Journal: Circ Heart Fail

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Abstract

Assessment of Heterogeneity in Heart Failure-Related Meta-Analyses.

Khan MS, Li L, Yasmin F, Khan SU, ... Butler J, Vaduganathan M
Background
Assessment of heterogeneity in meta-analyses is critical to ensure the consistency of pooled results. Therefore, we sought to assess the evaluation and reporting of heterogeneity in heart failure (HF) meta-analyses.
Methods
Study level meta-analyses pertaining to HF were selected from January 2009 to July 2019, published in 11 high impact factor journals. We tabulated the overall proportion of the meta-analyses reporting statistical heterogeneity and specific metrics and methods employed to quantify and explore heterogeneity.
Results
Of 126 HF meta-analyses (612 outcomes), heterogeneity was reported for 422 outcomes (68.9 %) in 108 meta-analyses. Out of the 422 outcomes reporting statistical heterogeneity, 137 outcomes (32.5%) had no observable heterogeneity: (=0%), 40 outcomes (9.5%) had low heterogeneity (<25%), 76 outcomes (18%) had moderate heterogeneity (=25%-50%), and 169 outcomes (40%) had high heterogeneity (>50%). Reporting of statistical heterogeneity was not significantly associated with year of publication, funding source, disclosure information, or the type of studies pooled. Sensitivity analysis (n=68) was the most common statistical technique employed to evaluate the source of heterogeneity followed by subgroup analyses (n=59) and meta-regression (n=40).
Conclusions
Despite being an essential component of meta-analyses, heterogeneity was not reported for nearly 30% of outcomes and variably handled in contemporary HF meta-analyses. As meta-analyses increase across HF science, interpreting and handling of heterogeneity should be standardized.



Circ Heart Fail: 01 Nov 2020:CIRCHEARTFAILURE120007070; epub ahead of print
Khan MS, Li L, Yasmin F, Khan SU, ... Butler J, Vaduganathan M
Circ Heart Fail: 01 Nov 2020:CIRCHEARTFAILURE120007070; epub ahead of print | PMID: 33131285
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Abstract

Durable Mechanical Circulatory Support in Patients with Amyloid Cardiomyopathy: Insights from INTERMACS.

Michelis KC, Zhong L, Tang WHW, Young JB, ... Maurer MS, Grodin JL

: Many patients with amyloid cardiomyopathy (ACM) develop advanced heart failure, and durable mechanical circulatory support (MCS) may be a consideration. However, data describing clinical outcomes after MCS in this population is limited. : Adult patients in the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) with dilated cardiomyopathy (DCM, n=19,921), non-amyloid restrictive cardiomyopathy (RCM, n=248), or ACM (n=46) between 2005 and 2017 were included. Patient and device characteristics were compared between cardiomyopathy groups. The primary endpoint was the cumulative incidence of death with heart transplantation as a competing risk. : Patients with ACM (n=46) were older (61 years [IQR 55-69 years] versus 58 years [IQR 49-66 years] for DCM and 55 years [IQR 46-62 years] for non-amyloid RCM, p<0.001) and INTERMACS profile 1 (30.4% versus 17.9% for DCM and 21.0% for non-amyloid RCM, p=0.04) at device implantation. Use of biventricular support (biventricular assist device or total artificial heart) was highest for ACM patients (41.3% versus 6.7% and 19.4% for DCM and non-amyloid RCM patients, respectively, p=0.014). The cumulative incidence of death was highest for patients with ACM than with DCM or non-amyloid RCM (p<0.001) but did not differ significantly between groups for those who required biventricular MCS. : Compared to DCM or non-amyloid RCM patients who received durable MCS, those with ACM experienced the highest use of biventricular support and the worst survival. These data highlight concerns with the use of durable MCS for ACM patients.



Circ Heart Fail: 08 Nov 2020; epub ahead of print
Michelis KC, Zhong L, Tang WHW, Young JB, ... Maurer MS, Grodin JL
Circ Heart Fail: 08 Nov 2020; epub ahead of print | PMID: 33164568
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Abstract

Patient Characteristics, Clinical Outcomes, and Effect of Dapagliflozin in Relation to Duration of Heart Failure: Is It Ever Too Late to Start a New Therapy?

Yeoh SE, Dewan P, Jhund PS, Inzucchi SE, ... Langkilde AM, McMurray JJ

: The impact of heart failure (HF) duration on outcomes and treatment effect is largely unknown. We aim to compare baseline patient characteristics, outcomes and the efficacy and safety of dapagliflozin, in relation to time from diagnosis of HF in DAPA-HF. : HF duration was categorized as ≥2 to ≤12 months, >1-2 years, >2-5 years and >5 years. Outcomes were adjusted for prognostic variables and analyzed using Cox regression. The primary endpoint was the composite of worsening HF or cardiovascular death. Treatment effect was examined within each duration category and by duration threshold. : The number of patients in each category was: 1098 (≥2 to ≤12 months), 686 (>1-2 years), 1105 (>2-5 years) and 1855 (>5 years). Longer-duration HF patients were older and more comorbid with worse symptoms. The rate of the primary outcome (per 100 person-years) increased with HF duration: 10.2 (95% CI 8.7-12.0) for ≥2 to ≤12 months, 10.6 (8.7-12.9) >1-2 years, 15.5 (13.6-17.7) >2-5 years and 15.9 (14.5-17.6) for >5 years. Similar trends were seen for all other outcomes. The benefit of dapagliflozin was consistent across HF duration and on threshold analysis. The hazard ratio for the primary outcome ≥2 to ≤12 months was 0.86 (0.63-1.18), >1-2 years 0.95 (0.64-1.42), >2-5 years 0.74 (0.57-0.96) and >5 years 0.64 (0.53-0.78), P-interaction=0.26. The absolute benefit was greatest in longest duration HF, with a number needed-to-treat of 18 for HF >5 years, compared with 28 for ≥2 to ≤12 months. : Longer-duration HF patients were older, had more comorbidity and symptoms, and higher rates of worsening HF and death. The benefits of dapagliflozin were consistent across HF duration. : ClinicalTrials.gov; Unique identifier: NCT03036124.



Circ Heart Fail: 08 Nov 2020; epub ahead of print
Yeoh SE, Dewan P, Jhund PS, Inzucchi SE, ... Langkilde AM, McMurray JJ
Circ Heart Fail: 08 Nov 2020; epub ahead of print | PMID: 33164553
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Abstract

Excess 30-Day Heart Failure Readmissions and Mortality in Black Patients Increases with Neighborhood Deprivation.

