Journal: Circ Heart Fail

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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

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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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

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

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

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

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

Patient-Specific Computational Fluid Dynamics Reveal Localized Flow Patterns Predictive of Post-Left Ventricular Assist Device Aortic Incompetence.

Shad R, Kaiser AD, Kong S, Fong R, ... Marsden AL, Hiesinger W
Background
Progressive aortic valve disease has remained a persistent cause of concern in patients with left ventricular assist devices. Aortic incompetence (AI) is a known predictor of both mortality and readmissions in this patient population and remains a challenging clinical problem.
Methods
Ten left ventricular assist device patients with de novo aortic regurgitation and 19 control left ventricular assist device patients were identified. Three-dimensional models of patients\' aortas were created from their computed tomography scans, following which large-scale patient-specific computational fluid dynamics simulations were performed with physiologically accurate boundary conditions using the SimVascular flow solver.
Results
The spatial distributions of time-averaged wall shear stress and oscillatory shear index show no significant differences in the aortic root in patients with and without AI (mean difference, 0.67 dyne/cm2 [95% CI, -0.51 to 1.85]; P=0.23). Oscillatory shear index was also not significantly different between both groups of patients (mean difference, 0.03 [95% CI, -0.07 to 0.019]; P=0.22). The localized wall shear stress on the leaflet tips was significantly higher in the AI group than the non-AI group (1.62 versus 1.35 dyne/cm2; mean difference [95% CI, 0.15-0.39]; P<0.001), whereas oscillatory shear index was not significantly different between both groups (95% CI, -0.009 to 0.001; P=0.17).
Conclusions
Computational fluid dynamics serves a unique role in studying the hemodynamic features in left ventricular assist device patients where 4-dimensional magnetic resonance imaging remains unfeasible. Contrary to the widely accepted notions of highly disturbed flow, in this study, we demonstrate that the aortic root is a region of relatively stagnant flow. We further identified localized hemodynamic features in the aortic root that challenge our understanding of how AI develops in this patient population.



Circ Heart Fail: 29 Jun 2021; 14:e008034
Shad R, Kaiser AD, Kong S, Fong R, ... Marsden AL, Hiesinger W
Circ Heart Fail: 29 Jun 2021; 14:e008034 | PMID: 34139862
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Abstract

Measured Versus Estimated Resting Metabolic Rate in Heart Failure With Preserved Ejection Fraction.

Anderson T, Cascino TM, Koelling TM, Perry D, ... Kitzman DW, Hummel SL
Background
Obesity is common in heart failure with preserved ejection fraction (HFpEF), and a hypocaloric diet can improve functional capacity. Malnutrition, sarcopenia, and frailty are also frequently present, and calorie restriction could harm some patients. Resting metabolic rate (RMR) is an essential determinant of caloric needs; however, it is rarely measured in clinical practice. The accuracy of commonly used predictive equations in HFpEF is unknown.
Methods
RMR was measured with indirect calorimetry in 43 patients with HFpEF undergoing right heart catheterization at the University of Michigan, and among 49 participants in the SECRET trial (Study of the Effects of Caloric Restriction and Exercise Training in Patients With Heart Failure and a Normal Ejection Fraction); SECRET patients also had dual-energy X-ray absorptiometry body composition measures. Measured RMR was compared with RMR estimated using the Harris Benedict, Mifflin-St Jeor, World Health Organization, and Academy for Nutrition and Dietetics equations.
Results
All predictive equations overestimated RMR (by >10%, P<0.001 for all), with mean (95% CI) differences Harris Benedict equation +250 (186-313), Mifflin-St. Jeor equation +169 (110-229), World Health Organization equation +300 (239-361), and Academy for Nutrition and Dietetics equation +794 (890-697) kcal/day. Results were similar across both patient groups, and the discrepancy between measured and estimated RMR tended to increase with body mass index. In SECRET, measured RMR was closely associated with lean body mass (ρ=0.74; by linear regression adjusted for age and sex: β=27 [95% CI, 18-36] kcal/day per kg, P<0.001; r2=0.56).
Conclusions
Commonly used predictive equations systematically overestimate measured RMR in patients with HFpEF. Direct measurement of RMR may be needed to effectively tailor dietary guidance in this population. Registration: URL: https://www.clinicaltrials.gov; Unique Identifier: NCT00959660.



Circ Heart Fail: 30 Jul 2021; 14:e007962
Anderson T, Cascino TM, Koelling TM, Perry D, ... Kitzman DW, Hummel SL
Circ Heart Fail: 30 Jul 2021; 14:e007962 | PMID: 34344169
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Abstract

Multiparametric Implantable Cardioverter-Defibrillator Algorithm for Heart Failure Risk Stratification and Management: An Analysis in Clinical Practice.

