Journal: Circ Heart Fail

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Abstract

Acute Effects of Left Ventricular Support With Impella 5.5 on Biventricular Hemodynamics.

Everett KD, Jain P, Botto R, Salama M, ... Kawabori M, Kapur NK
Identification of patients with cardiogenic shock and right ventricle (RV) dysfunction who may require biventricular rather than isolated left ventricular (LV) support remains challenging. In this setting, rigorous hemodynamic evaluation of biventricular contractility and load during initiation of LV support guides therapy. We now report a novel approach to assess biventricular pressure-volume loops in a patient receiving Impella 5.5 support for heart failure and shock.



Circ Heart Fail: 13 Sep 2021:CIRCHEARTFAILURE121008616; epub ahead of print
Everett KD, Jain P, Botto R, Salama M, ... Kawabori M, Kapur NK
Circ Heart Fail: 13 Sep 2021:CIRCHEARTFAILURE121008616; epub ahead of print | PMID: 34517730
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Abstract

Clinical Characteristics and Outcomes of Adults With a History of Heart Failure Hospitalized for COVID-19.

Goyal P, Reshetnyak E, Khan S, Musse M, ... Weinsaft JW, Safford MM
Background
It is important to understand the risk for in-hospital mortality of adults hospitalized with acute coronavirus disease 2019 (COVID-19) infection with a history of heart failure (HF).
Methods
We examined patients hospitalized with COVID-19 infection from January 1, 2020 to July 22, 2020, from 88 centers across the US participating in the American Heart Association\'s COVID-19 Cardiovascular Disease registry. The primary exposure was history of HF and the primary outcome was in-hospital mortality. To examine the association between history of HF and in-hospital mortality, we conducted multivariable modified Poisson regression models that included sociodemographics and comorbid conditions. We also examined HF subtypes based on left ventricular ejection fraction in the prior year, when available.
Results
Among 8920 patients hospitalized with COVID-19, mean age was 61.4±17.5 years and 55.5% were men. History of HF was present in 979 (11%) patients. In-hospital mortality occurred in 31.6% of patients with history of HF, and 16.9% in patients without a history of HF. In a fully adjusted model, history of HF was associated with increased risk for in-hospital mortality (relative risk: 1.16 [95% CI, 1.03-1.30]). Among 335 patients with left ventricular ejection fraction, heart failure with reduced ejection fraction was significantly associated with in-hospital mortality in a fully adjusted model (heart failure with reduced ejection fraction relative risk: 1.40 [95% CI, 1.10-1.79]; heart failure with mid-range ejection fraction relative risk: 1.06 [95% CI, 0.65-1.73]; heart failure with preserved ejection fraction relative risk, 1.06 [95% CI, 0.84-1.33]).
Conclusions
Risk for in-hospital mortality was substantial among adults with history of HF, in large part due to age and comorbid conditions. History of heart failure with reduced ejection fraction may confer especially elevated risk. This population thus merits prioritization for the COVID-19 vaccine.



Circ Heart Fail: 13 Sep 2021:CIRCHEARTFAILURE121008354; epub ahead of print
Goyal P, Reshetnyak E, Khan S, Musse M, ... Weinsaft JW, Safford MM
Circ Heart Fail: 13 Sep 2021:CIRCHEARTFAILURE121008354; epub ahead of print | PMID: 34517720
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Abstract

Identifying Discordance of Right- and Left-Ventricular Filling Pressures in Patients with Heart Failure by the Clinical Examination.