Patel SA, Krasnow M, Long K, Shirey T, Dickert N, Morris AA

: Longstanding racial disparities in heart failure (HF) outcomes exist in the United States, in part due to social determinants of health. We examined whether neighborhood environment modifies the disparity in 30-d HF readmissions and mortality between Black and White patients in the Southeastern US. : We created a geo-coded retrospective cohort of patients hospitalized for acute HF (AHF) within Emory Healthcare from 2010-2018. Quartiles of the Social Deprivation Index (SDI) characterized neighborhood deprivation at the census tract level. We estimated the relative risk of 30-d readmission and 30-d mortality following an index hospitalization for AHF. \"Excess\" readmissions and mortality were estimated as the absolute risk difference between Black and White patients within each SDI quartile, adjusted for geographical clustering, demographic, clinical, and hospital characteristics. : The cohort included 30,630 patients, mean age 66 years, 48% female, 53% Black. Compared with White patients, Black patients were more likely to reside in deprived census tracts, and have higher comorbidity scores. From 2010 to 2018, 29.4% of Black and 23.0% of White patients experienced either a 30-d HF readmission or 30-d death (p<0.001). Excess in composite 30-d HF readmissions and mortality for Black patients ranged from 3.9% (95%CI: 1.5%-6.3%; P=0.0002) to 6.8% (95%CI: 4.1% -9.5%; P<0.0001) across SDI quartiles. Accounting for traditional risk factors did not eliminate the Black excess in combined 30-d HF readmissions and/or mortality in any of the neighborhood quartiles. : Excess 30-d HF readmissions and mortality are present among Black patients in every neighborhood strata, and increase with progressive neighborhood socioeconomic deprivation.



Circ Heart Fail: 08 Nov 2020; epub ahead of print
Patel SA, Krasnow M, Long K, Shirey T, Dickert N, Morris AA
Circ Heart Fail: 08 Nov 2020; epub ahead of print | PMID: 33161734
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Abstract

Transcatheter Mitral Valve Repair in Patients With and Without Cardiac Resynchronization Therapy: The COAPT Trial.

Kosmidou I, Lindenfeld J, Abraham WT, Kar S, ... Mack MJ, Stone GW
Background
In the COAPT trial (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation), treatment of heart failure (HF) patients with moderate-severe or severe secondary mitral regurgitation with transcatheter mitral valve repair (TMVr) using the MitraClip plus guideline-directed medical therapy (GDMT) reduced 2-year rates of HF hospitalization and all-cause mortality compared with GDMT alone. Whether the benefits of the MitraClip extend to patients with previously implanted cardiac resynchronization therapy (CRT) is unknown. We sought to examine the effect of prior CRT in patients enrolled in COAPT.
Methods
Patients (N=614) with moderate-severe or severe secondary mitral regurgitation who remained symptomatic despite maximally tolerated doses of GDMT were randomized 1:1 to the MitraClip (TMVr arm) versus GDMT only (control arm). Outcomes were assessed according to prior CRT use.
Results
Among 614 patients, 224 (36.5%) had prior CRT (115 and 109 randomized to TMVr and control, respectively) and 390 (63.5%) had no CRT (187 and 203 randomized to TMVr and control, respectively). Patients with CRT had similar 2-year rates of the composite of death or HF hospitalization compared with those without CRT (57.6% versus 55%, =0.32). Death or HF hospitalization at 2 years was lower with TMVr versus control treatment in patients with prior CRT (48.6% versus 67.2%, hazard ratio, 0.60 [95% CI, 0.42-0.86]) and without CRT (42.5% versus 66.9%, hazard ratio, 0.52 [95% CI, 0.39-0.69]; adjusted =0.23). The effects of TMVr with the MitraClip on reducing the 2-year rates of all-cause death (adjusted =0.14) and HF hospitalization (adjusted =0.82) were also consistent in patients with and without CRT as were improvements in quality-of-life and exercise capacity.
Conclusions
In the COAPT trial, TMVr with the MitraClip improved the 2-year prognosis of patients with HF and moderate-severe or severe secondary mitral regurgitation who remained symptomatic despite maximally tolerated GDMT, regardless of prior CRT implantation.
Registration
URL: https://www.clinicaltrials.gov. Unique identifier: NCT01626079.



Circ Heart Fail: 11 Nov 2020:CIRCHEARTFAILURE120007293; epub ahead of print
Kosmidou I, Lindenfeld J, Abraham WT, Kar S, ... Mack MJ, Stone GW
Circ Heart Fail: 11 Nov 2020:CIRCHEARTFAILURE120007293; epub ahead of print | PMID: 33176460
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Abstract

Heart Failure and Shared Decision-Making: Patients Open to Medication-Related Cost Discussions.

Rao BR, Dickert NW, Morris AA, Speight CD, ... Shore S, Moore MA
Background
Discussions of medication costs between patients and clinicians are infrequent and often suboptimal. In the context of recently introduced drugs that are effective but expensive, patients with heart failure with reduced ejection fraction provide an ideal population to understand the perspectives of patients with chronic illness on medication cost and cost discussions.
Methods
To explore patients\' perspectives on discussing out-of-pocket medication costs with clinicians, 49 adults, aged 44 to 70 years, with heart failure with reduced ejection fraction were recruited from outpatient heart failure clinics. Descriptive qualitative analysis was performed on open-ended text data.
Results
Participants who had prior medication-related cost discussions described their experience as generally positive, but about half of the participants had never had a cost discussion with their clinician. Most participants were open to cost discussions with clinicians and preferred that the clinician initiate discussions regarding medication cost. Importantly, these preferences held constant across reported levels of financial burden.
Conclusions
These data suggest a substantial willingness on the part of patients with heart failure with reduced ejection fraction to incorporate cost discussions into their care and identify important aspects of these discussions for clinicians to consider when engaging in conversations where cost is relevant. Improving understanding about how to integrate patient preferences regarding cost discussions into clinical encounters is an important priority for advancing patient-centered care.



Circ Heart Fail: 11 Nov 2020:CIRCHEARTFAILURE120007094; epub ahead of print
Rao BR, Dickert NW, Morris AA, Speight CD, ... Shore S, Moore MA
Circ Heart Fail: 11 Nov 2020:CIRCHEARTFAILURE120007094; epub ahead of print | PMID: 33176459
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Abstract

Management of Acute Myocarditis and Chronic Inflammatory Cardiomyopathy: An Expert Consensus Document.

Ammirati E, Frigerio M, Adler ED, Basso C, ... Cooper LT, Camici PG

Myocarditis is an inflammatory disease of the heart that may occur because of infections, immune system activation, or exposure to drugs. The diagnosis of myocarditis has changed due to the introduction of cardiac magnetic resonance imaging. We present an expert consensus document aimed to summarize the common terminology related to myocarditis meanwhile highlighting some areas of controversies and uncertainties and the unmet clinical needs. In fact, controversies persist regarding mechanisms that determine the transition from the initial trigger to myocardial inflammation and from acute myocardial damage to chronic ventricular dysfunction. It is still uncertain which viruses (besides enteroviruses) cause direct tissue damage, act as triggers for immune-mediated damage, or both. Regarding terminology, myocarditis can be characterized according to etiology, phase, and severity of the disease, predominant symptoms, and pathological findings. Clinically, acute myocarditis (AM) implies a short time elapsed from the onset of symptoms and diagnosis (generally <1 month). In contrast, chronic inflammatory cardiomyopathy indicates myocardial inflammation with established dilated cardiomyopathy or hypokinetic nondilated phenotype, which in the advanced stages evolves into fibrosis without detectable inflammation. Suggested diagnostic and treatment recommendations for AM and chronic inflammatory cardiomyopathy are mainly based on expert opinion given the lack of well-designed contemporary clinical studies in the field. We will provide a shared and practical approach to patient diagnosis and management, underlying differences between the European and US scientific statements on this topic. We explain the role of histology that defines subtypes of myocarditis and its prognostic and therapeutic implications.



