and lack of specialist referral; and associated with greater risk of morbidity/mortality.

© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.

Heart: 06 Aug 2020; epub ahead of print
Schrage B, Lund LH, Benson L, Stolfo D, ... Ferreira JP, Savarese G
Heart: 06 Aug 2020; epub ahead of print | PMID: 32769169
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Impact:
Abstract

Machine Learning of 12-lead QRS Waveforms to Identify Cardiac Resynchronization Therapy Patients with Differential Outcomes.

Feeny AK, Rickard J, Trulock KM, Patel D, ... Madabhushi A, Chung MK

- Cardiac resynchronization therapy (CRT) improves heart failure outcomes but has significant non-response rates, highlighting limitations in ECG selection criteria: QRS duration (QRSd) ≥150 ms and subjective labeling of left bundle branch block (LBBB). We explored unsupervised machine learning of ECG waveforms to identify CRT subgroups that may differentiate outcomes beyond QRSd and LBBB.- We retrospectively analyzed 946 CRT patients with conduction delay. Principal components analysis (PCA) dimensionality reduction obtained a two-dimensional representation of pre-CRT 12-lead QRS waveforms. -means clustering of the two-dimensional PCA representation of 12-lead QRS waveforms identified two patient subgroups (QRS PCA groups). Vectorcardiographic QRS area was also calculated. We examined two primary outcomes: (1) composite endpoint of death, left ventricular assist device, or heart transplant, and (2) degree of echocardiographic left ventricular ejection fraction (LVEF) change after CRT.- Compared to QRS PCA Group 2 (=425), Group 1 (n=521) had lower risk for reaching the composite endpoint (HR 0.44, 95% CI, 0.38-0.53, p<0.001) and experienced greater mean LVEF improvement (11.1±11.7% vs. 4.8±9.7%, p<0.001), even among LBBB patients with QRSd ≥150 ms (HR 0.42, 95% CI, 0.30-0.57, p<0.001; mean LVEF change 12.5±11.8% vs. 7.3±8.1%, p=0.001). QRS area also stratified outcomes but had significant differences from QRS PCA groups. A stratification scheme combining QRS area and QRS PCA group identified LBBB patients with similar outcomes to non-LBBB patients (HR 1.32, 95% CI: 0.93-1.62; difference in mean LVEF change: 0.8%, 95% CI: -2.1%-3.7%). The stratification scheme also identified LBBB patients with QRSd <150 ms with comparable outcomes to LBBB patients with QRSd ≥150 ms (HR: 0.93, 95% CI: 0.67-1.29; difference in mean LVEF change: -0.2%, 95% CI: -2.7%-3.0%).- Unsupervised machine learning of ECG waveforms identified CRT subgroups with relevance beyond LBBB and QRSd. This method may assist in objective classification of bundle branch block morphology in CRT.



Circ Arrhythm Electrophysiol: 13 Jun 2020; epub ahead of print
Feeny AK, Rickard J, Trulock KM, Patel D, ... Madabhushi A, Chung MK
Circ Arrhythm Electrophysiol: 13 Jun 2020; epub ahead of print | PMID: 32538136
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Abstract

Preclinical evidence for the therapeutic value of TBX5 normalization in arrhythmia control.

Rathjens FS, Blenkle A, Iyer LM, Renger A, ... Zelarayan LC, Zafeiriou MP
Aims
Arrhythmias and sudden cardiac death (SCD) occur commonly in patients with heart failure. We found T-box 5 (TBX5) dysregulated in ventricular myocardium from heart failure patients and thus we hypothesized that TBX5 reduction contributes to arrhythmia development in these patients. To understand the underlying mechanisms, we aimed to reveal the ventricular TBX5-dependent transcriptional network and further test the therapeutic potential of TBX5 level normalization in mice with documented arrhythmias.
Methods and results
We used a mouse model of TBX5 conditional deletion in ventricular cardiomyocytes. Ventricular (v) TBX5 loss in mice resulted in mild cardiac dysfunction and arrhythmias and was associated with a high mortality rate (60%) due to SCD. Upon angiotensin stimulation, vTbx5KO mice showed exacerbated cardiac remodelling and dysfunction suggesting a cardioprotective role of TBX5. RNA sequencing of a ventricular specific TBX5KO mouse and TBX5 chromatin immunoprecipitation were used to dissect TBX5 transcriptional network in cardiac ventricular tissue. Overall, we identified 47 transcripts expressed under the control of TBX5, which may have contributed to the fatal arrhythmias in vTbx5KO mice. These included transcripts encoding for proteins implicated in cardiac conduction and contraction (Gja1, Kcnj5, Kcng2, Cacna1g, Chrm2), in cytoskeleton organization (Fstl4, Pdlim4, Emilin2, Cmya5), and cardiac protection upon stress (Fhl2, Gpr22, Fgf16). Interestingly, after TBX5 loss and arrhythmia development in vTbx5KO mice, TBX5 protein level normalization by systemic adeno-associated-virus (AAV) 9 application, re-established TBX5-dependent transcriptome. Consequently, cardiac dysfunction was ameliorated and the propensity of arrhythmia occurrence was reduced.
Conclusions
This study uncovers a novel cardioprotective role of TBX5 in the adult heart and provides preclinical evidence for the therapeutic value of TBX5 protein normalization in the control of arrhythmia.
Translational perspective
Cardiovascular disease (CVD) is the number one cause of death worldwide (WHO factsheets 09/2016). Although more than 60% of CVD-related deaths are due to out-of-hospital sudden cardiac death (SCD), we have little insight in the mechanisms underlying SCD pathophysiology. Our data show a link between TBX5 dysregulation and arrhythmia occurrence in patients. To test the therapeutic potential of TBX5, we normalized TBX5 levels in a mouse model with TBX5 dysregulation, which developed arrhythmias and SCD. TBX5 normalization re-established TBX5 target gene expression and more importantly, rescued the arrhythmia phenotype. Altogether, we provide proof-of-concept for the therapeutic potential of TBX5 expression restoration against arrhythmia and SCD.