Calò L, Bianchi V, Ferraioli D, Santini L, ... D\'Onofrio A, Full list of participant centers and investigators
Background
The HeartLogic algorithm combines multiple implantable cardioverter-defibrillator sensors to identify patients at risk of heart failure (HF) events. We sought to evaluate the risk stratification ability of this algorithm in clinical practice. We also analyzed the alert management strategies adopted in the study group and their association with the occurrence of HF events.
Methods
The HeartLogic feature was activated in 366 implantable cardioverter-defibrillator and cardiac resynchronization therapy implantable cardioverter-defibrillator patients at 22 centers. The median follow-up was 11 months [25th-75th percentile: 6-16]. The HeartLogic algorithm calculates a daily HF index and identifies periods IN alert state on the basis of a configurable threshold.
Results
The HeartLogic index crossed the threshold value 273 times (0.76 alerts/patient-year) in 150 patients. The time IN alert state was 11% of the total observation period. Patients experienced 36 HF hospitalizations, and 8 patients died of HF during the observation period. Thirty-five events were associated with the IN alert state (0.92 events/patient-year versus 0.03 events/patient-year in the OUT of alert state). The hazard ratio in the IN/OUT of alert state comparison was (hazard ratio, 24.53 [95% CI, 8.55-70.38], P<0.001), after adjustment for baseline clinical confounders. Alerts followed by clinical actions were associated with less HF events (hazard ratio, 0.37 [95% CI, 0.14-0.99], P=0.047). No differences in event rates were observed between in-office and remote alert management.
Conclusions
This multiparametric algorithm identifies patients during periods of significantly increased risk of HF events. The rate of HF events seemed lower when clinical actions were undertaken in response to alerts. Extra in-office visits did not seem to be required to effectively manage HeartLogic alerts.
Registration
URL: https://www.clinicaltrials.gov; Unique identifier: NCT02275637.



Circ Heart Fail: 29 Jun 2021:CIRCHEARTFAILURE120008134; epub ahead of print
Calò L, Bianchi V, Ferraioli D, Santini L, ... D'Onofrio A, Full list of participant centers and investigators
Circ Heart Fail: 29 Jun 2021:CIRCHEARTFAILURE120008134; epub ahead of print | PMID: 34190592
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Abstract

Remodeling of the Purkinje Network in Congestive Heart Failure in the Rabbit.

Logantha SJRJ, Cai XJ, Yanni J, Jones CB, ... Boyett MR, Hart G
Background
Purkinje fibers (PFs) control timing of ventricular conduction and play a key role in arrhythmogenesis in heart failure (HF) patients. We investigated the effects of HF on PFs.
Methods
Echocardiography, electrocardiography, micro-computed tomography, quantitative polymerase chain reaction, immunohistochemistry, volume electron microscopy, and sharp microelectrode electrophysiology were used.
Results
Congestive HF was induced in rabbits by left ventricular volume- and pressure-overload producing left ventricular hypertrophy, diminished fractional shortening and ejection fraction, and increased left ventricular dimensions. HF baseline QRS and corrected QT interval were prolonged by 17% and 21% (mean±SEMs: 303±6 ms HF, 249±11 ms control; n=8/7; P=0.0002), suggesting PF dysfunction and impaired ventricular repolarization. Micro-computed tomography imaging showed increased free-running left PF network volume and length in HF. mRNA levels for 40 ion channels, Ca2+-handling proteins, connexins, and proinflammatory and fibrosis markers were assessed: 50% and 35% were dysregulated in left and right PFs respectively, whereas only 12.5% and 7.5% changed in left and right ventricular muscle. Funny channels, Ca2+-channels, and K+-channels were significantly reduced in left PFs. Microelectrode recordings from left PFs revealed more negative resting membrane potential, reduced action potential upstroke velocity, prolonged duration (action potential duration at 90% repolarization: 378±24 ms HF, 249±5 ms control; n=23/38; P<0.0001), and arrhythmic events in HF. Similar electrical remodeling was seen at the left PF-ventricular junction. In the failing left ventricle, upstroke velocity and amplitude were increased, but action potential duration at 90% repolarization was unaffected.
Conclusions
Severe volume- followed by pressure-overload causes rapidly progressing HF with extensive remodeling of PFs. The PF network is central to both arrhythmogenesis and contractile dysfunction and the pathological remodeling may increase the risk of fatal arrhythmias in HF patients.



