Journal: Circ Heart Fail

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Abstract

Temporal Trends and Prognosis of Physical Examination Findings in Patients With Acute Decompensated Heart Failure: The ARIC Study Community Surveillance.

Kolupoti A, Fudim M, Pandey A, Kucharska-Newton A, ... Mentz RJ, Caughey MC
Background
Bedside evaluation of congestion is a mainstay of heart failure (HF) management. Whether detected physical examination signs have changed over time as obesity prevalence has increased in HF populations, or if the associated prognosis differs for HF with reduced or preserved ejection fraction (HFrEF or HFpEF) is uncertain.
Methods
From 2005 to 2014, the ARIC study (Atherosclerosis Risk in Communities) conducted adjudicated hospital surveillance of acute decompensated HF. We analyzed trends in physical examination findings, imaging signs, and symptoms related to congestion, both over time and by obesity class, and associated 28-day mortality risks.
Results
Of 24 937 weighted hospitalizations for acute decompensated HF (mean age 75 years, 53% women, 32% Black), 47% had HFpEF. The prevalence of obesity increased from 2005 to 2014 for both HF types. With increasing obesity category, detected edema increased, while jugular venous distension decreased, and rales remained stable. Detected edema also increased over time, for both HF types. Associations between 28-day mortality and individual signs and symptoms of congestion were similar for HFpEF and HFrEF; however, the adjusted mortality risk with all 3 (edema, rales, and jugular venous distension) versus <3 physical examination findings was higher for patients with HFpEF (odds ratio, 2.41 [95% CI, 1.53-3.79]) than HFrEF (odds ratio, 1.30 [95% CI, 0.87-1.93]); P for interaction by HF type =0.02.
Conclusions
In patients hospitalized with acute decompensated HF, detected physical examination findings differ both temporally and by obesity. Combined findings from the physical examination are more prognostic of 28-day mortality for patients with HFpEF than HFrEF.



Circ Heart Fail: 26 Oct 2021:CIRCHEARTFAILURE121008403; epub ahead of print
Kolupoti A, Fudim M, Pandey A, Kucharska-Newton A, ... Mentz RJ, Caughey MC
Circ Heart Fail: 26 Oct 2021:CIRCHEARTFAILURE121008403; epub ahead of print | PMID: 34702047
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Abstract

Changing Demographics, Temporal Trends in Waitlist, and Posttransplant Outcomes After Heart Transplantation in the United States: Analysis of the UNOS Database 1991-2019.

Akintoye E, Alvarez P, Shin D, Egbe A, ... Sellke F, Briasoulis A
Background
We sought to investigate temporal trends in patient characteristics, waitlist, and posttransplant outcomes after heart transplantation in the United States.
Methods
Using data from the United Network of Organ Sharing, we identified adults listed for heart transplantation between 1991 and 2019. Patients were divided into 4 eras based on the 3 time points in which changes were made to the patient selection/allocation policy (Era 1=January 1991-January 1999; Era 2=January 1999-July 2006; Era 3=July 2006-October 2018; and Era 4=October 2018-March 2020), and patient characteristics, waitlist, and posttransplant outcomes were evaluated for each era.
Results
Between 1991 and 2019, 95 179 patients were added to the heart transplantation waitlist. Compared with Era 1, patients listed in Era 4 were older (mean age: 50 versus 52 years) and with higher risk comorbidities (eg, 10% versus 28.8% diabetes, 23.3% versus 35.6% obese). Over the study period, 22 738 patients died or were permanently delisted for deterioration on the waitlist while 61 687 were transplanted. Compared with the preceding era, there was significant decrease in death or deterioration in the last 2 eras (sub-hazard ratio, 0.67 [95% CI, 0.65-0.70] for Era 3 versus Era 2 and sub-hazard ratio, 0.65 [95% CI, 0.58-0.73] for Era 4 versus 3). Across the years, 27.1% to 40.5% of those on the waitlist were transplanted. Among those transplanted, there was increase in the rates of in-hospital stroke (2.8% in Era 1 to 3.7% in Era 4), renal failure requiring dialysis (7.2%-17.1%), and length-of-stay (14-17days), P<0.001. However, this did not negatively impact short-term survival when compared with the preceding era (1-year graft survival from Era 1 to Era 4=84.1%, 86.4%, 90.4%, and 89.7%, respectively).
Conclusions
There have been significant changes in the characteristics of patients listed for heart transplantation. Although transplant volume has increased, the wide supply-demand gap persisted. The last two changes in the allocation policy achieved their primary objective of reducing waitlist mortality.



