Journal: Circ Heart Fail

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Abstract

Association Between Coffee Intake and Incident Heart Failure Risk: A Machine Learning Analysis of the FHS, the ARIC Study, and the CHS.

Stevens LM, Linstead E, Hall JL, Kao DP
Background
Coronary heart disease, heart failure (HF), and stroke are complex diseases with multiple phenotypes. While many risk factors for these diseases are well known, investigation of as-yet unidentified risk factors may improve risk assessment and patient adherence to prevention guidelines. We investigated the diet domain in FHS (Framingham Heart Study), CHS (Cardiovascular Heart Study), and the ARIC study (Atherosclerosis Risk in Communities) to identify potential lifestyle and behavioral factors associated with coronary heart disease, HF, and stroke.
Methods
We used machine learning feature selection based on random forest analysis to identify potential risk factors associated with coronary heart disease, stroke, and HF in FHS. We evaluated the significance of selected variables using univariable and multivariable Cox proportional hazards analysis adjusted for known cardiovascular risks. Findings from FHS were then validated using CHS and ARIC.
Results
We identified multiple dietary and behavioral risk factors for cardiovascular disease outcomes including marital status, red meat consumption, whole milk consumption, and coffee consumption. Among these dietary variables, increasing coffee consumption was associated with decreasing long-term risk of HF congruently in FHS, ARIC, and CHS.
Conclusions
Higher coffee intake was found to be associated with reduced risk of HF in all three studies. Further study is warranted to better define the role, possible causality, and potential mechanism of coffee consumption as a potential modifiable risk factor for HF.



Circ Heart Fail: 08 Feb 2021:CIRCHEARTFAILURE119006799; epub ahead of print
Stevens LM, Linstead E, Hall JL, Kao DP
Circ Heart Fail: 08 Feb 2021:CIRCHEARTFAILURE119006799; epub ahead of print | PMID: 33557575
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Abstract

Transcriptomic Analysis of Right Ventricular Remodeling in Two Rat Models of Pulmonary Hypertension: Identification and Validation of EMT in Human Right Ventricular Failure.

Park JF, Clark VR, Banerjee S, Hong J, ... Saddic L, Umar S
Background
Right ventricular (RV) dysfunction is a significant prognostic determinant of morbidity and mortality in pulmonary arterial hypertension (PAH). Despite the importance of RV function in PAH, the underlying molecular mechanisms of RV dysfunction secondary to PAH remain unclear. We aim to identify and compare molecular determinants of RV failure using RNA sequencing of RV tissue from 2 clinically relevant animal models of PAH.
Methods
We performed RNA sequencing on RV from rats treated with monocrotaline or Sugen with hypoxia/normoxia. PAH and RV failure were confirmed by catheterization and echocardiography. We validated the RV transcriptome results using quantitative real-time polymerase chain reaction, immunofluorescence, and Western blot. Immunohistochemistry and immunofluorescence were performed on human RV tissue from control (n=3) and PAH-induced RV failure patients (n=5).
Results
We identified similar transcriptomic profiles of RV from monocrotaline- and Sugen with hypoxia-induced RV failure. Pathway analysis showed genes enriched in epithelial-to-mesenchymal transition, inflammation, and metabolism. Histological staining of human RV tissue from patients with RV failure secondary to PAH revealed significant RV fibrosis and endothelial-to-mesenchymal transition, as well as elevated Cellular Communication Network Factor 2 (top gene implicated in epithelial-to-mesenchymal transition/endothelial-to-mesenchymal transition) expression in perivascular areas compared with normal RV.
Conclusions
Transcriptomic signature of RV failure in monocrotaline and Sugen with hypoxia models showed similar gene expressions and biological pathways. We provide translational relevance of this transcriptomic signature using RV from patients with PAH to demonstrate evidence of epithelial-to-mesenchymal transition/endothelial-to-mesenchymal transition and protein expression of Cellular Communication Network Factor 2 (CTGF [connective tissue growth factor]). Targeting specific molecular mechanisms responsible for RV failure in monocrotaline and Sugen with hypoxia models may identify novel therapeutic strategies for PAH-associated RV failure.



Circ Heart Fail: 04 Feb 2021:CIRCHEARTFAILURE120007058; epub ahead of print
Park JF, Clark VR, Banerjee S, Hong J, ... Saddic L, Umar S
Circ Heart Fail: 04 Feb 2021:CIRCHEARTFAILURE120007058; epub ahead of print | PMID: 33541093
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Abstract

Risk-Based Approach for the Prediction and Prevention of Heart Failure.