Circ Heart Fail: 29 Jun 2021; 14:e007505
Logantha SJRJ, Cai XJ, Yanni J, Jones CB, ... Boyett MR, Hart G
Circ Heart Fail: 29 Jun 2021; 14:e007505 | PMID: 34190577
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Abstract

Characteristics and Outcomes of Women Developing Heart Failure After Early Stage Breast Cancer Chemotherapy: A Population-Based Matched Cohort Study.

Abdel-Qadir H, Tai F, Croxford R, Austin PC, ... Lee DS, Thavendiranathan P
Background
The prognosis of heart failure (HF) after early stage breast cancer (EBC) treatment with anthracyclines or trastuzumab is not well-characterized.
Methods
Using administrative databases, women diagnosed with HF after receiving anthracyclines or trastuzumab for EBC in Ontario during 2007 to 2017 (the EBC-HF cohort) were categorized by cardiotoxic exposure (anthracycline alone, trastuzumab alone, sequential therapy with both agents) and matched on age with ≤3 cancer-free HF controls to compare baseline characteristics. To study prognosis after HF onset, we conducted a second match on age plus important HF prognostic factors. The cumulative incidence function was used to describe risk of hospitalization or emergency department visits (hospital presentations) for HF and cardiovascular death.
Results
A total of 804 women with EBC developed HF after anthracyclines (n=312), trastuzumab (n=112), or sequential therapy (n=380); they had significantly fewer comorbidities than 2411 age-matched HF controls. After the second match, the anthracycline-HF cohort had a similar 5-year incidence of HF hospital presentations (16.5% [95% CI, 12.0%-21.7%]) as controls (17.1% [95% CI, 14.4%-20.1%]); the 5-year incidence was lower than matched controls for the trastuzumab-HF (9.7% [95% CI, 4.7%-16.9%]; controls 16.4% [95% CI, 12.1%-21.3%]; P=0.03) and sequential-HF cohorts (2.7% [95% CI, 1.4%-4.8%]; controls 10.8% [95% CI, 8.9%-13.0%]; P<0.001). At 5 years, the incidence of cardiovascular death was 2.9% (95% CI, 1.2%-5.9%) in the anthracycline-HF cohort vs. 9.5% (95% CI, 6.9%-12.6%) in controls, and 1.7% (0.6%-3.7%) for women developing HF after trastuzumab vs. 4.3% (95% CI, 3.1-5.8%) for controls.
Conclusions
Women developing HF after cardiotoxic EBC chemotherapy have fewer comorbidities than cancer-free women with HF; trastuzumab-treated women who develop HF have better prognosis than matched HF controls.



Circ Heart Fail: 29 Jun 2021; 14:e008110
Abdel-Qadir H, Tai F, Croxford R, Austin PC, ... Lee DS, Thavendiranathan P
Circ Heart Fail: 29 Jun 2021; 14:e008110 | PMID: 34187164
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Impact:
Abstract

Comprehensive Proteomics Profiling Reveals Circulating Biomarkers of Hypertrophic Cardiomyopathy.

Shimada YJ, Raita Y, Liang LW, Maurer MS, ... Fifer MA, Reilly MP
Background
Hypertrophic cardiomyopathy (HCM) is caused by mutations in the genes coding for proteins essential in normal myocardial contraction. However, it remains unclear through which molecular pathways gene mutations mediate the development of HCM. The objectives were to determine plasma protein biomarkers of HCM and to reveal molecular pathways differentially regulated in HCM.
Methods
We conducted a multicenter case-control study of cases with HCM and controls with hypertensive left ventricular hypertrophy. We performed plasma proteomics profiling of 1681 proteins. We performed a sparse partial least squares discriminant analysis to develop a proteomics-based discrimination model with data from 1 institution (ie, the training set). We tested the discriminative ability in independent samples from the other institution (ie, the test set). As an exploratory analysis, we executed pathway analysis of significantly dysregulated proteins. Pathways with false discovery rate <0.05 were declared positive.
Results
The study included 266 cases and 167 controls (n=308 in the training set; n=125 in the test set). Using the proteomics-based model derived from the training set, the area under the receiver operating characteristic curve was 0.89 (95% CI, 0.83-0.94) in the test set. Pathway analysis revealed that the Ras-MAPK (mitogen-activated protein kinase) pathway, along with its upstream and downstream pathways, was upregulated in HCM. Pathways involved in inflammation and fibrosis-for example, the TGF (transforming growth factor)-β pathway-were also upregulated.
Conclusions
This study serves as the largest-scale investigation with the most comprehensive proteomics profiling in HCM, revealing circulating biomarkers and exhibiting both novel (eg, Ras-MAPK) and known (eg, TGF-β) pathways differentially regulated in HCM.