Circ Heart Fail: 24 Oct 2021:CIRCHEARTFAILURE121008764; epub ahead of print
Akintoye E, Alvarez P, Shin D, Egbe A, ... Sellke F, Briasoulis A
Circ Heart Fail: 24 Oct 2021:CIRCHEARTFAILURE121008764; epub ahead of print | PMID: 34689572
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Abstract

FGF-23 (Fibroblast Growth Factor-23) and Cardiorenal Interactions.

Ivey-Miranda JB, Stewart B, Cox ZL, McCallum W, ... Rao VS, Testani JM
Background
Animal models implicate FGF-23 (fibroblast growth factor-23) as a direct contributor to adverse cardiorenal interactions such as sodium avidity, diuretic resistance, and neurohormonal activation, but this has not been conclusively demonstrated in humans. Therefore, we aimed to evaluate whether FGF-23 is associated with parameters of cardiorenal dysfunction in humans with heart failure, independent of confounding factors.
Methods
One hundred ninety-nine outpatients with heart failure undergoing diuretic treatment at the Yale Transitional Care Center were enrolled and underwent blood collection, and urine sampling before and after diuretics.
Results
FGF-23 was associated with several metrics of disease severity such as higher home loop diuretic dose and NT-proBNP (N-terminal pro-B-type natriuretic peptide), and lower estimated glomerular filtration rate, serum chloride, and serum albumin. Multivariable analysis demonstrated no statistically significant association between FGF-23 and sodium avidity measured by fractional excretion of sodium, or proximal or distal tubular sodium reabsorption, either before diuretic administration or at peak diuresis (P≥0.11 for all). Likewise, FGF-23 was not independently associated with parameters of diuretic resistance (diuretic excretion, cumulative urine and sodium output, and loop diuretic efficiency [P≥0.33 for all]) or neurohormonal activation (plasma or urine renin [P≥0.36 for all]). Moreover, the upper boundary of the 95% CI of all the partial correlations were ≤0.30, supporting the lack of meaningful correlations. FGF-23 was not associated with mortality in multivariable analysis (P=0.44).
Conclusions
FGF-23 was not meaningfully associated with any cardiorenal parameter in patients with heart failure. While our methods cannot rule out a small effect, FGF-23 is unlikely to be a primary driver of cardiorenal interactions.



Circ Heart Fail: 24 Oct 2021:CIRCHEARTFAILURE121008385; epub ahead of print
Ivey-Miranda JB, Stewart B, Cox ZL, McCallum W, ... Rao VS, Testani JM
Circ Heart Fail: 24 Oct 2021:CIRCHEARTFAILURE121008385; epub ahead of print | PMID: 34689571
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Abstract

Association of Hyper-Polypharmacy With Clinical Outcomes in Heart Failure With Preserved Ejection Fraction.

Minamisawa M, Claggett B, Suzuki K, Hegde SM, ... Solomon SD, Vardeny O
Background
Polypharmacy is associated with a poor prognosis in the elderly, however, information on the association of polypharmacy with cardiovascular outcomes in heart failure with preserved ejection fraction is sparse. This study sought to investigate the relationship between polypharmacy and adverse cardiovascular events in patients with heart failure with preserved ejection fraction.
Methods
Baseline total number of medications was determined in 1758 patients with heart failure with preserved ejection fraction enrolled in the Americas regions of the TOPCAT trial (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist), by 3 categories: nonpolypharmacy (<5 medications), polypharmacy (5-9), and hyper-polypharmacy (≥10). We examined the relationship of polypharmacy status with the primary outcome (cardiovascular death, HF hospitalization, or aborted cardiac arrest), hospitalizations for any reason, and serious adverse events.
Results
The proportion of patients taking 5 or more medications was 92.5% (inclusive of polypharmacy [38.7%] and hyper-polypharmacy [53.8%]). Over a 2.9-year median follow-up, compared with patients with polypharmacy, hyper-polypharmacy was associated with an increased risk for the primary outcome, hospitalization for any reason and any serious adverse events in the univariable analysis, but not significantly associated with mortality. After multivariable adjustment for demographic and comorbidities, hyper-polypharmacy remained significantly associated with an increased risk for hospitalization for any reason (hazard ratio, 1.22 [95% CI, 1.05-1.41]; P=0.009) and any serious adverse events (hazard ratio, 1.23 [95% CI, 1.07-1.42]; P=0.005), whereas the primary outcome was no longer statistically significant.
Conclusions
Hyper-polypharmacy was common and associated with an elevated risk of hospitalization for any reason and any serious adverse events in patients with heart failure with preserved ejection fraction. There were no significant associations between polypharmacy status and mortality.