Circ Heart Fail: 11 Nov 2020:CIRCHEARTFAILURE120007405; epub ahead of print
Ammirati E, Frigerio M, Adler ED, Basso C, ... Cooper LT, Camici PG
Circ Heart Fail: 11 Nov 2020:CIRCHEARTFAILURE120007405; epub ahead of print | PMID: 33176455
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Abstract

Effects of Omecamtiv Mecarbil on Symptoms and Health-Related Quality of Life in Patients with Chronic Heart Failure: Results from the COSMIC-HF Study.

Felker GM, Solomon SD, McMurray JJV, Cleland JGF, ... Teerlink JR,

: Chronic HF with reduced ejection fraction (HFrEF) impairs health related quality of life (HRQL). Omecamtiv mecarbil, a novel activator of cardiac myosin, improves left ventricular systolic function and remodeling and reduces natriuretic peptides. We sought to evaluate the effect of omecamtiv mecarbil on symptoms and HRQL in patients with chronic HFrEF and elevated natriuretic peptides enrolled in the COSMIC-HF trial. : Patients (n = 448) were randomized 1:1:1 to placebo, 25 mg of omecamtiv mecarbil twice daily (OM 25 mg), or to pharmacokinetically-guided dose titration (OM-PK) for 20 weeks. The Kansas City Cardiomyopathy Questionnaire (KCCQ) was administered to assess HRQL at baseline, 16 weeks, and 20 weeks. The primary scores of interest were the Total Symptom Score (TSS), Physical Limitation Scale (PLS), and Clinical Summary Score (CSS). : Mean change in score from baseline to 20 weeks for the TSS was 5.0 (95%CI: 1.8-8.1) for placebo, 6.6(95%CI: 3.4-9.8) for OM 25 mg (p = 0.32 vs placebo), and 9.9 (95%CI: 6.7-13.0) for OM-PK (p = 0.03 vs placebo); for the PLS, it was 3.1 for placebo (95%CI: -0.3-6.6), 6.0 (95%CI: 3.1-8.9) for OM 25 mg (p=0.12), and 4.3 (95%CI: 0.7-7.9) for OM-PK (p=0.42); for the CSS, it was 4.1 (95%CI: 1.4-6.9) for placebo, 6.3 (95%CI: 3.6-9.0) for OM 25 mg (p=0.19), and 7.0 (95%CI: 4.1-10.0) for OM-PK (p=0.14). Differences between omecamtiv mecarbil and placebo were greater in patients who were more symptomatic at baseline. : HRQL as measured by the TSS improved in patients with HFrEF assigned to omecamtiv mecarbil (OM-PK group) relative to placebo. Ongoing trials are prospectively testing whether omecamtiv mecarbil improves symptoms and HRQL in HFrEF. : clinicaltrials.gov; Unique Identifier: NCT01786512.



Circ Heart Fail: 11 Nov 2020; epub ahead of print
Felker GM, Solomon SD, McMurray JJV, Cleland JGF, ... Teerlink JR,
Circ Heart Fail: 11 Nov 2020; epub ahead of print | PMID: 33176437
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Abstract

Myocardial Tissue Reverse Remodeling after Guideline-directed Medical Therapy in Idiopathic Dilated Cardiomyopathy.

Xu Y, Li W, Wan K, Liang Y, ... Han Y, Chen Y

- The prognosis of idiopathic dilated cardiomyopathy (DCM) patients has improved remarkably in recent decades with guideline-directed medical therapy (GDMT). Left ventricular reverse remodeling (LVRR) is one of the major therapeutic goals. Whether myocardial fibrosis or inflammation would reverse associated with LVRR remains unknown.- A total of 157 prospectively enrolled DCM patients underwent baseline and follow-up CMR examinations with a median interval of 13.7 months (interquartile range: 12.2-18.5 months). LVRR was defined as an absolute increase in LV ejection fraction (LVEF) of >10% to the final value of ≥ 35% and a relative decrease in LV end-diastolic volume (EDV) of >10%. Statistical analyses were performed using paired t-test and student t-test, logistic regression analysis, and linear regression analysis.- Forty-eight (31%) patients reached LVRR. At baseline, younger age, worse NYHA class, new-onset heart failure, lower LVEF, absence of late gadolinium enhancement (LGE), lower myocardial T2, and extracellular volume (ECV) were significant predictors of LVRR. During the follow-up, patients with and without LVRR both showed a significant decrease of myocardial native T1 (LVRR: [baseline]1303.0±43.6ms; [follow-up]1244.7±51.8ms; without LVRR: [baseline]1308.5±80.5ms; [follow-up]1287.6±74.9ms, both p < 0.001), matrix and cellular volumes while no significant difference was observed in T2 or ECV values after treatment.- In idiopathic DCM patients, the absence of LGE, lower T2, and ECV values at baseline are significant predictors of LVRR. The myocardial T1, matrix, and cell volume decrease significantly in patients with LVRR after GDMT.



Circ Heart Fail: 12 Nov 2020; epub ahead of print
Xu Y, Li W, Wan K, Liang Y, ... Han Y, Chen Y
Circ Heart Fail: 12 Nov 2020; epub ahead of print | PMID: 33185117
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Abstract

Polypharmacy in Older Adults Hospitalized for Heart Failure.

Unlu O, Levitan EB, Reshetnyak E, Kneifati-Hayek J, ... Lachs MS, Goyal P
Background
Despite potential harm that can result from polypharmacy, real-world data on polypharmacy in the setting of heart failure (HF) are limited. We sought to address this knowledge gap by studying older adults hospitalized for HF derived from the REGARDS study (Reasons for Geographic and Racial Differences in Stroke).
Methods
We examined 558 older adults aged ≥65 years with adjudicated HF hospitalizations from 380 hospitals across the United States. We collected and examined data from the REGARDS baseline assessment, medical charts from HF-adjudicated hospitalizations, the American Hospital Association annual survey database, and Medicare\'s Hospital Compare website. We counted the number of medications taken at hospital admission and discharge; and classified each medication as HF-related, non-HF cardiovascular-related, or noncardiovascular-related.
Results
The vast majority of participants (84% at admission and 95% at discharge) took ≥5 medications; and 42% at admission and 55% at discharge took ≥10 medications. The prevalence of taking ≥10 medications (polypharmacy) increased over the study period. As the number of total medications increased, the number of noncardiovascular medications increased more rapidly than the number of HF-related or non-HF cardiovascular medications.
Conclusions
Defining polypharmacy as taking ≥10 medications might be more ideal in the HF population as most patients already take ≥5 medications. Polypharmacy is common both at admission and hospital discharge, and its prevalence is rising over time. The majority of medications taken by older adults with HF are noncardiovascular medications. There is a need to develop strategies that can mitigate the negative effects of polypharmacy among older adults with HF.



Circ Heart Fail: 30 Oct 2020; 13:e006977
Unlu O, Levitan EB, Reshetnyak E, Kneifati-Hayek J, ... Lachs MS, Goyal P
Circ Heart Fail: 30 Oct 2020; 13:e006977 | PMID: 33045844
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Abstract

How Patients With Heart Failure Perform Daily Life Activities: An Innate Energy-Saving Strategy.