Circ Heart Fail: 29 Jun 2021; 14:e007849
Shimada YJ, Raita Y, Liang LW, Maurer MS, ... Fifer MA, Reilly MP
Circ Heart Fail: 29 Jun 2021; 14:e007849 | PMID: 34192899
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Impact:
Abstract

Liberation From Venoarterial Extracorporeal Membrane Oxygenation: A Review.

Brahmbhatt DH, Daly AL, Luk AC, Fan E, Billia F
Venoarterial extracorporeal membrane oxygenation may be used for circulatory support in cardiogenic shock as a bridge to recovery, a bridge to a ventricular assist device (VAD), or a bridge to transplant. While the determination of potential exit strategies is essential before cannulation, the final determination of a patient\'s options may change, in part, through their in-hospital clinical course. We propose that liberation from venoarterial extracorporeal membrane oxygenation should be conceptualized as a process of discovery in the assessment of a patient\'s underlying clinical status and a key driver of further clinical decision-making. A trial of liberation from support should be considered when the goals of the weaning trial are well-defined and, ideally, in the absence of potentially confounding clinical factors. In this review, we will discuss readiness to wean criteria from venoarterial extracorporeal membrane oxygenation, as well as specific clinical, biochemical, and echocardiographic parameters that may prove useful in determining weaning timing and revealing the patient\'s underlying hemodynamic status and prognosis. The role of various cannula configurations, support devices, and pharmacological adjuncts will also be discussed. Finally, we highlight current gaps in evidence and suggest areas of future research.



Circ Heart Fail: 29 Jun 2021; 14:e007679
Brahmbhatt DH, Daly AL, Luk AC, Fan E, Billia F
Circ Heart Fail: 29 Jun 2021; 14:e007679 | PMID: 34247519
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Impact:
Abstract

Ex Vivo Assessment of Different Oral Anticoagulant Regimens on Pump Thrombosis in a HeartWare Ventricular Assist Device.

Rao SD, Connor DE, Shehab S, Kerr NP, ... Jansz P, Hayward CS
Background
In light of decreased intracranial hemorrhage with direct oral anticoagulants and concerns about their safety in continuous flow left ventricular assist devices, we conducted an ex vivo study of thrombus formation using multiple anticoagulation agents.
Methods
A continuous flow left ventricular assist device (HeartWare ventricular assist device) hemocompatibility loop was run using human blood under 7 conditions: control (no anticoagulation or antiplatelet); in vitro addition of aspirin; in vitro addition of apixaban at low dose (equivalent 2.5 mg twice daily); addition of apixaban at high dose (equivalent 5 mg twice daily); patients on warfarin; patients on apixaban (5 mg twice daily); and patients on dabigatran (150 mg twice daily). The primary outcome was time to formation of intrapump thrombosis. Secondary outcomes were reduction in clotting times over 1 hour, hemolysis, reduced platelet aggregation, and von Willebrand activity.
Results
Twenty-one runs were completed. Times to thrombosis in median (interquartile range) were control, 131 (127-134.5); in vitro aspirin, 124 (114.5-137); and patients on dabigatran, 131 (130.5-135.5) minutes, respectively. Times in patients on warfarin were, 137 (136.5-143.5); in vitro low-dose apixaban, 141 (138.5-142); and patients on apixaban, 140 (138-142.5) minutes, respectively. No thrombus formed in the in vitro high-dose apixaban group. There were no significant differences between the individual groups. When all apixaban groups were compared with nonapixaban groups, the time to thrombosis formation was significantly longer, 143 (137-150) versus 133.5 (128.5-140) minutes, P=0.02. There were similar changes in lactate dehydrogenase levels and other secondary end points.
Conclusions
In an in vitro study of anticoagulation using human blood in a mock loop with a HeartWare HVAD, we demonstrated similar thrombosis times for apixaban and warfarin. Time to clotting was longer in the combined apixaban groups compared with combined other groups, but thrombosis times between individual groups were not significantly different.



Circ Heart Fail: 29 Jun 2021; 14:e007231
Rao SD, Connor DE, Shehab S, Kerr NP, ... Jansz P, Hayward CS
Circ Heart Fail: 29 Jun 2021; 14:e007231 | PMID: 34210157
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Impact:
Abstract

Avoidable Hospitalization for Heart Failure Among a Cohort of 18- to 64-Year-Old Italian Citizens and Immigrants: Results From the Italian Network for Longitudinal Metropolitan Studies.