Circ Heart Fail: 21 Oct 2021:CIRCHEARTFAILURE120008293; epub ahead of print
Minamisawa M, Claggett B, Suzuki K, Hegde SM, ... Solomon SD, Vardeny O
Circ Heart Fail: 21 Oct 2021:CIRCHEARTFAILURE120008293; epub ahead of print | PMID: 34674539
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Abstract

Diuretic Changes, Health Care Resource Utilization, and Clinical Outcomes for Heart Failure With Reduced Ejection Fraction: From the Change the Management of Patients With Heart Failure Registry.

Khan MS, Greene SJ, Hellkamp AS, DeVore AD, ... Fonarow GC, Butler J
Background
Diuretics are a mainstay therapy for the symptomatic treatment of heart failure. However, in contemporary US outpatient practice, the degree to which diuretic dosing changes over time and the associations with clinical outcomes and health care resource utilization are unknown.
Methods
Among 3426 US outpatients with chronic heart failure with reduced ejection fraction in the Change the Management of Patients with Heart Failure registry with complete medication data and who were prescribed a loop diuretic, diuretic dose increase was defined as: (1) change to a total daily dose higher than their previous total daily dose, (2) addition of metolazone to the regimen, (3) change from furosemide to either bumetanide or torsemide, and the change persists for at least 7 days. Adjusted hazard ratios or rate ratios along with 95% CIs were reported for clinical outcomes among patients with an increase in oral diuretic dose versus no increase in diuretic dose.
Results
Overall, 796 (23%) had a diuretic dose increase (18 episodes per 100 patient-years). The proportion of patients with dyspnea at rest (38% versus 26%), dyspnea at exertion (79% versus 67%), orthopnea (32% versus 21%), edema (60% versus 43%), and weight gain (40% versus 23%) were significantly (all P <0.001) higher in the diuretic increase group. Baseline angiotensin-converting enzyme inhibitor/angiotensin receptor blocker (hazard ratio, 0.75 [95% CI, 0.65-0.87]) use were associated with lower likelihood of diuretic increase over time. Patients with a diuretic dose increase had a significantly higher number of heart failure hospitalizations (rate ratio, 2.53 [95% CI, 2.10-3.05]), emergency department visits (rate ratio, 1.84 [95% CI, 1.56-2.17]), and home health visits (rate ratio, 1.88 [95% CI, 1.39-2.54]), but not all-cause mortality (hazard ratio, 1.10 [95% CI, 0.89-1.36]). Similarly, greater furosemide dose equivalent increases were associated with greater resource utilization but not with mortality, compared with smaller increases.
Conclusions
In this contemporary US registry, 1 in 4 patients with heart failure with reduced ejection fraction had outpatient escalation of diuretic therapy over longitudinal follow-up, and these patients were more likely to have sign/symptoms of congestion. Outpatient diuretic dose escalation of any magnitude was associated with heart failure hospitalizations and resource utilization, but not all-cause mortality.



Circ Heart Fail: 21 Oct 2021:CIRCHEARTFAILURE121008351; epub ahead of print
Khan MS, Greene SJ, Hellkamp AS, DeVore AD, ... Fonarow GC, Butler J
Circ Heart Fail: 21 Oct 2021:CIRCHEARTFAILURE121008351; epub ahead of print | PMID: 34674536
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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 Sep 2021; 14:e008134
Calò L, Bianchi V, Ferraioli D, Santini L, ... D'Onofrio A, Full list of participant centers and investigators
Circ Heart Fail: 29 Sep 2021; 14:e008134 | PMID: 34190592
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Abstract

Practice Patterns and Patient Outcomes After Widespread Adoption of Remote Heart Failure Care.