Pham D, Drazner MH, Ayers CR, Grodin JL, ... Morlend RM, Thibodeau JT
Background: In approximately 25% of patients with heart failure and reduced left-ventricular ejection fraction (HFrEF), right-ventricular (RV) and left-ventricular (LV) filling pressures are discordant (i.e., one is elevated while the other is not). Whether clinical assessment allows detection of this discordance is unknown. We sought to determine the agreement of clinically- versus invasively-determined patterns of ventricular congestion. Methods: In 156 HFrEF subjects undergoing invasive hemodynamic assessment, we categorized patterns of ventricular congestion (no congestion, RV only, LV only, or both) based on clinical findings of RV (jugular venous distention, JVD) or LV (hepatojugular reflux, orthopnea, or bendopnea) congestion. Agreement between clinically and invasively determined [RV congestion if right atrial pressure (RAP) ≥10 mmHg and LV congestion if pulmonary capillary wedge pressure (PCWP) ≥22 mmHg)] categorizations was the primary endpoint. Results: The frequency of clinical patterns of congestion was: 51% no congestion, 24% both RV and LV, 21% LV only, and 4% RV only. JVD had excellent discrimination for elevated RAP (C=0.88). However, agreement between clinical and invasive congestion patterns was poor, λ=0.44 (95% CI 0.34-0.55). While those with no clinical congestion usually had low RAP and PCWP (67/79, 85%), over one-half (24/38, 64%) with isolated LV clinical congestion had PCWP <22 mmHg, most (5/7, 71%) with isolated RV clinical congestion had PCWP ≥22 mmHg, and ∼one-third (10/32, 31%) with both RV and LV clinical congestion had elevated RAP but PCWP <22 mmHg. Conclusions: While clinical examination allows accurate detection of elevated RAP, it does not allow accurate detection of discordant RV and LV filling pressures.



Circ Heart Fail: 09 Sep 2021; epub ahead of print
Pham D, Drazner MH, Ayers CR, Grodin JL, ... Morlend RM, Thibodeau JT
Circ Heart Fail: 09 Sep 2021; epub ahead of print | PMID: 34503353
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Abstract

Stress and Coping Among Family Caregivers of Patients With a Destination Therapy Left Ventricular Assist Device: A Multicenter Mixed Methods Study.

McIlvennan CK, Jones J, Makic M, Meek PM, ... Matlock DD, Allen LA
Background
Family caregivers of patients with a destination therapy left ventricular assist device play a central and formalized role in postimplant care. We aimed to characterize longitudinal stress, predictors and correlates of stress, and coping processes among left ventricular assist device caregivers.
Methods
We performed a sequential, exploratory, mixed-methods study from 6 diverse left ventricular assist device programs. The primary outcome for the quantitative analysis was the Perceived Stress Scale-10 at 6 months (0-40). Based on the quantitative findings and guided by the Transactional Model of Stress and Coping, semistructured interviews explored causes of stress and coping processes. Integration was performed during the qualitative and interpretation phase.
Results
A total of 96 caregivers met inclusion criteria for quantitative analysis. Mean (SD) Perceived Stress Scale score was 14.3 (5.5) preimplant and 11.8 (6.9) at 6 months. Preimplant, only decreased preparedness for caregiving was associated with higher Perceived Stress Scale score at 6 months. At 6 months, increased caregiver depressive symptoms, decreased caregiver preparedness for caregiving, and lower patient quality of life were associated with higher Perceived Stress Scale score. Qualitative analysis of 25 caregivers revealed the causes of stress coalesced around 3 themes: (1) lack of preparedness to be a caregiver, (2) uniqueness of stress for the caregiver and patient situation, and (3) caregiving responsibilities physically and emotionally impacting caregivers. To cope with stress, most caregivers employed emotion-focused coping.
Conclusions
In family caregivers of patients with a left ventricular assist device, higher perceived stress was associated with lower caregiver preparedness, higher caregiver depressive symptoms, and lower patient quality of life. Emotion-focused coping strategies were common for caregivers. Future work should better prepare caregivers for this role and support them through the caregiving experience.
Registration
URL: https://www.clinicaltrials.gov; Unique identifier: NCT02344576.