Sinha A, Gupta DK, Yancy CW, Shah SJ, ... Lloyd-Jones DM, Khan SS
Targeted prevention of heart failure (HF) remains a critical need given the high prevalence of HF morbidity and mortality. Similar to risk-based prevention of atherosclerotic cardiovascular disease, optimal HF prevention strategies should include quantification of risk in the individual patient. In this review, we discuss incorporation of a quantitative risk-based approach into the existing HF staging landscape and the clinical opportunity that exists to translate available data on risk estimation to help guide personalized decision making. We first summarize the recent development of key HF risk prediction tools that can be applied broadly at a population level to estimate risk of incident HF. Next, we provide an in-depth description of the clinical utility of biomarkers to personalize risk estimation in select patients at the highest risk of developing HF. We also discuss integration of genomics-enhanced approaches (eg, Titin [TTN]) and other risk-enhancing features to reclassify risk with a precision medicine approach to HF prevention. Although sequential testing is very likely to identify low and high-risk individuals with excellent accuracy, whether or not interventions based on these risk models prevent HF in clinical practice requires prompt attention including randomized placebo-controlled trials of candidate therapies in risk-enriched populations. We conclude with a summary of unanswered questions and gaps in evidence that must be addressed to move the field of HF risk assessment forward.



Circ Heart Fail: 03 Feb 2021:CIRCHEARTFAILURE120007761; epub ahead of print
Sinha A, Gupta DK, Yancy CW, Shah SJ, ... Lloyd-Jones DM, Khan SS
Circ Heart Fail: 03 Feb 2021:CIRCHEARTFAILURE120007761; epub ahead of print | PMID: 33535771
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Abstract

Effect of Inotropes on Patient-Reported Health Status in End-Stage Heart Failure: A Review of Published Clinical Trials.

Clarke JD, Riello R, Allen LA, Psotka MA, ... Desai NR, Ahmad T
Background
A growing population of patients with end-stage heart failure (HF) with reduced ejection fraction has limited treatment options to improve their quality and quantity of life. Although positive inotropes have failed to show survival benefit, these agents may enhance patient-reported health status, that is, symptoms, functional status, and health-related quality of life. We sought to review the available clinical trial data on positive inotrope use in patients with end-stage HF and to summarize evidence supporting the use of these agents to improve health status of patients with end-stage HF.
Methods
A literature review of randomized controlled trials examining the use of positive inotropy in HF with reduced ejection fraction was conducted. We searched MEDLINE, SCOPUS, and Web of Science between January 1980 to December 2018 for randomized controlled trials that used as their main outcome measures the effects of inotrope therapy on (1) morbidity/mortality, (2) symptoms, (3) functional status, or (4) health-related quality of life. Inotropes of interest included adrenergic agents, phosphodiesterase inhibitors, calcium sensitizers, myosin activators, and SERCA2a (sarcoplasmic reticulum Ca2+-ATPase) modulators.
Results
Twenty-two out of 26 inotrope randomized controlled trials measured the effect of inotropes on at least one patient-reported health status domain. Among the 22 studies with patient-related health status outcomes, 11 (50%) gauged symptom response, 15 (68%) reported functional capacity changes, and 12 (54%) reported health-related quality of life measures. Fourteen (64%) of these trials noted positive outcomes in at least one health status domain measured; 11 (79%) of these positive studies used agents that worked through phosphodiesterase inhibition.
Conclusions
There has been a lack of standardization surrounding measurement of patient-centered outcomes in studies of inotropes for end-stage HF with reduced ejection fraction. The degree to which positive inotropes can improve patient-reported health status and the adverse risk they pose remains unknown.



Circ Heart Fail: 02 Feb 2021:CIRCHEARTFAILURE120007759; epub ahead of print
Clarke JD, Riello R, Allen LA, Psotka MA, ... Desai NR, Ahmad T
Circ Heart Fail: 02 Feb 2021:CIRCHEARTFAILURE120007759; epub ahead of print | PMID: 33530705
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Abstract

Efficacy and Safety of Sacubitril/Valsartan in High-Risk Patients in the PIONEER-HF Trial.