Dalla Zuanna T, Cacciani L, Barbieri G, Batzella E, ... Marino C, Canova C
Background
Heart failure (HF) represents a severe public health burden. In Europe, differences in hospitalizations for HF have been found between immigrants and native individuals, with inconsistent results. Immigrants face many barriers in their access to health services, and their needs may be poorly met. We aimed to compare the rates of avoidable hospitalization for HF among immigrants and native individuals in Italy.
Methods
All 18- to 64-year-old residents of Turin, Venice, Reggio Emilia, Modena, Bologna, and Rome between January 1, 2001 and December 31, 2013 were included in this multicenter open-cohort study. Immigrants from high migratory pressure countries (divided by area of origin) were compared with Italian citizens. Age-, sex-, and calendar year-adjusted hospitalization rate ratios and the 95% CIs of avoidable hospitalization for HF by citizenship were estimated using negative binomial regression models. The hospitalization rate ratios were summarized using a random effects meta-analysis. Additionally, we tested the contribution of socioeconomic status to these disparities.
Results
Of the 4 470 702 subjects included, 15.8% were immigrants from high migratory pressure countries. Overall, immigrants showed a nonsignificant increased risk of avoidable hospitalization for HF (hospitalization rate ratio, 1.26 [95% CI, 0.97-1.68]). Risks were higher for immigrants from Sub-Saharan Africa and for males from Northern Africa and Central-Eastern Europe than for their Italian citizen counterparts. Risks were attenuated adjusting for socioeconomic status, although they remained consistent with nonadjusted results.
Conclusions
Adult immigrants from different geographic macroareas had higher risks of avoidable hospitalization for HF than Italian citizens. Possible explanations might be higher risk factors among immigrants and reduced access to primary health care services.



Circ Heart Fail: 29 Jun 2021; 14:e008022
Dalla Zuanna T, Cacciani L, Barbieri G, Batzella E, ... Marino C, Canova C
Circ Heart Fail: 29 Jun 2021; 14:e008022 | PMID: 34235937
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Impact:
Abstract

ERBB4 and Multiple MicroRNAs That Target ERBB4 Participate in Pregnancy-Related Cardiomyopathy.

Feyen E, Ricke-Hoch M, Van Fraeyenhove J, Vermeulen Z, ... Hilfiker-Kleiner D, De Keulenaer GW
Background
Peripartum cardiomyopathy (PPCM) is a life-threatening disease in women without previously known cardiovascular disease. It is characterized by a sudden onset of heart failure before or after delivery. Previous studies revealed that the generation of a 16-kDa PRL (prolactin) metabolite, the subsequent upregulation of miR-146a, and the downregulation of the target gene Erbb4 is a common driving factor of PPCM.
Methods
miRNA profiling was performed in plasma of PPCM patients (n=33) and postpartum-matched healthy CTRLs (controls; n=36). Elevated miRNAs in PPCM plasma, potentially targeting ERBB4 (erythroblastic leukemia viral oncogene homolog 4), were overexpressed in cardiomyocytes using lentiviral vectors. Next, cardiac function, cardiac morphology, and PPCM phenotype were investigated after recurrent pregnancies of HZ (heterozygous) cardiomyocyte-specific Erbb4 mice (Erbb4F/+ αMHC-Cre+, n=9) with their age-matched nonpregnant CTRLs (n=9-10).
Results
Here, we identify 9 additional highly conserved miRNAs (miR-199a-5p and miR-199a-3p, miR-145a-5p, miR-130a-3p, miR-135a-5p, miR-221-3p, miR-222-3p, miR-23a-3p, and miR19b-3p) that target tyrosine kinase receptor ERBB4 and are over 4-fold upregulated in plasma of PPCM patients at the time of diagnosis. We confirmed that miR-146a, miR-199a-5p, miR-221-3p, miR-222-3p, miR-23a-3p, miR-130a-5p, and miR-135-3p overexpression decreases ERBB4 expression in cardiomyocytes (-29% to -50%; P<0.05). In addition, we demonstrate that genetic cardiomyocyte-specific downregulation of Erbb4 during pregnancy suffices to induce a variant of PPCM in mice, characterized by left ventricular dilatation (postpartum second delivery: left ventricular internal diameter in diastole, +19±7% versus HZ-CTRL; P<0.05), increased atrial natriuretic peptide (ANP) levels (4-fold increase versus HZ-CTRL mice, P<0.001), decreased VEGF (vascular endothelial growth factor) and VE-cadherin levels (-33±17%, P=0.07; -27±20%, P<0.05 versus HZ-CTRL), and histologically enlarged cardiomyocytes (+20±21%, versus HZ-CTRL, P<0.05) but without signs of myocardial apoptosis and inflammation.
Conclusions
ERBB4 is essential to protect the maternal heart from peripartum stress. Downregulation of ERBB4 in cardiomyocytes induced by multiple miRNAs in the peripartum period may be crucial in PPCM pathophysiology. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00998556.