Circ Heart Fail: 31 Aug 2021:CIRCHEARTFAILURE120008243; epub ahead of print
McIlvennan CK, Jones J, Makic M, Meek PM, ... Matlock DD, Allen LA
Circ Heart Fail: 31 Aug 2021:CIRCHEARTFAILURE120008243; epub ahead of print | PMID: 34465131
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Abstract

Psychometric Evaluation of the Kansas City Cardiomyopathy Questionnaire in Men and Women With Heart Failure.

Hejjaji V, Tang Y, Coles T, Jones PG, ... Piña IL, Spertus JA
Background
The Kansas City Cardiomyopathy Questionnaire (KCCQ) has been psychometrically evaluated in multiple heart failure (HF) populations, but the comparability of its psychometric properties between men and women is unknown.
Methods
Data from 3 clinical trials (1 in stable HF with preserved ejection fraction, 1 each in stable and acute HF with reduced ejection fraction) and 1 prospective cohort study (stable HF with reduced ejection fraction), incorporating 6773 men and 3612 women with HF, were used to compare the construct validity, internal and test-retest reliability, ability to detect change, predict mortality and hospitalizations and minimally important differences between the 2 sexes. Interactions of the KCCQ overall summary and subdomain scores by sex were independently examined.
Results
The KCCQ-Overall Summary score correlated well with New York Heart Association functional class in both sexes across patients with stable (correlation coefficient: -0.40 in men versus -0.49 in women) and acute (-0.37 in men versus -0.34 in women) HF. All KCCQ subdomains demonstrated concordant relationships with relevant comparison standards with no significant interactions by sex in 19 of 21 of these construct validity analyses. All KCCQ scores were equally predictive and other psychometric evaluations showed similar results by sex: test-retest reliability (intraclass correlation coefficient 0.94 in men versus 0.92 in women), responsive to change (standardized response mean 1.01 in both sexes), as were the minimally important differences and internal reliability.
Conclusions
The psychometric properties of the KCCQ, in terms of validity, prognosis, reliability, and sensitivity to change, are comparable in men and women with HF with preserved ejection fraction and HF with reduced ejection fraction.



Circ Heart Fail: 31 Aug 2021:CIRCHEARTFAILURE120008284; epub ahead of print
Hejjaji V, Tang Y, Coles T, Jones PG, ... Piña IL, Spertus JA
Circ Heart Fail: 31 Aug 2021:CIRCHEARTFAILURE120008284; epub ahead of print | PMID: 34465123
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Abstract

Socioeconomic Disparities in Referral for Invasive Hemodynamic Evaluation for Advanced Heart Failure: A Nationwide Cohort Study.

Larsson J, Kristensen SL, Madelaire C, Schou M, ... Køber L, Gustafsson F
Background
Factors determining referral for advanced heart failure (HF) evaluation are poorly studied. We studied the influence of socioeconomic aspects on the referral process in Denmark, which has a taxpayer-funded national health care system.
Methods
We identified all patients aged 18 to 75 years with a first diagnosis of HF during 2010 to 2018. Hospitalized patients had to be discharged alive and were then followed for the outcome of undergoing a right heart catheterization (RHC) used as a surrogate marker of advanced HF work-up.
Results
Of 36 637 newly diagnosed patients with HF, 680 (1.9%) underwent RHC during the follow-up period (median time to RHC of 280 days [interquartile range, 73-914]). Factors associated with a higher likelihood of RHC included the highest versus lowest household income quartile (HR, 1.56 [95% CI, 1.19-2.06]; P=0.001), being diagnosed with HF at a tertiary versus nontertiary hospital (HR, 1.68 [95% CI, 1.37-2.05]; P<0.001) and during a hospitalization versus outpatient visit (HR, 1.67 [95% CI, 1.42-1.95]; P<0.001). Level of education, occupational status, and distance to tertiary hospital were not independently associated with RHC. Older age, cancer, and a psychiatric diagnosis were independently associated with a decreased probability of RHC.
Conclusions
Higher household income, HF diagnosis during hospitalization, and first admission at a tertiary hospital were associated with increased likelihood of subsequent referral for RHC independent of other demographic and clinical variables. Greater attention may be required to ensure timely referral for advanced HF therapies in lower income groups.