Berg DD, Samsky MD, Velazquez EJ, Duffy CI, ... Morrow DA, DeVore AD
Background
In patients stabilized during hospitalization for acute decompensated heart failure (HF), initiation of sacubitril/valsartan compared with enalapril decreased the risk of cardiovascular death or rehospitalization for HF without increasing the risk of adverse events. It is unknown whether potentially high-risk subpopulations have a similar risk-benefit profile.
Methods
PIONEER-HF (Comparison of Sacubitril/Valsartan Versus Enalapril on Effect on NT-proBNP [N-terminal pro-B type natriuretic peptide] in Patients Stabilized From an Acute HF Episode) was a multicenter, randomized, double-blind trial of in-hospital initiation of sacubitril/valsartan (n=440) versus enalapril (n=441) in patients stabilized during hospitalization for acute decompensated HF. The composite of cardiovascular death or rehospitalization for HF was adjudicated. Safety outcomes included worsening renal function, symptomatic hypotension, and hyperkalemia. We evaluated heterogeneity in the effect of sacubitril/valsartan on these efficacy and safety outcomes in selected subgroups of clinical concern: patients with baseline systolic blood pressure ≤118 mm Hg (median; n=448), baseline NT-proBNP >2701 pg/mL (median; n=395), estimated glomerular filtration rate <60 mL/minute per 1.73 m2 (n=455), ≥1 additional hospitalization for HF within the prior year (n=343), admission to the ICU during the index hospitalization (n=96), inotrope use during the index hospitalization (n=68), and severe congestion (n=219).
Results
The relative risk reduction in cardiovascular death or rehospitalization for HF with sacubitril/valsartan versus enalapril was consistent across all high-risk subgroups (P interaction=non-significant [NS] for each). The risks of worsening renal function, symptomatic hypotension, and hyperkalemia with sacubitril/valsartan versus enalapril were also consistent in each high- versus low-risk subgroup (P interaction=NS for each).
Conclusions
In high-risk subpopulations admitted for acute decompensated HF, treatment with sacubitril/valsartan after initial stabilization conferred a consistent reduction in cardiovascular death or rehospitalization for HF and was well tolerated.



Circ Heart Fail: 02 Feb 2021:CIRCHEARTFAILURE120007034; epub ahead of print
Berg DD, Samsky MD, Velazquez EJ, Duffy CI, ... Morrow DA, DeVore AD
Circ Heart Fail: 02 Feb 2021:CIRCHEARTFAILURE120007034; epub ahead of print | PMID: 33530704
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Abstract

Better Understanding the Disparity Associated With Black Race in Heart Transplant Outcomes: A National Registry Analysis.

Maredia H, Bowring MG, Massie AB, Bae S, ... Segev DL, Bush EL
Background
Black heart transplant recipients have higher risk of mortality than White recipients. Better understanding of this disparity, including subgroups most affected and timing of the highest risk, is necessary to improve care of Black recipients. We hypothesize that this disparity may be most pronounced among young recipients, as barriers to care like socioeconomic factors may be particularly salient in a younger population and lead to higher early risk of mortality.
Methods
We studied 22 997 adult heart transplant recipients using the Scientific Registry of Transplant Recipients data from January 2005 to 2017 using Cox regression models adjusted for recipient, donor, and transplant characteristics.
Results
Among recipients aged 18 to 30 years, Black recipients had 2.05-fold (95% CI, 1.67-2.51) higher risk of mortality compared with non-Black recipients (P<0.001, interaction P<0.001); however, the risk was significant only in the first year post-transplant (first year: adjusted hazard ratio, 2.30 [95% CI, 1.60-3.31], P<0.001; after first year: adjusted hazard ratio, 0.84 [95% CI, 0.54-1.29]; P=0.4). This association was attenuated among recipients aged 31 to 40 and 41 to 60 years, in whom Black recipients had 1.53-fold ([95% CI, 1.25-1.89] P<0.001) and 1.20-fold ([95% CI, 1.09-1.33] P<0.001) higher risk of mortality. Among recipients aged 61 to 80 years, no significant association was seen with Black race (adjusted hazard ratio, 1.12 [95% CI, 0.97-1.29]; P=0.1).
Conclusions
Young Black recipients have a high risk of mortality in the first year after heart transplant, which has been masked in decades of research looking at disparities in aggregate. To reduce overall racial disparities, clinical research moving forward should focus on targeted interventions for young Black recipients during this period.



Circ Heart Fail: 01 Feb 2021:CIRCHEARTFAILURE119006107; epub ahead of print
Maredia H, Bowring MG, Massie AB, Bae S, ... Segev DL, Bush EL
Circ Heart Fail: 01 Feb 2021:CIRCHEARTFAILURE119006107; epub ahead of print | PMID: 33525893
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Abstract

Mineralocorticoid Receptor in Smooth Muscle Contributes to Pressure Overload-Induced Heart Failure.