Yuan N, Botting PG, Elad Y, Miller SJ, ... Ebinger JE, Kittleson MM
Background
An unprecedented shift to remote heart failure outpatient care occurred during the coronavirus disease 2019 (COVID-19) pandemic. Given challenges inherent to remote care, we studied whether remote visits (video or telephone) were associated with different patient usage, clinician practice patterns, and outcomes.
Methods
We included all ambulatory cardiology visits for heart failure at a multisite health system from April 1, 2019, to December 31, 2019 (pre-COVID) or April 1, 2020, to December 31, 2020 (COVID era), resulting in 10 591 pre-COVID in-person, 7775 COVID-era in-person, 1009 COVID-era video, and 2322 COVID-era telephone visits. We used multivariable logistic and Cox proportional hazards regressions with propensity weighting and patient clustering to study ordering practices and outcomes.
Results
Compared with in-person visits, video visits were used more often by younger (mean 64.7 years [SD 14.5] versus 74.2 [14.1]), male (68.3% versus 61.4%), and privately insured (45.9% versus 28.9%) individuals (P<0.05 for all). Remote visits were more frequently used by non-White patients (35.8% video, 37.0% telephone versus 33.2% in-person). During remote visits, clinicians were less likely to order diagnostic testing (odds ratio, 0.20 [0.18-0.22] video versus in-person, 0.18 [0.17-0.19] telephone versus in-person) or prescribe β-blockers (0.82 [0.68-0.99], 0.35 [0.26-0.47]), mineralocorticoid receptor antagonists (0.69 [0.50-0.96], 0.48 [0.35-0.66]), or loop diuretics (0.67 [0.53-0.85], 0.45 [0.37-0.55]). During telephone visits, clinicians were less likely to prescribe ACE (angiotensin-converting enzyme) inhibitor/ARB (angiotensin receptor blockers)/ARNIs (angiotensin receptor-neprilysin inhibitors; 0.54 [0.40-0.72]). Telephone visits but not video visits were associated with higher rates of 90-day mortality (1.82 [1.14-2.90]) and nonsignificant trends towards higher rates of 90-day heart failure emergency department visits (1.34 [0.97-1.86]) and hospitalizations (1.36 [0.98-1.89]).
Conclusions
Remote visits for heart failure care were associated with reduced diagnostic testing and guideline-directed medical therapy prescription. Telephone but not video visits were associated with increased 90-day mortality.



Circ Heart Fail: 29 Sep 2021:CIRCHEARTFAILURE121008573; epub ahead of print
Yuan N, Botting PG, Elad Y, Miller SJ, ... Ebinger JE, Kittleson MM
Circ Heart Fail: 29 Sep 2021:CIRCHEARTFAILURE121008573; epub ahead of print | PMID: 34587763
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Abstract

Clinical Heart Failure Among Patients With and Without Severe Mental Illness and the Association With Long-Term Outcomes.

Polcwiartek C, Loewenstein D, Friedman DJ, Johansson KG, ... Jackson KP, Atwater BD
Background
Patients with severe mental illness (SMI) including schizophrenia, bipolar disorder, and severe depression have earlier onset of cardiovascular risk factors, predisposing to worse future heart failure (HF) compared with the general population. We investigated associations between the presence/absence of SMI and long-term HF outcomes.
Methods
We identified patients with HF with and without SMI in the Duke University Health System from 2002 to 2017. Using multivariable Cox regression, we examined the primary outcome of all-cause mortality. Secondary outcomes included rates of implantable cardioverter defibrillator use, cardiac resynchronization therapy, left ventricular assist device implantation, and heart transplantation.
Results
We included 20 906 patients with HF (SMI, n=898; non-SMI, n=20 008). Patients with SMI presented clinically 7 years earlier than those without SMI. We observed an interaction between SMI and sex on all-cause mortality (P=0.002). Excess mortality was observed among men with SMI compared with men without SMI (hazard ratio, 1.36 [95% CI, 1.17-1.59]). No association was observed among women with and without SMI (hazard ratio, 0.97 [95% CI, 0.84-1.12]). Rates of implantable cardioverter defibrillator use, cardiac resynchronization therapy, left ventricular assist device implantation, and heart transplantation were similar between patients with and without SMI (6.1% versus 7.9%, P=0.095). Patients with SMI receiving these procedures for HF experienced poorer prognosis than those without SMI (hazard ratio, 2.12 [95% CI, 1.08-4.15]).
Conclusions
SMI was associated with adverse HF outcome among men and not women. Despite equal access to procedures for HF between patients with and without SMI, those with SMI experienced excess postprocedural mortality. Our data highlight concurrent sex- and mental health-related disparities in HF prognosis, suggesting that patients with SMI, especially men, merit closer follow-up.



Circ Heart Fail: 29 Sep 2021:CIRCHEARTFAILURE121008364; epub ahead of print
Polcwiartek C, Loewenstein D, Friedman DJ, Johansson KG, ... Jackson KP, Atwater BD
Circ Heart Fail: 29 Sep 2021:CIRCHEARTFAILURE121008364; epub ahead of print | PMID: 34587762
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Abstract

Protein Aggregation Is an Early Manifestation of Phospholamban p.(Arg14del)-Related Cardiomyopathy: Development of PLN-R14del-Related Cardiomyopathy.