Mapelli M, Salvioni E, Bonomi A, Gugliandolo P, ... Berna G, Agostoni P
Background
Cardiopulmonary exercise test and 6-minute walking test are frequently used tools to evaluate physical performance in heart failure (HF), but they do neither represent activities of daily living (ADLs) nor fully reproduce patients\' symptoms. We assessed differences in task oxygen uptake, both as absolute value and as percentage of peak oxygen consumption (peakVO), ventilation efficiency (VE/VCO ratio), and dyspnea intensity (Borg scale) in HF and healthy subjects during standard ADLs and other common physical actions.
Methods
Healthy and HF subjects (ejection fraction <45%, stable conditions) underwent cardiopulmonary exercise test. All of them, carrying a wearable metabolic cart, performed a 6-minute walking test, two 4-minute treadmill exercises (at 2 and 3 km/h), and ADLs: ADL1 (getting dressed), ADL2 (folding 8 towels), ADL3 (putting away 6 bottles), ADL4 (making a bed), ADL5 (sweeping the floor for 4 minutes), ADL6 (climbing 1 flight of stairs carrying a load).
Results
Sixty patients with HF (age 65.2±12.1 years; ejection fraction 30.4±6.7%, peakVO 14.2±4.0 mL/[min·kg]) and 40 healthy volunteers (58.9±8.2 years, peakVO 28.1±7.4 mL/[min·kg]) were enrolled. For each exercise, patients showed higher VE/VCO ratio, percentage of peakVO, and Borg scale value than controls, while absolute values of task oxygen uptake and exercise duration were lower and higher, respectively, in all activities, except for treadmill (fixed execution time and intensity). Differently from Borg Scale data, metabolic values and exercise time length changed in parallel with HF severity, except for ADL duration in very short (ADL3) and composite (ADL1) activities. Borg scale values correlated with percentage of peakVO.
Conclusions
During ADLs, patients self-regulated activities in parallel with HF severity by decreasing intensity (VO) and prolonging the effort.



Circ Heart Fail: 30 Oct 2020; 13:e007503
Mapelli M, Salvioni E, Bonomi A, Gugliandolo P, ... Berna G, Agostoni P
Circ Heart Fail: 30 Oct 2020; 13:e007503 | PMID: 33201750
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Abstract

Racial and Ethnic Differences in Biomarkers, Health Status, and Cardiac Remodeling in Patients With Heart Failure With Reduced Ejection Fraction Treated With Sacubitril/Valsartan.

Ibrahim NE, Piña IL, Camacho A, Bapat D, ... Januzzi JL,
Background
Among patients with heart failure and reduced ejection fraction (left ventricular (LV) ejection fraction ≤40%), sacubitril/valsartan (S/V) treatment is associated with improved health status and reverse cardiac remodeling. Data regarding racial and ethnic differences in response to S/V are lacking.
Methods
This was an analysis from the PROVE-HF study (Prospective Study of Biomarkers, Symptom Improvement and Ventricular Remodeling During Entresto Therapy for Heart Failure). Longitudinal changes in NT-proBNP (N-terminal pro-B-type natriuretic peptide), cardiac reverse remodeling, and health status scores were compared between groups using multivariate latent growth curve modeling.
Results
Among the 782 patients included in this study, 22.7% were non-Hispanic Black (from here referred to as Black), 14.9% were Hispanic, and 62.4% were non-Hispanic White (from here referred to as White). At baseline, compared with White patients, Black and Hispanic patients had lower NT-proBNP (=0.34) and differences between groups in baseline values for LV end-diastolic volume index and LV end-systolic volume index were negligible (<0.10). Following S/V initiation, NT-proBNP decreased in all 3 groups (<0.0001) associated with improvements in LV ejection fraction, LV end-diastolic volume index, and LV end-systolic volume index. Although total improvement in LV measures was similar between groups, Black patients averaged larger gains in the first half of the trial while White patients averaged larger gains in the second half. Improvements in Kansas City Cardiomyopathy Questionnaire-23 Total Symptom scores were seen in all 3 groups. Treatment with S/V was well-tolerated.
Conclusions
Among Black, Hispanic, and White patients with heart failure and reduced ejection fraction, treatment with S/V was associated with similar reduction in NT-proBNP, improvement in health status, and reverse remodeling. More data regarding racial and ethnic responses to heart failure and reduced ejection fraction treatment are needed. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02887183.



Circ Heart Fail: 30 Oct 2020; 13:e007829
Ibrahim NE, Piña IL, Camacho A, Bapat D, ... Januzzi JL,
Circ Heart Fail: 30 Oct 2020; 13:e007829 | PMID: 33016100
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Abstract

Association of Sedentary Time and Incident Heart Failure Hospitalization in Postmenopausal Women.

LaMonte MJ, Larson JC, Manson JE, Bellettiere J, ... Wactawski-Wende J, Eaton CB
Background
The 2018 US Physical Activity Guidelines recommend reducing sedentary behavior (SB) for cardiovascular health. SB\'s role in heart failure (HF) is unclear.
Methods
We studied 80 982 women in the Women\'s Health Initiative Observational Study, aged 50 to 79 years, who were without known HF and reported ability to walk ≥1 block unassisted at baseline. Mean follow-up was 9 years for physician-adjudicated incident HF hospitalization (1402 cases). SB was assessed repeatedly by questionnaire. Time-varying total SB was categorized according to awake time spent sitting or lying down (≤6.5, 6.6-9.5, >9.5 h/d); sitting time (≤4.5, 4.6-8.5, >8.5 h/d) was also evaluated. Hazard ratios and 95% CI were estimated using Cox regression.
Results
Controlling for age, race/ethnicity, education, income, smoking, alcohol, menopausal hormone therapy, and hysterectomy status, higher HF risk was observed across incremental tertiles of time-varying total SB (hazard ratios [95% CI], 1.00 [referent], 1.15 [1.01-1.31], 1.42 [1.25-1.61], trend <0.001) and sitting time (1.00 [referent], 1.14 [1.01-1.28], 1.54 [1.34-1.78], trend <0.001). The inverse trends remained significant after further controlling for comorbidities including time-varying myocardial infarction and coronary revascularization (hazard ratios: SB, 1.00, 1.11, 1.27; sitting, 1.00, 1.09, 1.37, trend <0.001 each) and for baseline physical activity (hazard ratios: SB 1.00, 1.10, 1.24; sitting 1.00, 1.08, 1.33, trend <0.001 each). Associations with SB exposures were not different according to categories of baseline age, race/ethnicity, body mass index, physical activity, physical functioning, diabetes, hypertension, or coronary heart disease.
Conclusions
SB was associated with increased risk of incident HF hospitalization in postmenopausal women. Targeted efforts to reduce SB could enhance HF prevention in later life.



Circ Heart Fail: 23 Nov 2020:CIRCHEARTFAILURE120007508; epub ahead of print
LaMonte MJ, Larson JC, Manson JE, Bellettiere J, ... Wactawski-Wende J, Eaton CB
Circ Heart Fail: 23 Nov 2020:CIRCHEARTFAILURE120007508; epub ahead of print | PMID: 33228398
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Abstract

Association Between β-Blocker Use and Mortality/Morbidity in Patients With Heart Failure With Reduced, Midrange, and Preserved Ejection Fraction and Advanced Chronic Kidney Disease.