Kim SK, Biwer LA, Moss ME, Man JJ, ... Alcaide P, Jaffe IZ
Background
Mineralocorticoid receptor (MR) antagonists decrease heart failure (HF) hospitalization and mortality, but the mechanisms are unknown. Preclinical studies reveal that the benefits on cardiac remodeling and dysfunction are not completely explained by inhibition of MR in cardiomyocytes, fibroblasts, or endothelial cells. The role of MR in smooth muscle cells (SMCs) in HF has never been explored.
Methods
Male mice with inducible deletion of MR from SMCs (SMC-MR-knockout) and their MR-intact littermates were exposed to HF induced by 27-gauge transverse aortic constriction versus sham surgery. HF phenotypes and mechanisms were measured 4 weeks later using cardiac ultrasound, intracardiac pressure measurements, exercise testing, histology, cardiac gene expression, and leukocyte flow cytometry.
Results
Deletion of MR from SMC attenuated transverse aortic constriction-induced HF with statistically significant improvements in ejection fraction, cardiac stiffness, chamber dimensions, intracardiac pressure, pulmonary edema, and exercise capacity. Mechanistically, SMC-MR-knockout protected from adverse cardiac remodeling as evidenced by decreased cardiomyocyte hypertrophy and fetal gene expression, interstitial and perivascular fibrosis, and inflammatory and fibrotic gene expression. Exposure to pressure overload resulted in a statistically significant decline in cardiac capillary density and coronary flow reserve in MR-intact mice. These vascular parameters were improved in SMC-MR-knockout mice compared with MR-intact littermates exposed to transverse aortic constriction.
Conclusions
These results provide a novel paradigm by which MR inhibition may be beneficial in HF by blocking MR in SMC thereby improving cardiac blood supply in the setting of pressure overload-induced hypertrophy thereby mitigating the adverse cardiac remodeling that contributes to HF progression and symptoms.



Circ Heart Fail: 31 Jan 2021:CIRCHEARTFAILURE120007279; epub ahead of print
Kim SK, Biwer LA, Moss ME, Man JJ, ... Alcaide P, Jaffe IZ
Circ Heart Fail: 31 Jan 2021:CIRCHEARTFAILURE120007279; epub ahead of print | PMID: 33517669
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Abstract

Exercise Ventricular Rates, Cardiopulmonary Exercise Performance, and Mortality in Patients With Heart Failure With Atrial Fibrillation.

Elshazly MB, Wilkoff BL, Tarakji K, Wu Y, ... Wazni O, Cho L
Background
In heart failure (HF) with sinus rhythm, resting and exercise heart rates correlate with exercise capacity and mortality. However, in HF with atrial fibrillation (AF), this correlation is unknown. Our aim is to investigate the association of resting and exercise ventricular rates (VRs) with exercise capacity and mortality in HF with AF.
Methods
We identified 903 patients with HF and AF referred for cardiopulmonary stress testing. AF was defined as history of AF and AF during cardiopulmonary stress testing. We constructed multivariable models to evaluate the association of resting VR, peak exercise VR, VR reserve (peak VR-resting VR), and chronotropic index with (1) peak oxygen consumption (PVO) ≤18 mL/kg per minute, (2) continuous PVO, and (3) 10-year all-cause mortality.
Results
Median (25th-75th percentile) age was 60 (52-67) years, left ventricular ejection fraction was 25 (15-50)%, and 76.1% were males. Patients with lower (quartile 1) compared with higher (quartile 4) peak VR, VR reserve, and chronotropic index were more likely to have PVO ≤18 mL/kg per min (adjusted odds ratio [95% CI]: 14.92 [8.07-27.58], 24.60 [12.36-48.98], and 22.31 [11.24-44.27], respectively), and higher all-cause mortality (adjusted hazard ratio [95% CI]: 2.56 [1.62-4.04], 2.29 [1.47-3.59], and 2.30 [1.51-3.49], respectively). For every 10 beats per minute increase in VR reserve, PVO increased by 1.05 mL/kg per minute (B-coefficient [95% CI]: 1.05 [0.94-1.15]) and mortality decreased by 12% (adjusted hazard ratio [95% CI]: 0.88 [0.83-0.94]). Resting VR was associated with PVO (B-coefficient [95% CI]: -0.46 [-0.70 to -0.23]) but not mortality (adjusted hazard ratio [95% CI]: 0.97 [0.88-1.06]).
Conclusions
In patients with HF and AF, higher resting VR and lower peak exercise VR, VR reserve, and chronotropic index were all associated with worse peak exercise capacity, but only lower exercise VR parameters were associated with higher mortality. Dedicated studies are needed to gauge whether modulating exercise VR enhances exercise performance and outcomes.



Circ Heart Fail: 21 Jan 2021:CIRCHEARTFAILURE120007451; epub ahead of print
Elshazly MB, Wilkoff BL, Tarakji K, Wu Y, ... Wazni O, Cho L
Circ Heart Fail: 21 Jan 2021:CIRCHEARTFAILURE120007451; epub ahead of print | PMID: 33478244
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Abstract

Sustained Improvement in Diastolic Reserve Following Percutaneous Pericardiotomy in a Porcine Model of Heart Failure With Preserved Ejection Fraction.