Circ Heart Fail: 30 Aug 2021:CIRCHEARTFAILURE121008662; epub ahead of print
Larsson J, Kristensen SL, Madelaire C, Schou M, ... Køber L, Gustafsson F
Circ Heart Fail: 30 Aug 2021:CIRCHEARTFAILURE121008662; epub ahead of print | PMID: 34461745
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Abstract

Acute Hemodynamic Effects and Tolerability of Phosphodiesterase-1 Inhibition With ITI-214 in Human Systolic Heart Failure.

Gilotra NA, DeVore AD, Povsic TJ, Hays AG, ... Davis R, Kass DA
Background
PDE1 (phosphodiesterase type 1) hydrolyzes cyclic adenosine and guanosine monophosphate. ITI-214 is a highly selective PDE1 inhibitor that induces arterial vasodilation and positive inotropy in larger mammals. Here, we assessed pharmacokinetics, hemodynamics, and tolerability of single-dose ITI-214 in humans with stable heart failure with reduced ejection fraction.
Methods
Patients with heart failure with reduced ejection fraction were randomized 3:1 to 10, 30, or 90 mg ITI-214 single oral dose or placebo (n=9/group). Vital signs and electrocardiography were monitored predose to 5 hours postdose and transthoracic echoDoppler cardiography predose and 2-hours postdose.
Results
Patient age averaged 54 years; 42% female, and 60% Black. Mean systolic blood pressure decreased 3 to 8 mm Hg (P<0.001) and heart rate increased 5 to 9 bpm (P≤0.001 for 10, 30 mg doses, RM-ANCOVA). After 4 hours, neither blood pressure or heart rate significantly differed among cohorts (supine or standing). ITI-214 increased mean left ventricular power index, a relatively load-insensitive inotropic index, by 0.143 Watts/mL2·104 (P=0.03, a +41% rise; 5-71 CI) and cardiac output by 0.83 L/min (P=0.002, +31%, 13-49 CI) both at the 30 mg dose. Systemic vascular resistance declined with 30 mg (-564 dynes·s/cm-5, P<0.001) and 90 mg (-370, P=0.016). Diastolic changes were minimal, and no parameters were significantly altered with placebo. ITI-214 was well-tolerated. Five patients had mild-moderate hypotension or orthostatic hypotension recorded adverse events. There were no significant changes in arrhythmia outcome and no serious adverse events.
Conclusions
Single-dose ITI-214 is well-tolerated and confers inodilator effects in humans with heart failure with reduced ejection fraction. Further investigations of its therapeutic utility are warranted.
Registration
URL: https://www.clinicaltrials.gov; Unique identifier: NCT03387215.



Circ Heart Fail: 30 Aug 2021:CIRCHEARTFAILURE120008236; epub ahead of print
Gilotra NA, DeVore AD, Povsic TJ, Hays AG, ... Davis R, Kass DA
Circ Heart Fail: 30 Aug 2021:CIRCHEARTFAILURE120008236; epub ahead of print | PMID: 34461742
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Abstract

Prevalence and Incidence of Heart Failure Among Urban Patients in China: A National Population-Based Analysis.