Fu EL, Uijl A, Dekker FW, Lund LH, Savarese G, Carrero JJ
Background
It is unknown if β-blockers reduce mortality/morbidity in patients with heart failure (HF) and advanced chronic kidney disease (CKD), a population underrepresented in HF trials.
Methods
Observational cohort of HF patients with advanced CKD (estimated glomerular filtration rate <30 mL/min per 1.73 m) from the Swedish Heart Failure Registry between 2001 and 2016. We first explored associations between β-blocker use, 5-year death, and the composite of cardiovascular death/HF hospitalization among 3775 patients with HF with reduced ejection fraction (HFrEF) and advanced CKD. We compared observed hazards with those from a control cohort of 15 346 patients with HFrEF and moderate CKD (estimated glomerular filtration rate <60-30 mL/min per 1.73 m), for whom β-blocker trials demonstrate benefit. Second, we explored outcomes associated to β-blocker among advanced CKD participants with preserved (HFpEF; N=2009) and midrange ejection fraction (HFmrEF; N=1514).
Results
During a median follow-up of 1.3 years, 2012 patients had a subsequent HF hospitalization, and 2849 died in the HFrEF cohort, of which 2016 died due to cardiovascular causes. Among patients with HFrEF, β-blocker use was associated with lower risk of death (adjusted hazard ratio 0.85 [95% CI, 0.75-0.96]) and cardiovascular mortality/HF hospitalization (0.87 [0.77-0.98]) compared with nonuse. The magnitude of the associations was similar to that observed for HFrEF patients with moderate CKD. Conversely, no significant association was observed for β-blocker users in advanced CKD with HFpEF (death: 0.88 [0.77-1.02], cardiovascular mortality/HF hospitalization: 1.05 [0.90-1.23]) or HFmrEF (death: 0.95 [0.79-1.14], cardiovascular mortality/HF hospitalization: 1.09 [0.90-1.31]).
Conclusions
In HFrEF patients with advanced CKD, the use of β-blockers was associated with lower morbidity and mortality. Although inconclusive due to limited power, these benefits were not observed in similar patients with HFpEF or HFmrEF.



Circ Heart Fail: 30 Oct 2020; 13:e007180
Fu EL, Uijl A, Dekker FW, Lund LH, Savarese G, Carrero JJ
Circ Heart Fail: 30 Oct 2020; 13:e007180 | PMID: 33070637
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Abstract

Predictive Accuracy of Heart Failure-Specific Risk Equations in an Electronic Health Record-Based Cohort.

Bavishi A, Bruce M, Ning H, Freaney PM, ... Lloyd-Jones DM, Khan SS
Background
Guidelines recommend identification of individuals at risk for heart failure (HF). However, implementation of risk-based prevention strategies requires validation of HF-specific risk scores in diverse, real-world cohorts. Therefore, our objective was to assess the predictive accuracy of the Pooled Cohort Equations to Prevent HF within a primary prevention cohort derived from the electronic health record.
Methods
We retrospectively identified patients between the ages of 30 to 79 years in a multi-center integrated healthcare system, free of cardiovascular disease, with available data on HF risk factors, and at least 5 years of follow-up. We applied the Pooled Cohort Equations to Prevent HF tool to calculate sex and race-specific 5-year HF risk estimates. Incident HF was defined by thecodes. We assessed model discrimination and calibration, comparing predicted and observed rates for incident HF.
Results
Among 31 256 eligible adults, mean age was 51.4 years, 57% were women and 11% Black. Incident HF occurred in 568 patients (1.8%) over 5-year follow-up. The modified Pooled Cohort Equations to Prevent HF model for 5-year risk prediction of HF had excellent discrimination in White men (C-statistic 0.82 [95% CI, 0.79-0.86]) and women (0.82 [0.78-0.87]) and adequate discrimination in Black men (0.69 [0.60-0.78]) and women (0.69 [0.52-0.76]). Calibration was fair in all race-sex subgroups (χ<20).
Conclusions
A novel sex- and race-specific risk score predicts incident HF in a real-world, electronic health record-based cohort. Integration of HF risk into the electronic health record may allow for risk-based discussion, enhanced surveillance, and targeted preventive interventions to reduce the public health burden of HF.



Circ Heart Fail: 30 Oct 2020; 13:e007462
Bavishi A, Bruce M, Ning H, Freaney PM, ... Lloyd-Jones DM, Khan SS
Circ Heart Fail: 30 Oct 2020; 13:e007462 | PMID: 33092406
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Abstract

Altered Enhancer and Promoter Usage Leads to Differential Gene Expression in the Normal and Failed Human Heart.

Gacita AM, Dellefave-Castillo L, Page PGT, Barefield DY, ... Nobrega MA, McNally EM
Background
The failing heart is characterized by changes in gene expression. However, the regulatory regions of the genome that drive these gene expression changes have not been well defined in human hearts.
Methods
To define genome-wide enhancer and promoter use in heart failure, cap analysis of gene expression sequencing was applied to 3 healthy and 4 failed human hearts to identify promoter and enhancer regions used in left ventricles. Healthy hearts were derived from donors unused for transplantation and failed hearts were obtained as discarded tissue after transplantation.
Results
Cap analysis of gene expression sequencing identified a combined potential for ≈23 000 promoters and ≈5000 enhancers active in human left ventricles. Of these, 17 000 promoters and 1800 enhancers had additional support for their regulatory function. Comparing promoter usage between healthy and failed hearts highlighted promoter shifts which altered aminoterminal protein sequences. Enhancer usage between healthy and failed hearts identified a majority of differentially used heart failure enhancers were intronic and primarily localized within the first intron, revealing this position as a common feature associated with tissue-specific gene expression changes in the heart.
Conclusions
This data set defines the dynamic genomic regulatory landscape underlying heart failure and serves as an important resource for understanding genetic contributions to cardiac dysfunction. Additionally, regulatory changes contributing to heart failure are attractive therapeutic targets for controlling ventricular remodeling and clinical progression.



Circ Heart Fail: 29 Sep 2020; 13:e006926
Gacita AM, Dellefave-Castillo L, Page PGT, Barefield DY, ... Nobrega MA, McNally EM
Circ Heart Fail: 29 Sep 2020; 13:e006926 | PMID: 32993371
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Abstract

Clinical and Genetic Investigations of 109 Index Patients With Dilated Cardiomyopathy and 445 of Their Relatives.