Jain CC, Pedrotty D, Araoz PA, Sugrue A, ... Asirvatham SJ, Borlaug BA
Background
Heart failure with preserved ejection fraction is increasing in prevalence, but few effective treatments are available. Elevated left ventricular (LV) diastolic filling pressures represent a key therapeutic target. Pericardial restraint contributes to elevated LV end-diastolic pressure, and acute studies have shown that pericardiotomy attenuates the rise in LV end-diastolic pressure with volume loading. However, whether these acute effects are sustained chronically remains unknown.
Methods
Minimally invasive pericardiotomy was performed percutaneously using a novel device in a porcine model of heart failure with preserved ejection fraction. Hemodynamics were assessed at baseline and following volume loading with pericardium intact, acutely following pericardiotomy, and then again chronically after 4 weeks. Cardiac structure was assessed by magnetic resonance imaging.
Results
The increase in LV end-diastolic pressure with volume loading was mitigated by 41% (95% CI, 27%-45%, <0.0001; ΔLV end-diastolic pressure reduced from +9±3 mm Hg to +5±3 mm Hg, =0.0003, 95% CI, -2.2 to -5.5). The effect was sustained at 4 weeks (+5±2 mm Hg, =0.28 versus acute). There was no statistically significant effect of pericardiotomy on ventricular remodeling compared with age-matched controls. None of the animals developed hemodynamic or pathological indicators of pericardial constriction or frank systolic dysfunction.
Conclusions
The acute hemodynamic benefits of pericardiotomy are sustained for at least 4 weeks in a swine model of heart failure with preserved ejection fraction, without excessive chamber remodeling, pericarditis, or clinically significant systolic dysfunction. These data support trials evaluating minimally invasive pericardiotomy as a novel treatment for heart failure with preserved ejection fraction in humans.



Circ Heart Fail: 21 Jan 2021:CIRCHEARTFAILURE120007530; epub ahead of print
Jain CC, Pedrotty D, Araoz PA, Sugrue A, ... Asirvatham SJ, Borlaug BA
Circ Heart Fail: 21 Jan 2021:CIRCHEARTFAILURE120007530; epub ahead of print | PMID: 33478242
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Abstract

Proteomic and Functional Studies Reveal Detyrosinated Tubulin as Treatment Target in Sarcomere Mutation-Induced Hypertrophic Cardiomyopathy.

Schuldt M, Pei J, Harakalova M, Dorsch LM, ... van der Velden J, Kuster DWD
Background
Hypertrophic cardiomyopathy (HCM) is the most common genetic heart disease. While ≈50% of patients with HCM carry a sarcomere gene mutation (sarcomere mutation-positive, HCM), the genetic background is unknown in the other half of the patients (sarcomere mutation-negative, HCM). Genotype-specific differences have been reported in cardiac function. Moreover, HCM patients have later disease onset and a better prognosis than HCM patients. To define if genotype-specific derailments at the protein level may explain the heterogeneity in disease development, we performed a proteomic analysis in cardiac tissue from a clinically well-phenotyped HCM patient group.
Methods
A proteomics screen was performed in cardiac tissue from 39 HCM patients, 11HCM patients, and 8 nonfailing controls. Patients with HCM had obstructive cardiomyopathy with left ventricular outflow tract obstruction and diastolic dysfunction. A novelmouse model was used to confirm functional relevance of our proteomic findings.
Results
In all HCM patient samples, we found lower levels of metabolic pathway proteins and higher levels of extracellular matrix proteins. Levels of total and detyrosinated α-tubulin were markedly higher in HCM than in HCM and controls. Higher tubulin detyrosination was also found in 2 unrelatedmouse models and its inhibition with parthenolide normalized contraction and relaxation time of isolated cardiomyocytes.
Conclusions
Our findings indicate that microtubules and especially its detyrosination contribute to the pathomechanism of patients with HCM. This is of clinical importance since it represents a potential treatment target to improve cardiac function in patients with HCM, whereas a beneficial effect may be limited in patients with HCM.



Circ Heart Fail: 11 Jan 2021:CIRCHEARTFAILURE120007022; epub ahead of print
Schuldt M, Pei J, Harakalova M, Dorsch LM, ... van der Velden J, Kuster DWD
Circ Heart Fail: 11 Jan 2021:CIRCHEARTFAILURE120007022; epub ahead of print | PMID: 33430602
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Abstract

Myocardial Tissue Reverse Remodeling After Guideline-Directed Medical Therapy in Idiopathic Dilated Cardiomyopathy.