Circ Heart Fail: 29 Jun 2021; 14:e006898
Feyen E, Ricke-Hoch M, Van Fraeyenhove J, Vermeulen Z, ... Hilfiker-Kleiner D, De Keulenaer GW
Circ Heart Fail: 29 Jun 2021; 14:e006898 | PMID: 34247489
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Impact:
Abstract

Temporal Trends and Clinical Trial Characteristics Associated With the Inclusion of Women in Heart Failure Trial Steering Committees: A Systematic Review.

Eliya Y, Whitelaw S, Thabane L, Voors AA, Douglas PS, Van Spall HGC
Background
Trial steering committees (TSCs) steer the conduct of randomized controlled trials (RCTs). We examined the gender composition of TSCs in impactful heart failure RCTs and explored whether trial leadership by a woman was independently associated with the inclusion of women in TSCs.
Methods
We systematically searched MEDLINE, EMBASE, and CINAHL for heart failure RCTs published in journals with impact factor ≥10 between January 2000 and May 2019. We used the Jonckheere-Terpstra test to assess temporal trends and multivariable logistic regression to explore trial characteristics associated with TSC inclusion of women.
Results
Of 403 RCTs that met inclusion criteria, 127 (31.5%) reported having a TSC but 20 of these (15.7%) did not identify members. Among 107 TSCs that listed members, 56 (52.3%) included women and 6 of these (10.7%) restricted women members to the RCT leaders. Of 1213 TSC members, 11.1% (95% CI, 9.4%-13.0%) were women, with no change in temporal trends (P=0.55). Women had greater odds of TSC inclusion in RCTs led by women (adjusted odds ratio, 2.48 [95% CI, 1.05-8.72], P=0.042); this association was nonsignificant when analysis excluded TSCs that restricted women to the RCT leaders (adjusted odds ratio 1.46 [95% CI, 0.43-4.91], P=0.36).
Conclusions
Women were included in 52.3% of TSCs and represented 11.1% of TSC members in 107 heart failure RCTs, with no change in trends since 2000. RCTs led by women had higher adjusted odds of including women in TSCs, partly due to the self-inclusion of RCT leaders in TSCs.



Circ Heart Fail: 30 Jul 2021; 14:e008064
Eliya Y, Whitelaw S, Thabane L, Voors AA, Douglas PS, Van Spall HGC
Circ Heart Fail: 30 Jul 2021; 14:e008064 | PMID: 34281362
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Impact:
Abstract

Disparity in the Setting of Incident Heart Failure Diagnosis.

Sandhu AT, Tisdale RL, Rodriguez F, Stafford RS, ... Lewis E, Heidenreich PA
Background
Early heart failure (HF) recognition can reduce morbidity, yet HF is often initially diagnosed only after a patient clinically worsens. We sought to identify characteristics that predict diagnosis in the acute care setting versus the outpatient setting.
Methods
We estimated the proportion of incident HF diagnosed in the acute care setting (inpatient hospital or emergency department) versus outpatient setting based on diagnostic codes from a claims database covering commercial insurance and Medicare Advantage between 2003 and 2019. After excluding new-onset HF potentially caused by a concurrent acute cause (eg, acute myocardial infarction), we identified demographic, clinical, and socioeconomic predictors of diagnosis setting. Patients were linked to their primary care clinicians to evaluate diagnosis setting variation across clinicians.
Results
Of 959 438 patients with new HF, 38% were diagnosed in acute care. Of these, 46% had potential HF symptoms in the prior 6 months. Over time, the relative odds of acute care diagnosis increased by 3.2% annually after adjustment for patient characteristics (95% CI, 3.1%-3.3%). Acute care diagnosis setting was more likely for women compared with men (adjusted odds ratio, 1.11 [95% CI, 1.10-1.12]) and for Black patients compared with White patients (adjusted odds ratio, 1.18 [95% CI, 1.16-1.19]). The proportion of acute care diagnosis varied substantially (interquartile range: 24%-39%) among clinicians after adjusting for patient-level risk factors.
Conclusions
A large proportion of first HF diagnoses occur in the acute care setting, particularly among women and Black patients, yet many had potential HF symptoms in the months before acute care visits. These results raise concerns that many HF diagnoses are missed in the outpatient setting. Earlier diagnosis could allow for timelier high-value interventions, addressing disparities and reducing the progression of HF.



Circ Heart Fail: 30 Jul 2021; 14:e008538
Sandhu AT, Tisdale RL, Rodriguez F, Stafford RS, ... Lewis E, Heidenreich PA
Circ Heart Fail: 30 Jul 2021; 14:e008538 | PMID: 34311559
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Impact:
Abstract

Intoxicated Donors and Heart Transplant Outcomes: Long-Term Safety.