Hey TM, Rasmussen TB, Madsen T, Aagaard MM, ... Eiskjær H, Mogensen J
Background
It was the aim to investigate the frequency and genetic basis of dilated cardiomyopathy (DCM) among relatives of index patients with unexplained heart failure at a tertiary referral center.
Methods
Clinical investigations were performed in 109 DCM index patients and 445 of their relatives. All index patients underwent genetic investigations of 76 disease-associated DCM genes. A family history of DCM occurred in 11% (n=12) while clinical investigations identified familial DCM in a total of 32% (n=35). One-fifth of all relatives (n=95) had DCM of whom 60% (n=57) had symptoms of heart failure at diagnosis, whereas 40% (n=38) were asymptomatic. Symptomatic relatives had a shorter event-free survival than asymptomatic DCM relatives (<0.001).
Results
Genetic investigations identified 43 pathogenic (n=27) or likely pathogenic (n=16) variants according to the American College of Medical Genetics and Genomics and the Association for Molecular Pathology criteria. Forty-four percent (n=48/109) of index patients carried a pathogenic/likely pathogenic variant of whom 36% (n=27/74) had sporadic DCM, whereas 60% (21/35) were familial cases. Thirteen of the pathogenic/likely pathogenic variants were also present in ≥7 affected individuals and thereby considered to be of sufficient high confidence for use in predictive genetic testing.
Conclusions
A family history of DCM identified only 34% (n=12/35) of hereditary DCM, whereas systematic clinical screening identified the remaining 66% (n=23) of DCM families. This emphasized the importance of clinical investigations to identify familial DCM. The high number of pathogenic/likely pathogenic variants identified in familial DCM provides a firm basis for offering genetic investigations in affected families. This should also be considered in sporadic cases since adequate family evaluation may not always be possible and the results of the genetic investigations may carry prognostic information with an impact on individual management.



Circ Heart Fail: 29 Sep 2020; 13:e006701
Hey TM, Rasmussen TB, Madsen T, Aagaard MM, ... Eiskjær H, Mogensen J
Circ Heart Fail: 29 Sep 2020; 13:e006701 | PMID: 33019804
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Abstract

How Big Is Too Big?: Donor Severe Obesity and Heart Transplant Outcomes.

Krebs ED, Beller JP, Mehaffey JH, Teman NR, ... Ailawadi G, Yarboro LT
Background
As the population becomes increasingly obese, so does the pool of potential organ donors. We sought to investigate the impact of donors with body mass index ≥40 (severe obesity) on heart transplant outcomes.
Methods
Single-organ first-time adult heart transplants from 2003 to 2017 were evaluated from the United Network for Organ Sharing database and stratified by donor severe obesity status (body mass index ≥40). Demographics were compared, and univariate and risk-adjusted analyses evaluated the relationship between severe obesity and short-term outcomes and long-term mortality. Further analysis evaluated the prevalence of severe obesity within the pool of organ donation candidates.
Results
A total of 26 532 transplants were evaluated, of which 939 (3.5%) had donors with body mass index ≥40, with prevalence increasing over time (2.2% in 2003, 5.3% in 2017). Severely obese donors more likely had diabetes mellitus (10.4% versus 3.1%, <0.01) and hypertension (33.3% versus 14.8%, <0.01), and 67.4% were size mismatched (donor weight >130% of recipient). Short-term outcomes were similar, including 1-year survival (10.6% versus 10.7%), with no significant difference in unadjusted and risk-adjusted long-term survival (log-rank =0.67, hazard ratio, 0.928, =0.30). Organ donation candidates also exhibited an increase in severe obesity over time, from 3.5% to 6.8%, with a lower proportion of hearts from severely obese donors being transplanted (19.5% versus 31.6%, <0.01).
Conclusions
Donor severe obesity was not associated with adverse post-transplant outcomes. Increased evaluation of hearts from obese donors, even those with body mass index ≥40, has the potential to expand the critically low donor pool.



Circ Heart Fail: 29 Sep 2020; 13:e006688
Krebs ED, Beller JP, Mehaffey JH, Teman NR, ... Ailawadi G, Yarboro LT
Circ Heart Fail: 29 Sep 2020; 13:e006688 | PMID: 32933324
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Abstract

Clinical Phenotypes and Prognosis of Dilated Cardiomyopathy Caused by Truncating Variants in the Gene.

Akhtar MM, Lorenzini M, Cicerchia M, Ochoa JP, ... Monserrat L, Elliott PM
Background
Truncating variants in thegene (TTNtv) are the commonest cause of heritable dilated cardiomyopathy. This study aimed to study the phenotypes and outcomes of TTNtv carriers.
Methods
Five hundred thirty-seven individuals (61% men; 317 probands) with TTNtv were recruited in 14 centers (372 [69%] with baseline left ventricular systolic dysfunction [LVSD]). Baseline and longitudinal clinical data were obtained. The primary end point was a composite of malignant ventricular arrhythmia and end-stage heart failure. The secondary end point was left ventricular reverse remodeling (left ventricular ejection fraction increase by ≥10% or normalization to ≥50%).
Results
Median follow-up was 49 (18-105) months. Men developed LVSD more frequently and earlier than women (45±14 versus 49±16 years, respectively; =0.04). By final evaluation, 31%, 45%, and 56% had atrial fibrillation, frequent ventricular ectopy, and nonsustained ventricular tachycardia, respectively. Seventy-six (14.2%) individuals reached the primary end point (52 [68%] end-stage heart failure events, 24 [32%] malignant ventricular arrhythmia events). Malignant ventricular arrhythmia end points most commonly occurred in patients with severe LVSD. Male sex (hazard ratio, 1.89 [95% CI, 1.04-3.44]; =0.04) and left ventricular ejection fraction (per 10% decrement from left ventricular ejection fraction, 50%; hazard ratio, 1.63 [95% CI, 1.30-2.04]; <0.001) were independent predictors of the primary end point. Two hundred seven of 300 (69%) patients with LVSD had evidence of left ventricular reverse remodeling. In a subgroup of 29 of 74 (39%) patients with initial left ventricular reverse remodeling, there was a subsequent left ventricular ejection fraction decrement. TTNtv location was not associated with statistically significant differences in baseline clinical characteristics, left ventricular reverse remodeling, or outcomes on multivariable analysis (=0.07).
Conclusions
TTNtv is characterized by frequent arrhythmia, but malignant ventricular arrhythmias are most commonly associated with severe LVSD. Male sex and LVSD are independent predictors of outcomes. Mutation location does not impact clinical phenotype or outcomes.



Circ Heart Fail: 29 Sep 2020; 13:e006832
Akhtar MM, Lorenzini M, Cicerchia M, Ochoa JP, ... Monserrat L, Elliott PM
Circ Heart Fail: 29 Sep 2020; 13:e006832 | PMID: 32964742
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Abstract

YKL-40 (Chitinase-3-Like Protein 1) Serum Levels in Aortic Stenosis.

Arain F, Abraityte A, Bogdanova M, Solberg OG, ... Gullestad L, Ueland T
Background
Identification of novel biomarkers could provide prognostic information and improve risk stratification in patients with aortic stenosis (AS). YKL-40 (chitinase-3-like protein 1), a protein involved in atherogenesis, is upregulated in human calcific aortic valves. We hypothesized that circulating YKL-40 would be elevated and associated with the degree of AS severity and outcome in patients with symptomatic AS.
Methods
Plasma YKL-40 was analyzed in 2 AS populations, one severe AS (n=572) with outcome measures and one with mixed severity (n=67). YKL-40 expression in calcified valves and in an experimental pressure overload model was assessed.
Results
We found (1) patients with AS had upregulated circulating YKL-40 compared with healthy controls (median 109 versus 34 ng/mL, <0.001), but levels were not related to the degree of AS severity. (2) High YKL-40 levels (quartile 4) were associated with long-term (median follow-up 4.7 years) all-cause mortality (adjusted hazard ratio, 1.93 [95% CI, 1.37-2.73], <0.001). (3) YKL-40 protein expression in human calcific valves co-localized with its putative receptor IL-13rα2 in close proximity to valve interstitial cells. (4) Myocardial YKL-40 increased in experimental pressure overload (6-fold in decompensated versus sham mice).
Conclusions
YKL-40 levels were elevated in AS and associated with mortality but not with other metrics of disease severity including the degree of AS severity. Despite scientific rationale for its role in AS, the clinical utility of circulating YKL-40 as a biomarker is limited. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01794832.