Eijgenraam TR, Boogerd CJ, Stege NM, Oliveira Nunes Teixeira V, ... Silljé HHW, de Boer RA
Background
The p.(Arg14del) pathogenic variant (R14del) of the PLN (phospholamban) gene is a prevalent cause of cardiomyopathy with heart failure. The exact underlying pathophysiology is unknown, and a suitable therapy is unavailable. We aim to identify molecular perturbations underlying this cardiomyopathy in a clinically relevant PLN-R14del mouse model.
Methods
We investigated the progression of cardiomyopathy in PLN-R14∆/∆ mice using echocardiography, ECG, and histological tissue analysis. RNA sequencing and mass spectrometry were performed on cardiac tissues at 3 (before the onset of disease), 5 (mild cardiomyopathy), and 8 (end stage) weeks of age. Data were compared with cardiac expression levels of mice that underwent myocardial ischemia-reperfusion or myocardial infarction surgery, in an effort to identify alterations that are specific to PLN-R14del-related cardiomyopathy.
Results
At 3 weeks of age, PLN-R14∆/∆ mice had normal cardiac function, but from the age of 4 weeks, we observed increased myocardial fibrosis and impaired global longitudinal strain. From 5 weeks onward, ventricular dilatation, decreased contractility, and diminished ECG voltages were observed. PLN protein aggregation was present before onset of functional deficits. Transcriptomics and proteomics revealed differential regulation of processes involved in remodeling, inflammation, and metabolic dysfunction, in part, similar to ischemic heart disease. Altered protein homeostasis pathways were identified exclusively in PLN-R14∆/∆ mice, even before disease onset, in concert with aggregate formation.
Conclusions
We mapped the development of PLN-R14del-related cardiomyopathy and identified alterations in proteostasis and PLN protein aggregation among the first manifestations of this disease, which could possibly be a novel target for therapy.



Circ Heart Fail: 29 Sep 2021:CIRCHEARTFAILURE121008532; epub ahead of print
Eijgenraam TR, Boogerd CJ, Stege NM, Oliveira Nunes Teixeira V, ... Silljé HHW, de Boer RA
Circ Heart Fail: 29 Sep 2021:CIRCHEARTFAILURE121008532; epub ahead of print | PMID: 34587756
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Abstract

Yellow Wine Polyphenolic Compound Protects Against Doxorubicin-Induced Cardiotoxicity by Modulating the Composition and Metabolic Function of the Gut Microbiota.

Lin H, Meng L, Sun Z, Sun S, ... Chi J, Guo H
Background
Dietary polyphenols help to prevent cardiovascular diseases, and interactions between polyphenols and gut microbiota are known to exist. In this study, we speculated that gut microbiota-mediated metabolite regulation might contribute to the anticardiotoxic effects of yellow wine polyphenolic compound (YWPC) in doxorubicin (DOX)-treated rats.
Methods
16S-rDNA sequencing was performed to analyze the effects of YWPC on the gut microbiota in DOX-treated rats (n=6). Antibiotics were used to investigate the contribution of the altered microbiome to the role of YWPC (n=6). Plasma metabolomics were also analyzed by untargeted gas chromatography-mass spectrometry systems.
Results
YWPC ameliorated DOX-mediated cardiotoxicity, as evidenced by increased cardiac and mitochondrial function and reduced levels of inflammation and myocardial apoptosis (P<0.05 for all). The low abundance of Escherichia-Shigella, Dubosiella, and Allobaculum, along with enrichment of Muribaculaceae_unclassified, Ralstonia, and Rikenellaceae_RC9_gut_group in the gut, suggested that YWPC ameliorated DOX-induced microbial dysbiosis. YWPC also influenced the levels of metabolites altered by DOX, resulting in lower arachidonic acid and linoleic acid metabolism and higher tryptophan metabolite levels (P<0.05 for all). Correlational studies indicated that YWPC alleviated DOX-induced inflammation and mitochondrial dysfunction by modulating the gut microbial community and its associated metabolites. Antibiotic treatment exacerbated cardiotoxicity in DOX-treated rats, and its effect on the gut microbiota partly abolished the anticardiotoxic effects of YWPC, suggesting that the microbiota is required for the cardioprotective role of YWPC.
Conclusions
YWPC protected against DOX-induced cardiotoxicity in a gut microbiota-dependent manner. This supports the use of dietary polyphenols as a therapeutic approach for the treatment of cardiovascular diseases via microbiota regulation.