Wang H, Chai K, Du M, Wang S, ... Zhan S, Yang J
Background
Large-scale and population-based studies of heart failure (HF) incidence and prevalence are scarce in China. The study sought to estimate the prevalence, incidence, and cost of HF in China.
Methods
We conducted a population-based study using records of 50.0 million individuals ≥25 years old from the national urban employee basic medical insurance from 6 provinces in China in 2017. Incident cases were individuals with a diagnosis of HF (International Classification of Diseases code, and text of diagnosis) in 2017 with a 4-year disease-free period (2013-2016). We calculated standardized rates by applying age standardization to the 2010 Chinese census population.
Results
The age-standardized prevalence and incidence were 1.10% (1.10% among men and women) and 275 per 100 000 person-years (287 among men and 261 among women), respectively, accounting for 12.1 million patients with HF and 3.0 million patients with incident HF ≥25 years old. Both prevalence and incidence increased with increasing age (0.57%, 3.86%, and 7.55% for prevalence and 158, 892, and 1655 per 100 000 person-years for incidence among persons who were 25-64, 65-79, and ≥80 years of age, respectively). The inpatient mean cost per-capita was $4406.8 and the proportion with ≥3 hospitalizations among those hospitalized was 40.5%. The outpatient mean cost per-capita was $892.3.
Conclusions
HF has placed a considerable burden on health systems in China, and strategies aimed at the prevention and treatment of HF are needed. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: ChiCTR2000029094.



Circ Heart Fail: 27 Aug 2021:CIRCHEARTFAILURE121008406; epub ahead of print
Wang H, Chai K, Du M, Wang S, ... Zhan S, Yang J
Circ Heart Fail: 27 Aug 2021:CIRCHEARTFAILURE121008406; epub ahead of print | PMID: 34455858
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Abstract

Characterizing Sex Differences in Physical Frailty Phenotypes in Heart Failure.

Denfeld QE, Habecker BA, Camacho SA, Roberts Davis M, ... Winters-Stone K, Lee CS
Background
Although women with heart failure (HF) are potentially more likely to be physically frail compared with men with HF, the underlying contributors to this sex difference are poorly understood. The purpose of this study was to characterize sex differences in physical frailty phenotypes in HF.
Methods
We prospectively enrolled adults with class I-IV HF. Physical frailty was measured with the frailty phenotype criteria. Symptoms of dyspnea, sleep-related impairment, pain interference, depression, and anxiety were assessed. Body composition was measured using dual-energy x-ray absorptiometry. Simple comparative statistics and stepwise regression modeling were used.
Results
The average age of the sample (n=115) was 63.6±15.7 years, 49% were women, and 73% had nonischemic cause. Forty-three percent of the sample was physically frail. Women had a 4.6 times greater odds of being physically frail compared with men, adjusting for covariates (odds ratio=4.63 [95% CI, 1.81-11.84], P=0.001). Both physically frail men and women were characterized by more type 2 diabetes, higher comorbidity burden, and worse dyspnea symptoms. Physically frail women had significantly worse symptoms compared with non-physically frail women but no difference in body composition characteristics. Physically frail men had significantly lower appendicular muscle mass, higher percent fat, lower hemoglobin, and more depressive symptoms compared with non-physically frail men.
Conclusions
Women are significantly more likely to be physically frail compared with men in HF. Physical frailty in both women and men is characterized by comorbidities and worse symptoms; physical frailty in men is characterized by worse physiological characteristics.



Circ Heart Fail: 24 Aug 2021:CIRCHEARTFAILURE120008076; epub ahead of print
Denfeld QE, Habecker BA, Camacho SA, Roberts Davis M, ... Winters-Stone K, Lee CS
Circ Heart Fail: 24 Aug 2021:CIRCHEARTFAILURE120008076; epub ahead of print | PMID: 34428925
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Abstract

Small Endogeneous Peptide Mitigates Myocardial Remodeling in a Mouse Model of Cardioselective Galectin-3 Overexpression.