Circ Heart Fail: 29 Sep 2020; 13:e006643
Arain F, Abraityte A, Bogdanova M, Solberg OG, ... Gullestad L, Ueland T
Circ Heart Fail: 29 Sep 2020; 13:e006643 | PMID: 32962417
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Abstract

The Upcoming Epidemic of Heart Failure in South Asia.

Martinez-Amezcua P, Haque W, Khera R, Kanaya AM, ... Nasir K, Cainzos-Achirica M

Currently, South Asia accounts for a quarter of the world population, yet it already claims ≈60% of the global burden of heart disease. Besides the epidemics of type 2 diabetes mellitus and coronary heart disease already faced by South Asian countries, recent studies suggest that South Asians may also be at an increased risk of heart failure (HF), and that it presents at earlier ages than in most other racial/ethnic groups. Although a frequently underrecognized threat, an eventual HF epidemic in the densely populated South Asian nations could have dramatic health, social and economic consequences, and urgent interventions are needed to flatten the curve of HF in South Asia. In this review, we discuss recent studies portraying these trends, and describe the mechanisms that may explain an increased risk of premature HF in South Asians compared with other groups, with a special focus on highly relevant features in South Asian populations including premature coronary heart disease, early type 2 diabetes mellitus, ubiquitous abdominal obesity, exposure to the world\'s highest levels of air pollution, highly prevalent pretransition forms of HF such as rheumatic heart disease, and underdevelopment of healthcare systems. Other rising lifestyle-related risk factors such as use of tobacco products, hypertension, and general obesity are also discussed. We evaluate the prognosis of HF in South Asian countries and the implications of an anticipated HF epidemic. Finally, we discuss proposed interventions aimed at curbing these adverse trends, management approaches that can improve the prognosis of prevalent HF in South Asian countries, and research gaps in this important field.



Circ Heart Fail: 29 Sep 2020; 13:e007218
Martinez-Amezcua P, Haque W, Khera R, Kanaya AM, ... Nasir K, Cainzos-Achirica M
Circ Heart Fail: 29 Sep 2020; 13:e007218 | PMID: 32962410
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Abstract

Sex Disparities in the Management and Outcomes of Cardiogenic Shock Complicating Acute Myocardial Infarction in the Young.

Vallabhajosyula S, Ya\'Qoub L, Singh M, Bell MR, ... Holmes DR, Barsness GW
Background
There are limited data on how sex influences the outcomes of acute myocardial infarction-cardiogenic shock (AMI-CS) in young adults.
Methods
A retrospective cohort of AMI-CS admissions aged 18 to 55 years, during 2000 to 2017, was identified using the National Inpatient Sample. Use of coronary angiography, percutaneous coronary intervention, mechanical circulatory support and noncardiac interventions was identified. Outcomes of interest included in-hospital mortality, use of cardiac interventions, hospitalization costs, and length of stay.
Results
A total 90 648 AMI-CS admissions ≤55 years of age were included, of which 26% were women. Higher rates of CS were noted in men (2.2% in 2000 to 4.8% in 2017) compared with women (2.6% in 2000 to 4.0% in 2017; <0.001). Compared with men, women with AMI-CS were more frequently of Black race, from a lower socioeconomic status, with higher comorbidity, and admitted to rural and small hospitals (all <0.001). Women had lower rates of ST-segment elevation presentation (73.0% versus 78.7%), acute noncardiac organ failure, cardiac arrest (34.3% versus 35.7%), and received less-frequent coronary angiography (78.3% versus 81.4%), early coronary angiography (49.2% versus 54.1%), percutaneous coronary intervention (59.2% versus 64.0%), and mechanical circulatory support (50.3% versus 59.2%; all <0.001). Female sex was an independent predictor of in-hospital mortality (23.0% versus 21.7%; adjusted odds ratio, 1.11 [95% CI, 1.07-1.16]; <0.001). Women had lower hospitalization costs ($156 372±$198 452 versus $167 669±$208 577; <0.001) but comparable lengths of stay compared with men.
Conclusions
In young AMI-CS admissions, women are treated less aggressively and experience higher in-hospital mortality than men.



Circ Heart Fail: 29 Sep 2020; 13:e007154
Vallabhajosyula S, Ya'Qoub L, Singh M, Bell MR, ... Holmes DR, Barsness GW
Circ Heart Fail: 29 Sep 2020; 13:e007154 | PMID: 32988218
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Abstract

Multidisciplinary Cardiac Rehabilitation and Long-Term Prognosis in Patients With Heart Failure.

Kamiya K, Sato Y, Takahashi T, Tsuchihashi-Makaya M, ... Makita S, Isobe M
Background
Exercise-based cardiac rehabilitation (CR) improves health-related quality of life and exercise capacity in patients with heart failure (HF). However, CR efficacy in patients with HF who are elderly, frail, or have HF with preserved ejection fraction remains unclear. We examined whether participation in multidisciplinary outpatient CR is associated with long-term survival and rehospitalization in patients with HF, with subgroup analysis by age, sex, comorbidities, frailty, and HF with preserved ejection fraction.
Methods
This multicenter retrospective cohort study was performed in patients hospitalized for acute HF at 15 hospitals in Japan, 2007 to 2016. The primary outcome (composite of all-cause mortality and HF rehospitalization after discharge) and secondary outcomes (all-cause mortality and HF rehospitalization) were analyzed in outpatient CR program participants versus nonparticipants.
Results
Of the 3277 patients, 26% (862) participated in outpatient CR. After propensity matching for potential confounders, 1592 patients were included (n=796 pairs), of which 511 had composite outcomes (223 [14%] all-cause deaths and 392 [25%] HF rehospitalizations, median 2.4-year follow-up). Hazard ratios associated with CR participation were 0.77 (95% CI, 0.65-0.92) for composite outcome, 0.67 (95% CI, 0.51-0.87) for all-cause mortality, and 0.82 (95% CI, 0.67-0.99) for HF-related rehospitalization. CR participation was also associated with numerically lower rates of composite outcome in patients with HF with preserved ejection fraction or frail patients.
Conclusions
Outpatient CR participation was associated with substantial prognostic benefit in a large HF cohort regardless of age, sex, comorbidities, frailty, and HF with preserved ejection fraction.



Circ Heart Fail: 29 Sep 2020; 13:e006798
Kamiya K, Sato Y, Takahashi T, Tsuchihashi-Makaya M, ... Makita S, Isobe M
Circ Heart Fail: 29 Sep 2020; 13:e006798 | PMID: 32986957
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Abstract

Predicting the Risk of Right Ventricular Failure in Patients Undergoing Left Ventricular Assist Device Implantation: A Systematic Review.