Circ Heart Fail: 29 Sep 2021; 14:e008220
Lin H, Meng L, Sun Z, Sun S, ... Chi J, Guo H
Circ Heart Fail: 29 Sep 2021; 14:e008220 | PMID: 34665676
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Abstract

Endothelial Stromal PD-L1 (Programmed Death Ligand 1) Modulates CD8 T-Cell Infiltration After Heart Transplantation.

Bracamonte-Baran W, Gilotra NA, Won T, Rodriguez KM, ... Brandacher G, Čiháková D
Background
The role of checkpoint axes in transplantation has been partially addressed in animal models but not in humans. Occurrence of fulminant myocarditis with allorejection-like immunologic features in patients under anti-PD1 (programmed death cell protein 1) treatment suggests a key role of the PD1/PD-L1 (programmed death ligand 1) axis in cardiac immune homeostasis.
Methods
We cross-sectionally studied 23 heart transplant patients undergoing surveillance endomyocardial biopsy. Endomyocardial tissue and peripheral blood mononuclear cells were analyzed by flow cytometry. Multivariate logistic regression analyses including demographic, clinical, and hemodynamic parameters were performed. Murine models were used to evaluate the impact of PD-L1 endothelial graft expression in allorejection.
Results
We found that myeloid cells dominate the composition of the graft leukocyte compartment in most patients, with variable T-cell frequencies. The CD (cluster of differentiation) 4:CD8 T-cell ratios were between 0 and 1.5. The proportion of PD-L1 expressing cells in graft endothelial cells, fibroblasts, and myeloid leukocytes ranged from negligible up to 60%. We found a significant inverse logarithmic correlation between the proportion of PD-L1+HLA (human leukocyte antigen)-DR+ endothelial cells and CD8+ T cells (slope, -18.3 [95% CI, -35.3 to -1.3]; P=0.030). PD-L1 expression and leukocyte patterns were independent of demographic, clinical, and hemodynamic parameters. We confirmed the importance of endothelial PD-L1 expression in a murine allogeneic heart transplantation model, in which Tie2Crepdl1fl/fl grafts lacking PD-L1 in endothelial cells were rejected significantly faster than controls.
Conclusions
Loss of graft endothelial PD-L1 expression may play a role in regulating CD8+ T-cell infiltration in human heart transplantation. Murine model results suggest that loss of graft endothelial PD-L1 may facilitate alloresponses and rejection.



Circ Heart Fail: 23 Sep 2021:CIRCHEARTFAILURE120007982; epub ahead of print
Bracamonte-Baran W, Gilotra NA, Won T, Rodriguez KM, ... Brandacher G, Čiháková D
Circ Heart Fail: 23 Sep 2021:CIRCHEARTFAILURE120007982; epub ahead of print | PMID: 34555935
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Abstract

Clinically Translatable Prevention of Anthracycline Cardiotoxicity by Dexrazoxane Is Mediated by Topoisomerase II Beta and Not Metal Chelation.

Jirkovský E, Jirkovská A, Bavlovič-Piskáčková H, Skalická V, ... Štěrbová-Kovaříková P, Štěrba M
Background
Anthracycline-induced heart failure has been traditionally attributed to direct iron-catalyzed oxidative damage. Dexrazoxane (DEX)-the only drug approved for its prevention-has been believed to protect the heart via its iron-chelating metabolite ADR-925. However, direct evidence is lacking, and recently proposed TOP2B (topoisomerase II beta) hypothesis challenged the original concept.
Methods
Pharmacokinetically guided study of the cardioprotective effects of clinically used DEX and its chelating metabolite ADR-925 (administered exogenously) was performed together with mechanistic experiments. The cardiotoxicity was induced by daunorubicin in neonatal ventricular cardiomyocytes in vitro and in a chronic rabbit model in vivo (n=50).
Results
Intracellular concentrations of ADR-925 in neonatal ventricular cardiomyocytes and rabbit hearts after treatment with exogenous ADR-925 were similar or exceeded those observed after treatment with the parent DEX. However, ADR-925 did not protect neonatal ventricular cardiomyocytes against anthracycline toxicity, whereas DEX exhibited significant protective effects (10-100 µmol/L; P<0.001). Unlike DEX, ADR-925 also had no significant impact on daunorubicin-induced mortality, blood congestion, and biochemical and functional markers of cardiac dysfunction in vivo (eg, end point left ventricular fractional shortening was 32.3±14.7%, 33.5±4.8%, 42.7±1.0%, and 41.5±1.1% for the daunorubicin, ADR-925 [120 mg/kg]+daunorubicin, DEX [60 mg/kg]+daunorubicin, and control groups, respectively; P<0.05). DEX, but not ADR-925, inhibited and depleted TOP2B and prevented daunorubicin-induced genotoxic damage. TOP2B dependency of the cardioprotective effects was probed and supported by experiments with diastereomers of a new DEX derivative.
Conclusions
This study strongly supports a new mechanistic paradigm that attributes clinically effective cardioprotection against anthracycline cardiotoxicity to interactions with TOP2B but not metal chelation and protection against direct oxidative damage.