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

Cardiovasc Res: 09 Aug 2020; epub ahead of print
Rathjens FS, Blenkle A, Iyer LM, Renger A, ... Zelarayan LC, Zafeiriou MP
Cardiovasc Res: 09 Aug 2020; epub ahead of print | PMID: 32777030
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Abstract

Self-reported snoring patterns predict stroke events in high-risk patients with obstructive sleep apnea: post-hoc analyses of the SAVE study.

Li J, McEvoy RD, Zheng D, Loffler KA, ... Woodman RJ, Anderson CS
Background
The relation of snoring to risks of stroke and other major cardiovascular (CV) events is uncertain.
Research question
We aimed to determine associations of snoring patterns and major CV events in relation to the obstructive sleep apnea (OSA), among participants of the international Sleep Apnea cardiovascular Endpoints (SAVE) trial.
Study design
and Methods: Post-hoc analyses of the SAVE trial, which involved 2687 patients with co-existing moderate-severe OSA and established coronary or cerebral CV disease, who were randomly allocated to continuous positive airway pressure (CPAP) treatment plus usual care or usual care alone, and followed up for a median 3.5 years. Associations of self-reported snoring patterns (frequency and loudness) and breathing pauses collected on the Berlin questionnaire at baseline and multiple times during follow-up, and adjudicated composites of CV outcomes (primary, CV death, non-fatal myocardial infarction, non-fatal stroke, and hospitalization for unstable angina, heart failure, or transient ischemic attack; and separately of cardiac and cerebral events), were evaluated in time-dependent Cox proportional hazards models adjusted for various confounders including apnea-hypopnea index.
Results
Increase (per category) of snoring frequency (adjusted hazard ratio [HR] 1.10, 95% confidence interval [CI] 1.02-1.20; P=0.015), loudness (HR 1.16, 95% CI 1.06-1.27; P=0.001), and breathing pauses (HR 1.16, 95% CI 1.08-1.25; P<0.001) at any timepoint during follow-up were each associated with the primary composite CV outcome. These associations were driven by significant associations for cerebral rather than cardiac events, and positive interactions between the three snoring patterns for cerebral events. There is no significant interaction between CPAP treatment and snoring variables for cerebral events.
Interpretation
Snoring in OSA patients with established CV disease is associated with greater risks of cerebral but not cardiac events, independent of CPAP treatment and frequency of apnea and hypopnea events.
Clinical trial registration
The trial is registered at ClinicalTrials.gov (NCT00738179).

Copyright © 2020. Published by Elsevier Inc.

Chest: 13 Jul 2020; epub ahead of print
Li J, McEvoy RD, Zheng D, Loffler KA, ... Woodman RJ, Anderson CS
Chest: 13 Jul 2020; epub ahead of print | PMID: 32679238
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Abstract

Low prognostic value of novel nocturnal oxygen saturation metrics in patients with obstructive sleep apnea and high cardiovascular event risk: post-hoc analyses of the SAVE study.

Linz D, Loffler KA, Sanders P, Catcheside P, ... Baumert M,
Background
Traditional methods for quantifying obstructive sleep apnea (OSA) severity may not encapsulate potential relationships between hypoxaemia in OSA and cardiovascular (CV) risk.
Research question
Do novel nocturnal oxygen saturation metrics have prognostic value in patients with OSA and high cardiovascular event risk?
Study design
Post-hoc analyses of the Sleep Apnea CV Endpoints (SAVE) trial.
Methods
In 2687 individuals, Cox proportional hazards models stratified for treatment allocation were used to determine the associations between clinical characteristics, pulse oximetry-derived metrics designed to quantify sustained and episodic features of hypoxaemia, and CV outcomes. Metrics included: oxygen desaturation index, time <90% oxygen saturation (SpO), average SpO for the entire recording (mean SpO); average SpO during desaturation events (desaturation SpO); average baseline SpO interpolated across episodic desaturation events (baseline SpO); episodic desaturation event duration and desaturation/resaturation-time ratio; mean and standard deviation of pulse rate.
Results
Neither AHI, ODI nor any of the novel SpO metrics were associated with the primary SAVE composite CV outcome. Mean and baseline SpO were associated with heart failure (hazard ratio [HR] 0.81, 95% confidence interval [CI] 0.69-0.95; P=0.009 and HR 0.78, 95% CI 0.67-0.90; P=0.001, respectively) and myocardial infarction (HR 0.86, 95% CI 0.77-0.95; P=0.003 and HR 0.81, 95% CI 0.73-0.90; P<0.001, respectively). Desaturation duration and desaturation/resaturation-time ratio, with established risk factors, predicted future heart failure (AUC 0.86, 95% CI 0.79-0.93).
Interpretation
AHI and ODI were not associated with CV outcomes. In contrast, the pattern of oxygen desaturation was associated with heart failure and myocardial infarction. However, concomitant risk factors remained the predominant determinants for secondary CV events and thus deserve the most intensive management.

Copyright © 2020. Published by Elsevier Inc.

Chest: 13 Jul 2020; epub ahead of print
Linz D, Loffler KA, Sanders P, Catcheside P, ... Baumert M,
Chest: 13 Jul 2020; epub ahead of print | PMID: 32679239
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