Xu Y, Li W, Wan K, Liang Y, ... Han Y, Chen Y
Background
The prognosis of patients with idiopathic dilated cardiomyopathy (DCM) has improved remarkably in recent decades with guideline-directed medical therapy. Left ventricular (LV) reverse remodeling (LVRR) is one of the major therapeutic goals. Whether myocardial fibrosis or inflammation would reverse associated with LVRR remains unknown.
Methods
A total of 157 prospectively enrolled patients with DCM underwent baseline and follow-up cardiovascular magnetic resonance examinations with a median interval of 13.7 months (interquartile range, 12.2-18.5 months). LVRR was defined as an absolute increase in LV ejection fraction of >10% to the final value of ≥35% and a relative decrease in LV end-diastolic volume of >10%. Statistical analyses were performed using paired t test and student t test, logistic regression analysis, and linear regression analysis.
Results
Forty-eight (31%) patients reached LVRR. At baseline, younger age, worse New York Heart Association class, new-onset heart failure, lower LV ejection fraction, absence of late gadolinium enhancement, lower myocardial T2, and extracellular volume were significant predictors of LVRR. During the follow-up, patients with and without LVRR both showed a significant decrease of myocardial native T1 (LVRR: [baseline] 1303.0±43.6 ms; [follow-up] 1244.7±51.8 ms; without LVRR: [baseline] 1308.5±80.5 ms; [follow-up] 1287.6±74.9 ms, both P<0.001), matrix and cellular volumes while no significant difference was observed in T2 or extracellular volume values after treatment.
Conclusions
In patients with idiopathic DCM, the absence of late gadolinium enhancement, lower T2, and extracellular volume values at baseline are significant predictors of LVRR. The myocardial T1, matrix, and cell volume decrease significantly in patients with LVRR after guideline-directed medical therapy. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: ChiCTR1800017058.



Circ Heart Fail: 30 Dec 2020; 14:e007944
Xu Y, Li W, Wan K, Liang Y, ... Han Y, Chen Y
Circ Heart Fail: 30 Dec 2020; 14:e007944 | PMID: 33185117
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Abstract

Brain-Derived Neurotrophic Factor Improves Impaired Fatty Acid Oxidation Via the Activation of Adenosine Monophosphate-Activated Protein Kinase-ɑ - Proliferator-Activated Receptor-r Coactivator-1ɑ Signaling in Skeletal Muscle of Mice With Heart Failure.

Matsumoto J, Takada S, Furihata T, Nambu H, ... Sabe H, Kinugawa S
Background
We recently reported that treatment with rhBDNF (recombinant human brain-derived neurotrophic factor) improved the reduced exercise capacity of mice with heart failure (HF) after myocardial infarction (MI). Since BDNF is reported to enhance fatty acid oxidation, we herein conducted an in vivo investigation to determine whether the improvement in exercise capacity is due to the enhancement of the fatty acid oxidation of skeletal muscle via the AMPKα-PGC1α (adenosine monophosphate-activated protein kinase-ɑ-proliferator-activated receptor-r coactivator-1ɑ) axis.
Methods
MI and sham operations were conducted in C57BL/6J mice. Two weeks postsurgery, we randomly divided the MI mice into groups treated with rhBDNF or vehicle for 2 weeks. AMPKα-PGC1α signaling and mitochondrial content in the skeletal muscle of the mice were evaluated by Western blotting and transmission electron microscopy. Fatty acid β-oxidation was examined by high-resolution respirometry using permeabilized muscle fiber. BDNF-knockout mice were treated with 5-aminoimidazole-4-carboxamide-1-beta-d-riboruranoside, an activator of AMPK.
Results
The rhBDNF treatment significantly increased the expressions of phosphorylated AMPKα and PGC1α protein and the intermyofibrillar mitochondrial density in the MI mice. The lowered skeletal muscle mitochondrial fatty acid oxidation was significantly improved in the rhBDNF-treated MI mice. The reduced exercise capacity and mitochondrial dysfunction of the BDNF-knockout mice were improved by 5-aminoimidazole-4-carboxamide-1-beta-d-riboruranoside.
Conclusions
Beneficial effects of BDNF on the exercise capacity of mice with HF are mediated through an enhancement of fatty acid oxidation via the activation of AMPKα-PGC1α in skeletal muscle. BDNF may become a therapeutic option to improve exercise capacity as an alternative or adjunct to exercise training.



Circ Heart Fail: 30 Dec 2020; 14:e005890
Matsumoto J, Takada S, Furihata T, Nambu H, ... Sabe H, Kinugawa S
Circ Heart Fail: 30 Dec 2020; 14:e005890 | PMID: 33356364
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Abstract

Ketone Ester Treatment Improves Cardiac Function and Reduces Pathologic Remodeling in Preclinical Models of Heart Failure.