Circ Heart Fail: 22 Sep 2021:CIRCHEARTFAILURE120008209; epub ahead of print
Jirkovský E, Jirkovská A, Bavlovič-Piskáčková H, Skalická V, ... Štěrbová-Kovaříková P, Štěrba M
Circ Heart Fail: 22 Sep 2021:CIRCHEARTFAILURE120008209; epub ahead of print | PMID: 34551586
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Abstract

Impact of Race on Clinical Outcomes After Implantation With a Fully Magnetically Levitated Left Ventricular Assist Device: An Analysis From the MOMENTUM 3 Trial.

Sheikh FH, Ravichandran AK, Goldstein DJ, Agarwal R, ... Franke A, Mehra MR
Background
Heart failure disproportionately affects Black patients. Whether differences among race influence outcomes in advanced heart failure with use of a fully magnetically levitated continuous-flow left ventricular assist device remains uncertain.
Methods
We included 515 IDE (Investigational Device Exemption) clinical trial patients and 500 Continued Access Protocol patients implanted with the HeartMate 3 left ventricular assist device in the MOMENTUM 3 study (Multicenter Study of MagLev Technology in Patients Undergoing Mechanical Circulatory Support Therapy With HeartMate 3). Outcomes were compared between Black and White left ventricular assist device recipients for the primary end point of survival free of disabling stroke or reoperation to replace or remove a malfunctioning device at 2 years, overall survival, adverse events, 6-minute walk distance, and quality of life scores.
Results
Of 1015 HeartMate 3 patients, 675 were self-identified as White and 285 as Black individuals. The Black patient cohort was younger, more obese and with a history of hypertension, and more nonischemic cause of heart failure, relative to the White patient group. Black and White patients did not experience a difference in the primary end point (81.1% versus 77.9%; hazard ratio, 1.08 [95% CI, 0.76-1.54], P=0.6568). Black patients were at higher risk of adverse events (calculated as events per 100 patient-years), including bleeding (75.4 versus 63.5; P<0.0001), stroke (9.5 versus 7.2; P=0.0183), and hypertension (10.1 versus 3.2; P<0.0001). The 6-minute walk distance was not different at baseline and 6 months between the groups, however, the absolute change from baseline was greater for White patients (median: +183.0 [interquartile range, 42.0-335.3] versus +163.8 [interquartile range, 42.3-315.0] meters, P=0.01). The absolute quality of life measurement (EuroQoL group, 5-dimension, 5-level instrument visual analog scale) at baseline and 6 months was better in the Black patient group, but relative improvement from baseline to 6 months was greater in White patients (median: +20.0 [interquartile range, 5.0-40.0] versus +25.0 [interquartile range, 10.0-45.0]; P=0.0298).
Conclusions
Although the survival free of disabling stroke or reoperation to replace/remove a malfunctioning device at 2 years with the HM 3 left ventricular assist device did not differ by race, Black HeartMate 3 patients experienced a higher morbidity burden and smaller gains in functional capacity and quality of life when compared with White patients. These findings require efforts designed to better understand and overcome these gaps through systematic identification and tackling of putative factors.
Registration
URL: https://www.clinicaltrials.gov; Unique identifiers: NCT02224755 and NCT02892955.



Circ Heart Fail: 15 Sep 2021:CIRCHEARTFAILURE120008360; epub ahead of print
Sheikh FH, Ravichandran AK, Goldstein DJ, Agarwal R, ... Franke A, Mehra MR
Circ Heart Fail: 15 Sep 2021:CIRCHEARTFAILURE120008360; epub ahead of print | PMID: 34525837
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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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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