Sonkawade SD, Pokharel S, Karthikeyan B, Kim M, ... Spernyak JA, Sharma UC
Background
Myocardial Gal3 (galectin-3) expression is associated with cardiac inflammation and fibrosis. Increased Gal3 portends susceptibility to heart failure and death. There are no data reporting the causative role of Gal3 to mediate cardiac fibro-inflammatory response and heart failure.
Methods
We developed a cardioselective Gal3 gain-of-function mouse (Gal3+/+) using α-myosin heavy chain promotor. We confirmed Gal3-transgene expression with real-time polymerase chain reaction and quantified cardiac/circulating Gal3 with Western blot and immunoassays. We used echocardiogram and cardiac magnetic resonance imaging to measure cardiac volumes, function, and myocardial velocities. Ex vivo, we studied myocardial inflammation/fibrosis and downstream TGF (transforming growth factor) β1-mRNA expression. We examined the effects of acute myocardial ischemia in presence of excess Gal3 by inducing acute myocardial infarction in mice. Two subsets of mice including mice treated with N-acetyl-seryl-aspartyl-lysyl-proline (a Gal3-inhibitor) and mice with genetic Gal3 loss-of-function (Gal3-/-) were studied for comparative analysis of Gal3 function.
Results
Gal3+/+ mice had increased cardiac/circulating Gal3. Gal3+/+ mice showed excess pericardial fat pad, dilated ventricles and cardiac dysfunction, which was partly normalized by N-acetyl-seryl-aspartyl-lysyl-proline. Cardiac magnetic resonance imaging showed reduced myocardial contractile velocities in Gal3+/+. The majority of Gal3+/+ mice did not survive acute myocardial infarction, and the survivors had profound cardiac dysfunction. Myocardial histology of Gal3+/+ mice showed macrophage/mast-cell infiltration, fibrosis and higher TGFβ1-mRNA expression, which were mitigated by both Gal3 gene deletion and N-acetyl-seryl-aspartyl-lysyl-proline administration.
Conclusions
Our study shows that cardioselective Gal3 overexpression leads to multiple cardiac phenotypic defects including ventricular dilation and cardiac dysfunction. Pharmacological Gal3 inhibition conferred protective effects with reduction of inflammation and fibrosis. Our study highlights the importance of translational studies to counteract Gal3 function and prevent cardiac dysfunction.



Circ Heart Fail: 19 Aug 2021:CIRCHEARTFAILURE121008510; epub ahead of print
Sonkawade SD, Pokharel S, Karthikeyan B, Kim M, ... Spernyak JA, Sharma UC
Circ Heart Fail: 19 Aug 2021:CIRCHEARTFAILURE121008510; epub ahead of print | PMID: 34415177
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Abstract

Optical Coherence Tomography in Cardiac Allograft Vasculopathy: State-of-the-Art Review.

Acharya D, Loyaga-Rendon RY, Chatterjee A, Rajapreyar I, Lee K
Cardiac allograft vasculopathy (CAV) is a challenging complication of heart transplantation. CAV pathophysiology is incompletely understood, standard screening modalities such as angiography have significant limitations, and currently available therapies have only modest efficacy in preventing progression. Optical coherence tomography is a light-based technique that provides microscopic level catheter-based intravascular imaging and has dramatically expanded our understanding of CAV, demonstrating it to be a complex, heterogeneous, and dynamic process. This review covers characteristics and uses of optical coherence tomography, including vessel characterization, serial use to assess progression of disease, guiding percutaneous intervention, and monitoring response to CAV therapies. We also discuss the potential of optical coherence tomography in providing individualized assessment and enable customized CAV therapies, which may lead to improvements in long-term transplant outcomes.



Circ Heart Fail: 19 Aug 2021:CIRCHEARTFAILURE121008416; epub ahead of print
Acharya D, Loyaga-Rendon RY, Chatterjee A, Rajapreyar I, Lee K
Circ Heart Fail: 19 Aug 2021:CIRCHEARTFAILURE121008416; epub ahead of print | PMID: 34414769
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Abstract

Early Preventive Treatment With Enalapril Improves Cardiac Function and Delays Mortality in Mice With Arrhythmogenic Right Ventricular Cardiomyopathy Type 5.