Frankfurter C, Molinero M, Vishram-Nielsen JKK, Foroutan F, ... Orchanian-Cheff A, Alba AC
Background
Right ventricular failure (RVF) is a cause of major morbidity and mortality after left ventricular assist device (LVAD) implantation. It is, therefore, integral to identify patients who may benefit from biventricular support early post-LVAD implantation. Our objective was to explore the performance of risk prediction models for RVF in adult patients undergoing LVAD implantation.
Methods
A systematic search was performed on Medline, Embase, Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews from inception until August 2019 for all relevant studies. Performance was assessed by discrimination (via C statistic) and calibration if reported. Study quality was assessed using the Prediction Model Risk of Bias Assessment Tool criteria.
Results
After reviewing 3878 citations, 25 studies were included, featuring 20 distinctly derived models. Five models were derived from large multicenter cohorts: the European Registry for Patients With Mechanical Circulatory Support, Interagency Registry for Mechanically Assisted Circulatory Support, Kormos, Pittsburgh Bayesian, and Mechanical Circulatory Support Research Network RVF models. Seventeen studies (68%) were conducted in cohorts implanted with continuous-flow LVADs exclusively. The definition of RVF as an outcome was heterogenous among models. Seven derived models (28%) were validated in at least 2 cohorts, reporting limited discrimination (C-statistic range, 0.53-0.65). Calibration was reported in only 3 studies and was variable.
Conclusions
Existing RVF prediction models exhibit heterogeneous derivation and validation methodologies, varying definitions of RVF, and are mostly derived from single centers. Validation studies of these prediction models demonstrate poor-to-modest discrimination. Newer models are derived in cohorts implanted with continuous-flow LVADs exclusively and exhibit modest discrimination. Derivation of enhanced discriminatory models and their validations in multicenter cohorts is needed.



Circ Heart Fail: 29 Sep 2020; 13:e006994
Frankfurter C, Molinero M, Vishram-Nielsen JKK, Foroutan F, ... Orchanian-Cheff A, Alba AC
Circ Heart Fail: 29 Sep 2020; 13:e006994 | PMID: 32981331
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Impact:
Abstract

Polygenic Score for Beta-Blocker Survival Benefit in European Ancestry Patients with Reduced Ejection Fraction Heart Failure.

Lanfear DE, Luzum JA, She R, Gui H, ... Li J, Williams LK

: Beta-blockers (BB) are mainstay therapy for heart failure with reduced ejection fraction (HFrEF). However, individual patient responses to BB vary, which may be partially due to genetic variation. The goal of this study was to derive and validate the first polygenic response predictor (PRP) for BB survival benefit in HFrEF patients. : Derivation and validation analyses were performed in n=1,436 total HF patients of European descent and with EF <50%. The PRP was derived in a random subset of the Henry Ford Pharmacogenomic Registry (HFPGR; n=248), and then validated in a meta-analysis of the remaining patients from HFPGR (n=247), the TIME-CHF (n=431), and HF-ACTION trial (n=510). The PRP was constructed from a genome-wide analysis of BB*genotype interaction predicting time to all-cause mortality, adjusted for MAGGIC score, genotype, level of BB exposure, and BB propensity score. : Five-fold cross-validation summaries out to 1000 SNPs identified optimal prediction with a 44 SNP score and cutoff at the 30th percentile. In validation testing (n=1188) greater BB exposure was associated with reduced all-cause mortality in patients with low-PRP score (n=251; HR=0.19 [95% CI=0.04-0.51], =0.0075), but not high-PRP score (n=937; HR=0.84 [95% CI=0.53-1.3], =0.448), a difference that was statistically significant ( interaction =0.0235). Results were consistent regardless of atrial fibrillation, EF (≤40% vs. 41-50%), or when examining cardiovascular death. : Among patients of European ancestry with HFrEF, a PRP distinguished patients who derived substantial survival benefit from BB exposure from a larger group that did not. Additional work is needed prospectively test clinical utility and to develop PRPs for other population groups and other medications.



Circ Heart Fail: 03 Oct 2020; epub ahead of print
Lanfear DE, Luzum JA, She R, Gui H, ... Li J, Williams LK
Circ Heart Fail: 03 Oct 2020; epub ahead of print | PMID: 33012170
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Abstract

Mitochondrial Reversible Changes Determine Diastolic Function Adaptations During Myocardial (Reverse) Remodeling.

Miranda-Silva D, G Rodrigues P, Alves E, Rizo D, ... Leite-Moreira A, Falcão-Pires I
Background
Often, pressure overload-induced myocardial remodeling does not undergo complete reverse remodeling after decreasing afterload. Recently, mitochondrial abnormalities and oxidative stress have been successively implicated in the pathogenesis of several chronic pressure overload cardiac diseases. Therefore, we aim to clarify the myocardial energetic dysregulation in (reverse) remodeling, mainly focusing on the mitochondria.
Methods
Thirty-five Wistar Han male rats randomly underwent sham or ascending (supravalvular) aortic banding procedure. Echocardiography revealed that banding induced concentric hypertrophy and diastolic dysfunction (early diastolic transmitral flow velocity to peak early-diastolic annular velocity ratio, E/E\': sham, 13.6±2.1, banding, 18.5±4.1, =0.014) accompanied by increased oxidative stress (dihydroethidium fluorescence: sham, 1.6×10±6.1×10, banding, 2.6×10±4.5×10, <0.001) and augmented mitochondrial function. After 8 to 9 weeks, half of the banding animals underwent overload relief by an aortic debanding surgery (n=10).
Results
Two weeks later, hypertrophy decreased with the decline of oxidative stress (dihydroethidium fluorescence: banding, 2.6×10±4.5×10, debanding, 1.96×10±6.8×10, <0.001) and diastolic dysfunction improved simultaneously (E/E\': banding, 18.5±4.1, debanding, 15.1±1.8, =0.029). The reduction of energetic demands imposed by overload relief allowed the mitochondria to reduce its activity and myocardial levels of phosphocreatine, phosphocreatine/ATP, and ATP/ADP to normalize in debanding towards sham values (phosphocreatine: sham, 38.4±7.4, debanding, 35.6±8.7, =0.71; phosphocreatine/ATP: sham, 1.22±0.23 debanding, 1.11±0.24, =0.59; ATP/ADP: sham, 6.2±0.9, debanding, 5.6±1.6, =0.66). Despite the decreased mitochondrial area, complex III and V expression increased in debanding compared with sham or banding. Autophagy and mitophagy-related markers increased in banding and remained higher in debanding rats.
Conclusions
During compensatory and maladaptive hypertrophy, mitochondria become more active. However, as the disease progresses, the myocardial energetic demands increase and the myocardium becomes energy deficient. During reverse remodeling, the concomitant attenuation of cardiac hypertrophy and oxidative stress allowed myocardial energetics, left ventricle hypertrophy, and diastolic dysfunction to recover. Autophagy and mitophagy are probably involved in the myocardial adaptation to overload and to unload. We conclude that these mitochondrial reversible changes underlie diastolic function adaptations during myocardial (reverse) remodeling.



Circ Heart Fail: 30 Oct 2020; 13:e006170
Miranda-Silva D, G Rodrigues P, Alves E, Rizo D, ... Leite-Moreira A, Falcão-Pires I
Circ Heart Fail: 30 Oct 2020; 13:e006170 | PMID: 33176457
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Impact:

This program is still in alpha version.