Baran DA, Lansinger J, Long A, Herre JM, ... Stelling K, Copeland H
Background
The opioid crisis has led to an increase in available donor hearts, although questions remain about the long-term outcomes associated with the use of these organs. Prior studies have relied on historical information without examining the toxicology results at the time of organ offer. The objectives of this study were to examine the long-term survival of heart transplants in the recent era, stratified by results of toxicological testing at the time of organ offer as well as comparing the toxicology at the time of donation with variables based on reported history.
Methods
The United Network for Organ Sharing database was requested as well as the donor toxicology field. Between 2007 and 2017, 23 748 adult heart transplants were performed. United Network for Organ Sharing historical variables formed a United Network for Organ Sharing Toxicology Score and the measured toxicology results formed a Measured Toxicology Score. Survival was examined by the United Network for Organ Sharing Toxicology Score and Measured Toxicology Score, as well as Cox proportional hazards models incorporating a variety of risk factors.
Results
The number and percent of donors with drug use has significantly increased over the study period (P<0.0001). Cox proportional hazards modeling of survival including toxicological and historical data did not demonstrate differences in post-transplant mortality. Combinations of drugs identified by toxicology were not associated with differences in survival. Lower donor age and ischemic time were significantly positively associated with survival (P<0.0001).
Conclusions
Among donors accepted for transplantation, neither history nor toxicological evidence of drug use was associated with significant differences in survival. Increasing use of such donors may help alleviate the chronic donor shortage.



Circ Heart Fail: 30 Jul 2021; 14:e007433
Baran DA, Lansinger J, Long A, Herre JM, ... Stelling K, Copeland H
Circ Heart Fail: 30 Jul 2021; 14:e007433 | PMID: 34315226
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Impact:
Abstract

Safety of Endomyocardial Biopsy in New-Onset Acute Heart Failure Requiring Veno-Arterial Extracorporeal Membrane Oxygenation.

van der Boon RMA, den Dekker WK, Meuwese CL, Lorusso R, ... van Mieghem NMDA, den Uil CA
Background
Endomyocardial biopsy (EMB) has an important role in determining the pathogenesis of new-onset acute heart failure (new-AHF) when noninvasive testing is impossible. However, data on safety and histopathologic outcomes in patients requiring veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is lacking.
Methods
A retrospective, multicenter cohort of patients undergoing EMB while requiring VA-ECMO for new-AHF between 1990 and 2020 was compared with a cohort of nontransplant related biopsies not requiring VA-ECMO. Primary end point of the study was to determine the safety of EMB. Additionally, we describe the underlying pathogenesis causing new-AHF based on histopathologic examination of the samples obtained.
Results
A total of 23 patients underwent EMB while requiring VA-ECMO (10.0%), 125 (54.3%) during an unplanned admission, and 82 (35.7%) in elective setting. Major complications occurred in 8.3% of all procedures with a significantly higher rate in patients requiring VA-ECMO (26.1% versus 8.0% versus 3.7%, P=0.003) predominately due to the occurrence of sustained ventricular tachycardia or need of resuscitation (13.0% versus 3.2% versus 1.2%, P=0.02). EMB led to a histopathologic diagnosis in 78.3% of the patients requiring VA-ECMO which consisted primarily of patients with myocarditis (73.9%).
Conclusions
EMB in patients requiring VA-ECMO can be performed albeit with a substantial risk of major complications. The risk of the procedure was offset by a histopathologic diagnosis in 78.3% of the patients, which for the majority consisted of patients with myocarditis. The important therapeutic and prognostic implications of establishing an underlying pathogenesis causing new-AHF in this population warrant further refinement to improve procedural safety.



Circ Heart Fail: 30 Jul 2021; 14:e008387
van der Boon RMA, den Dekker WK, Meuwese CL, Lorusso R, ... van Mieghem NMDA, den Uil CA
Circ Heart Fail: 30 Jul 2021; 14:e008387 | PMID: 34344163
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Impact:
Abstract

NAD Redox Imbalance in the Heart Exacerbates Diabetic Cardiomyopathy.