Domínguez F, Lalaguna L, López-Olañeta M, Villalba-Orero M, ... García-Pavía P, Lara-Pezzi E
Background
Arrhythmogenic right ventricular cardiomyopathy type 5 (ARVC5) is an inherited cardiac disease with complete penetrance and an aggressive clinical course caused by mutations in TMEM43 (transmembrane protein 43). There is no cure for ARVC5 and palliative treatment is started once the phenotype is present. A transgenic mouse model of ARVC5 expressing human TMEM43-S358L (TMEM43mut) recapitulates the human disease, enabling the exploration of preventive treatments. The aim of this study is to determine whether preventive treatment with heart failure drugs (β-blockers, ACE [angiotensin-converting enzyme] inhibitors, mineralocorticoid-receptor antagonists) improves the disease course of ARVC5 in TMEM43mut mice.
Methods
TMEM43mut male/female mice were treated with metoprolol (β-blockers), enalapril (ACE inhibitor), spironolactone (mineralocorticoid-receptor antagonist), ACE inhibitor + mineralocorticoid-receptor antagonist, ACE inhibitor + mineralocorticoid-receptor antagonist + β-blockers or left untreated. Drugs were initiated at 3 weeks of age, before ARVC5 phenotype, and serial ECG and echocardiograms were performed.
Results
TMEM43mut mice treated with enalapril showed a significantly increased median survival compared with untreated mice (26 versus 21 weeks; P=0.003). Enalapril-treated mice also exhibited increased left ventricular ejection fraction at 4 months compared with controls (37.0% versus 24.9%; P=0.004), shorter QRS duration and reduced left ventricle fibrosis. Combined regimens including enalapril also showed positive effects. Metoprolol decreased QRS voltage prematurely and resulted in a nonsignificant decrease in left ventricular ejection fraction compared with untreated TMEM43mut mice.
Conclusions
Preventive enalapril-based regimens reduced fibrosis, improved ECG, echocardiographic parameters and survival of ARVC5 mice. Early metoprolol did not show positive effects and caused premature ECG abnormalities. Our findings pave the way to consider prophylactic enalapril in asymptomatic ARVC5 genetic carriers.



Circ Heart Fail: 19 Aug 2021:CIRCHEARTFAILURE120007616; epub ahead of print
Domínguez F, Lalaguna L, López-Olañeta M, Villalba-Orero M, ... García-Pavía P, Lara-Pezzi E
Circ Heart Fail: 19 Aug 2021:CIRCHEARTFAILURE120007616; epub ahead of print | PMID: 34412508
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Abstract

Endothelial-Mesenchymal Transition in Heart Failure With a Preserved Ejection Fraction: Insights Into the Cardiorenal Syndrome.

Valero-Muñoz M, Oh A, Faudoa E, Bretón-Romero R, ... Bujor A, Sam F
Background
The management of clinical heart failure with a preserved ejection fraction (HFpEF) is often complicated by concurrent renal dysfunction, known as the cardiorenal syndrome. This, combined with the notable lack of evidence-based therapies for HFpEF, highlights the importance of examining mechanisms and targetable pathways in HFpEF with the cardiorenal syndrome.
Methods
HFpEF was induced in mice by uninephrectomy, infusion of d-aldosterone (HFpEF; N=10) or saline (Sham; N=8), and given 1% NaCl drinking water for 4 weeks. Renal fibrosis and endothelial-mesenchymal transition (endo-MT) were evident once HFpEF developed. Human aortic endothelial cells were treated for 4 days with 10% serum obtained from patients with chronically stable HFpEF with the cardiorenal syndrome (N=12) and compared with serum-treated human aortic endothelial cells from control subjects (no cardiac/renal disease; N=12) to recapitulate the in vivo findings.
Results
Kidneys from HFpEF mice demonstrated hypertrophy, interstitial fibrosis (1.9-fold increase; P<0.05) with increased expression of endo-MT transcripts, including pdgfrβ (platelet-derived growth factor receptor β), snail, fibronectin, fsp1 (fibroblast-specific protein 1), and vimentin by 1.7- (P=0.004), 1.7- (P=0.05), 1.8- (P=0.005), 2.6- (P=0.001), and 2.0-fold (P=0.001) versus Sham. Immunostaining demonstrated co-localization of CD31 and ACTA2 (actin α2) in kidney sections suggesting evidence of endo-MT. Similar to the findings in HFpEF mice, comparable endo-MT markers were also significantly elevated in human aortic endothelial cells treated with serum from patients with HFpEF compared with human aortic endothelial cells treated with serum from control subjects.
Conclusions
These translational findings demonstrate a plausible role for endo-MT in HFpEF with cardiorenal syndrome and may have therapeutic implications in drug development for patients with HFpEF and concomitant renal dysfunction.