Yurista SR, Matsuura TR, Silljé HHW, Nijholt KT, ... Kelly DP, Westenbrink BD
Background
Accumulating evidence suggests that the failing heart reprograms fuel metabolism toward increased utilization of ketone bodies and that increasing cardiac ketone delivery ameliorates cardiac dysfunction. As an initial step toward development of ketone therapies, we investigated the effect of chronic oral ketone ester (KE) supplementation as a prevention or treatment strategy in rodent heart failure models.
Methods
Two independent rodent heart failure models were used for the studies: transverse aortic constriction/myocardial infarction (MI) in mice and post-MI remodeling in rats. Seventy-five mice underwent a prevention treatment strategy with a KE comprised of hexanoyl-hexyl-3-hydroxybutyrate KE (KE-1) diet, and 77 rats were treated in either a prevention or treatment regimen using a commercially available β-hydroxybutyrate-(R)-1,3-butanediol monoester (DeltaG; KE-2) diet.
Results
The KE-1 diet in mice elevated β-hydroxybutyrate levels during nocturnal feeding, whereas the KE-2 diet in rats induced ketonemia throughout a 24-hour period. The KE-1 diet preventive strategy attenuated development of left ventricular dysfunction and remodeling post-transverse aortic constriction/MI (left ventricular ejection fraction±SD, 36±8 in vehicle versus 45±11 in KE-1; P=0.016). The KE-2 diet therapeutic approach also attenuated left ventricular dysfunction and remodeling post-MI (left ventricular ejection fraction, 41±11 in MI-vehicle versus 61±7 in MI-KE-2; P<0.001). In addition, ventricular weight, cardiomyocyte cross-sectional area, and the expression of ANP (atrial natriuretic peptide) were significantly attenuated in the KE-2-treated MI group. However, treatment with KE-2 did not influence cardiac fibrosis post-MI. The myocardial expression of the ketone transporter and 2 ketolytic enzymes was significantly increased in rats fed KE-2 diet along with normalization of myocardial ATP levels to sham values.
Conclusions
Chronic oral supplementation with KE was effective in both prevention and treatment of heart failure in 2 preclinical animal models. In addition, our results indicate that treatment with KE reprogrammed the expression of genes involved in ketone body utilization and normalized myocardial ATP production following MI, consistent with provision of an auxiliary fuel. These findings provide rationale for the assessment of KEs as a treatment for patients with heart failure.



Circ Heart Fail: 30 Dec 2020; 14:e007684
Yurista SR, Matsuura TR, Silljé HHW, Nijholt KT, ... Kelly DP, Westenbrink BD
Circ Heart Fail: 30 Dec 2020; 14:e007684 | PMID: 33356362
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Abstract

Automated E-Counseling for Chronic Heart Failure: CHF-CePPORT Trial.

Nolan RP, Ross HJ, Farkouh ME, Huszti E, ... Wielgosz A, Mielniczuk LM
Background
International task force statements advocate telehealth programs to promote health-related quality of life for patients with chronic heart failure (CHF). To that end, we evaluated the efficacy and usability of an automated e-counseling program.
Methods
This Canadian multi-site double-blind randomized trial assessed whether usual care plus either internet-based e-counseling (motivational and cognitive-behavioral tools for CHF self-care) or e-based conventional CHF self-care education (e-UC) improved 12-month Kansas City Cardiomyopathy Questionnaire Overall Summary (KCCQ-OS). Secondary outcomes included program engagement (total logon weeks, logons, and logon hours), total CHF self-care behaviors, diet (fruit and vegetable servings), 6-minute walk test, and 4-day step count. The association between program engagement and health-related quality of life was assessed using KCCQ-OS tertiles.
Results
We enrolled 231 patients, median age =59.5 years, 22% female, and elevated median KCCQ-OS=83.0 (interquartile range, 68-93). KCCQ-OS increase ≥5 points was not more prevalent for e-counseling, n=29 (29.6%) versus e-UC, n=32 (34.0%), P=0.51. E-Counseling versus e-UC increased total logon weeks (P=0.02), logon hours (P=0.001), and logons (P<0.001). Only e-counseling showed a positive association between 12-month KCCQ-OS tertile and logon weeks (P=0.04) and logon hours (P=0.004). E-Counseling increased CHF self-care behavior and diet but not 6-minute walk test or 4-day step count.
Conclusions
The primary KCCQ-OS end point was negative for this trial. Only e-counseling showed a positive association between program engagement and 12-month KCCQ-OS tertile, and it improved CHF self-care behavior and diet. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01864369.



Circ Heart Fail: 30 Dec 2020; 14:e007073
Nolan RP, Ross HJ, Farkouh ME, Huszti E, ... Wielgosz A, Mielniczuk LM
Circ Heart Fail: 30 Dec 2020; 14:e007073 | PMID: 33464959
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Impact:
Abstract

Metabolomic Profiles and Heart Failure Risk in Black Adults: Insights From the Jackson Heart Study.