Chiao YA, Chakraborty AD, Light CM, Tian R, ... Gu H, Lee CF
Background
Diabetes is a risk factor for heart failure and promotes cardiac dysfunction. Diabetic tissues are associated with nicotinamide adenine dinucleotide (NAD+) redox imbalance; however, the hypothesis that NAD+ redox imbalance causes diabetic cardiomyopathy has not been tested. This investigation used mouse models with altered NAD+ redox balance to test this hypothesis.
Methods
Diabetic stress was induced in mice by streptozotocin. Cardiac function was measured by echocardiography. Heart and plasma samples were collected for biochemical, histological, and molecular analyses. Two mouse models with altered NAD+ redox states (1, Ndufs4 [NADH:ubiquinone oxidoreductase subunit S4] knockout, cKO, and 2, NAMPT [nicotinamide phosphoribosyltranferase] transgenic mice, NMAPT) were used.
Results
Diabetic stress caused cardiac dysfunction and lowered NAD+/NADH ratio (oxidized/reduced ratio of nicotinamide adenine dinucleotide) in wild-type mice. Mice with lowered cardiac NAD+/NADH ratio without baseline dysfunction, cKO mice, were challenged with chronic diabetic stress. NAD+ redox imbalance in cKO hearts exacerbated systolic (fractional shortening: 27.6% versus 36.9% at 4 weeks, male cohort P<0.05), and diastolic dysfunction (early-to-late ratio of peak diastolic velocity: 0.99 versus 1.20, P<0.05) of diabetic mice in both sexes. Collagen levels and transcripts of fibrosis and extracellular matrix-dependent pathways did not show changes in diabetic cKO hearts, suggesting that the exacerbated cardiac dysfunction was due to cardiomyocyte dysfunction. NAD+ redox imbalance promoted superoxide dismutase 2 acetylation, protein oxidation, troponin I S150 phosphorylation, and impaired energetics in diabetic cKO hearts. Importantly, elevation of cardiac NAD+ levels by NAMPT normalized NAD+ redox balance, alleviated cardiac dysfunction (fractional shortening: 40.2% versus 24.8% in cKO:NAMPT versus cKO, P<0.05; early-to-late ratio of peak diastolic velocity: 1.32 versus 1.04, P<0.05), and reversed pathogenic mechanisms in diabetic mice.
Conclusions
Our results show that NAD+ redox imbalance to regulate acetylation and phosphorylation is a critical mediator of the progression of diabetic cardiomyopathy and suggest the therapeutic potential for diabetic cardiomyopathy by harnessing NAD+ metabolism.



Circ Heart Fail: 30 Jul 2021; 14:e008170
Chiao YA, Chakraborty AD, Light CM, Tian R, ... Gu H, Lee CF
Circ Heart Fail: 30 Jul 2021; 14:e008170 | PMID: 34374300
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Impact:
Abstract

Long-Term Trajectories of Left Ventricular Ejection Fraction in Patients With Chronic Inflammatory Diseases and Heart Failure: An Analysis of Electronic Health Records.

Rivera AS, Sinha A, Ahmad FS, Thorp E, ... Lloyd-Jones DM, Feinstein MJ
Background
Immune regulation and inflammation play a role in the pathogenesis and progression of acute and chronic heart failure (HF). Although the clinical course of acute, severe inflammatory cardiomyopathy is well described, the effects of chronic systemic inflammation on cardiovascular function over time are less clear. To investigate this question, we compared trajectories over time in left ventricular ejection fraction for patients with HF with different chronic inflammatory diseases (CIDs): HIV, systemic lupus erythematosus, systemic sclerosis, rheumatoid arthritis, inflammatory bowel disease, and/or psoriasis.
Methods
Using a database of patients receiving care in a large metropolitan health care system since January 1, 2000, we analyzed serial, clinically indicated echocardiograms from patients with HF with CIDs and frequency-matched patients with HF without CIDs. We included patients with ≥3 serial echocardiograms (N=974; median 6.1 years between first and most recent echo). We assessed left ventricular ejection fraction trajectories over time using latent trajectory models, then investigated differences in left ventricular ejection fraction trajectories for specific CID subtypes compared with controls.
Results
Overall, the majority of patients studied (N=687; 70.5%) had left ventricular ejection fraction trajectories consistent with HF with preserved or midrange EF, whereas 255 (26.2%) had HF with reduced EF and 32 (3.3%) had HF with recovered EF. Compared with non-CID controls with HF, patients with rheumatoid arthritis, inflammatory bowel disease, and systemic lupus erythematosus were significantly more likely than controls to have HF with preserved or midrange EF whereas patients with HIV were significantly more likely to have HF with reduced EF.
Conclusions
Among patients with HF with CIDs, distinct left ventricular ejection fraction trajectory patterns associate with different specific individual CIDs. This highlights the heterogeneity of HF subtypes and changes over time across different CIDs.



Circ Heart Fail: 30 Jul 2021; 14:e008478
Rivera AS, Sinha A, Ahmad FS, Thorp E, ... Lloyd-Jones DM, Feinstein MJ
Circ Heart Fail: 30 Jul 2021; 14:e008478 | PMID: 34372666
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Impact:
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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Impact:
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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Impact:
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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This program is still in alpha version.