Circ Heart Fail: 18 Aug 2021:CIRCHEARTFAILURE121008372; epub ahead of print
Valero-Muñoz M, Oh A, Faudoa E, Bretón-Romero R, ... Bujor A, Sam F
Circ Heart Fail: 18 Aug 2021:CIRCHEARTFAILURE121008372; epub ahead of print | PMID: 34407636
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Abstract

Participation in a Heart Failure Clinical Trial: Perspectives and Opportunities From the VICTORIA Trial and VICTORIA Simultaneous Registry.

Ezekowitz J, Mentz RJ, Westerhout CM, Sweitzer NK, ... Hernandez AF, Armstrong PW
Background
Randomized controlled trials (RCTs) often target enrollment of patients with demographics and outcomes less representative of the broader population of interest. To provide context for the VICTORIA trial (Vericiguat Global Study in Subjects With Heart Failure With Reduced Ejection Fraction), we designed a registry of hospitalized patients with worsening heart failure to characterize their clinical profile, outcomes, and reasons for their nonparticipation in a RCT.
Methods
Fifty-one RCT sites in Canada and the United States participated. Eligible patients included those with chronic heart failure, hospitalized for heart failure, and an ejection fraction <45%; no other exclusions were applied. Sites identified patients between 2017 and 2019 during the RCT enrollment period. RCT eligibility criteria were applied, and non-mutually exclusive reasons for nonenrollment were captured. Mortality at 1 year was estimated via the Meta-Analysis Global Group in Chronic Heart Failure risk score or as observed in the RCT.
Results
Overall, 2056 patients were enrolled in the registry; 61% (n=1256) were ineligible for the RCT, 37% (n=766) were eligible but not enrolled, and 2% (n=34) were also enrolled in the RCT. Registry participants had a median age of 70, 33% were women, and 63% were White. The median risk score predicted a 20.9% 1-year mortality, higher than in the RCT (predicted 14.7% and observed 11.5%). Major reasons for ineligibility in the RCT included the use of nitrates (23%), systolic blood pressure <100 mm Hg (12%), and substance use (11%) with other exclusion criteria <10%. For eligible patients, reasons for nonparticipation in the RCT included lack of interest in participating (28%), poor compliance (25%), inability to complete follow-up (23%), too sick (20%), unable to provide consent (17%), and distance from site (15%).
Conclusions
Patients with worsening heart failure in routine clinical practice exhibit high-risk features, and approximately one-third were eligible for an RCT but excluded. The majority of these nonparticipating patients had modifiable reasons.
Registration
URL: https://www.clinicaltrials.gov; Unique identifier: NCT02861534.



Circ Heart Fail: 18 Aug 2021:CIRCHEARTFAILURE120008242; epub ahead of print
Ezekowitz J, Mentz RJ, Westerhout CM, Sweitzer NK, ... Hernandez AF, Armstrong PW
Circ Heart Fail: 18 Aug 2021:CIRCHEARTFAILURE120008242; epub ahead of print | PMID: 34407626
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Impact:

This program is still in alpha version.