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: 30 Aug 2021; 14:e008372
Valero-Muñoz M, Oh A, Faudoa E, Bretón-Romero R, ... Bujor A, Sam F
Circ Heart Fail: 30 Aug 2021; 14:e008372 | PMID: 34407636
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Impact:
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: 30 Aug 2021; 14:e008242
Ezekowitz J, Mentz RJ, Westerhout CM, Sweitzer NK, ... Hernandez AF, Armstrong PW
Circ Heart Fail: 30 Aug 2021; 14:e008242 | PMID: 34407626
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Impact:
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: 30 Aug 2021; 14:e008510
Sonkawade SD, Pokharel S, Karthikeyan B, Kim M, ... Spernyak JA, Sharma UC
Circ Heart Fail: 30 Aug 2021; 14:e008510 | PMID: 34415177
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Impact:
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: 30 Aug 2021; 14:e008416
Acharya D, Loyaga-Rendon RY, Chatterjee A, Rajapreyar I, Lee K
Circ Heart Fail: 30 Aug 2021; 14:e008416 | 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: 30 Aug 2021; 14:e007616
Domínguez F, Lalaguna L, López-Olañeta M, Villalba-Orero M, ... García-Pavía P, Lara-Pezzi E
Circ Heart Fail: 30 Aug 2021; 14:e007616 | PMID: 34412508
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Impact:
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: 30 Aug 2021; 14:e008076
Denfeld QE, Habecker BA, Camacho SA, Roberts Davis M, ... Winters-Stone K, Lee CS
Circ Heart Fail: 30 Aug 2021; 14:e008076 | PMID: 34428925
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Impact:
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; 14:e008236
Gilotra NA, DeVore AD, Povsic TJ, Hays AG, ... Davis R, Kass DA
Circ Heart Fail: 30 Aug 2021; 14:e008236 | 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: 30 Aug 2021; 14:e008284
Hejjaji V, Tang Y, Coles T, Jones PG, ... Piña IL, Spertus JA
Circ Heart Fail: 30 Aug 2021; 14:e008284 | PMID: 34465123
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Abstract

Long-Term Electrocardiographic and Echocardiographic Progression of Arrhythmogenic Right Ventricular Cardiomyopathy and Their Correlation With Ventricular Tachyarrhythmias.

Kalantarian S, Åström Aneq M, Svetlichnaya J, Sharma S, ... Klein L, Scheinman MM
Background
Prior studies of structural and electrocardiographic changes in arrhythmogenic right ventricular (RV) cardiomyopathy and their role in predicting ventricular arrhythmias (ventricular tachycardia) have shown conflicting results.
Methods
We reviewed 405 ECGs, 315 transthoracic echocardiographies, and 441 implantable cardioverter defibrillator interrogations in 64 arrhythmogenic RV cardiomyopathy patients (56% men, mean age [SD], 44.2 [14.6] years) over a mean follow-up of 10 (range, 2.3-19) years. Generalized estimating equations were used to identify the association between ECG abnormalities, clinical variables, and transthoracic echocardiographic measurements (>mild degree of tricuspid regurgitation, RV outflow tract diameter in parasternal long axis and short axis, RV end-diastolic area, fractional area change).
Results
There was a 4.65 (95% CI, 0.51%-8.8%) increase in RV end-diastolic area, a 3.75 (95% CI, 1.17%-6.34%) decrease in fractional area change, and 1.9 (95% CI, 1.3-2.8) higher odds (odds ratio) of RV wall motion abnormality with every 5-year increase in age after patients\' first transthoracic echocardiography. >Mild tricuspid regurgitation was an independent predictor of RV enlargement and dysfunction (hazard ratio of >10% drop in fractional area change from baseline [95% CI], 3.51 [1.77-6.95] and hazard ratio of >10% increase in RV end-diastolic area from baseline [95% CI], 4.90 [2.52-9.52]). Patients with implantable cardioverter defibrillator were more likely to develop >mild tricuspid regurgitation and larger structural and functional disease progression. More pronounced increase in RV end-diastolic area was translated into higher rates of any ventricular tachycardia. Inferior T-wave inversions and sum of R waves (mm) in V1 to V3 were predictors of RV enlargement and dysfunction with the former also predicting risk of any ventricular tachycardia.
Conclusions
Arrhythmogenic RV cardiomyopathy is a progressive disease. Tricuspid regurgitation is an independent predictor of structural disease progression, which may be exacerbated by use of a transvenous implantable cardioverter defibrillator lead.



Circ Heart Fail: 30 Aug 2021; 14:e008121
Kalantarian S, Åström Aneq M, Svetlichnaya J, Sharma S, ... Klein L, Scheinman MM
Circ Heart Fail: 30 Aug 2021; 14:e008121 | PMID: 34550004
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Impact:
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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Impact:
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

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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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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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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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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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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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:

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