Tahir UA, Katz DH, Zhao T, Ngo D, ... Wilson JG, Gerszten RE
Background
Heart failure (HF) is a heterogeneous disease characterized by significant metabolic disturbances; however, the breadth of metabolic dysfunction before the onset of overt disease is not well understood. The purpose of this study was to determine the association of circulating metabolites with incident HF to uncover novel metabolic pathways to disease.
Methods
We performed targeted plasma metabolomic profiling in a deeply phenotyped group of Black adults from the JHS (Jackson Heart Study; n=2199). We related metabolites associated with incident HF to established etiological mechanisms, including increased left ventricular mass index and incident coronary heart disease. Furthermore, we evaluated differential associations of metabolites with HF with preserved ejection fraction versus HF with reduced ejection fraction.
Results
Metabolites associated with incident HF included products of posttranscriptional modifications of RNA, as well as polyamine and nitric oxide metabolism. A subset of metabolite-HF associations was independent of well-established HF pathways such as increased left ventricular mass index and incident coronary heart disease and included homoarginine (per 1 SD increase in metabolite level, hazard ratio, 0.77; P=1.2×10-3), diacetylspermine (hazard ratio, 1.34; P=3.4×10-3), and uridine (hazard ratio, 0.79; P, 3×10-4). Furthermore, metabolites involved in pyrimidine metabolism (orotic acid) and collagen turnover (N-methylproline) among others were part of a distinct metabolic signature that differentiated individuals with HF with preserved ejection fraction versus HF with reduced ejection fraction.
Conclusions
The integration of clinical phenotyping with plasma metabolomic profiling uncovered novel metabolic processes in nontraditional disease pathways underlying the heterogeneity of HF development in Black adults.



Circ Heart Fail: 30 Dec 2020; 14:e007275
Tahir UA, Katz DH, Zhao T, Ngo D, ... Wilson JG, Gerszten RE
Circ Heart Fail: 30 Dec 2020; 14:e007275 | PMID: 33464957
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Abstract

CRD-733, a Novel PDE9 (Phosphodiesterase 9) Inhibitor, Reverses Pressure Overload-Induced Heart Failure.

Richards DA, Aronovitz MJ, Liu P, Martin GL, ... Mendelsohn ME, Blanton RM
Background
Augmentation of NP (natriuretic peptide) receptor and cyclic guanosine monophosphate (cGMP) signaling has emerged as a therapeutic strategy in heart failure (HF). cGMP-specific PDE9 (phosphodiesterase 9) inhibition increases cGMP signaling and attenuates stress-induced hypertrophic heart disease in preclinical studies. A novel cGMP-specific PDE9 inhibitor, CRD-733, is currently being advanced in human clinical studies. Here, we explore the effects of chronic PDE9 inhibition with CRD-733 in the mouse transverse aortic constriction pressure overload HF model.
Methods
Adult male C57BL/6J mice were subjected to transverse aortic constriction and developed significant left ventricular (LV) hypertrophy after 7 days (P<0.001). Mice then received daily treatment with CRD-733 (600 mg/kg per day; n=10) or vehicle (n=17), alongside sham-operated controls (n=10).
Results
CRD-733 treatment reversed existing LV hypertrophy compared with vehicle (P<0.001), significantly improved LV ejection fraction (P=0.009), and attenuated left atrial dilation (P<0.001), as assessed by serial echocardiography. CRD-733 prevented elevations in LV end diastolic pressures (P=0.037) compared with vehicle, while lung weights, a surrogate for pulmonary edema, were reduced to sham levels. Chronic CRD-733 treatment increased plasma cGMP levels compared with vehicle (P<0.001), alongside increased phosphorylation of Ser273 of cardiac myosin binding protein-C, a cGMP-dependent protein kinase I phosphorylation site.
Conclusions
The PDE9 inhibitor, CRD-733, improves key hallmarks of HF including LV hypertrophy, LV dysfunction, left atrial dilation, and pulmonary edema after pressure overload in the mouse transverse aortic constriction HF model. Additionally, elevated plasma cGMP may be used as a biomarker of target engagement. These findings support future investigation into the therapeutic potential of CRD-733 in human HF.



Circ Heart Fail: 30 Dec 2020; 14:e007300
Richards DA, Aronovitz MJ, Liu P, Martin GL, ... Mendelsohn ME, Blanton RM
Circ Heart Fail: 30 Dec 2020; 14:e007300 | PMID: 33464954
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Abstract

Impairments in Blood Pressure Regulation and Cardiac Baroreceptor Sensitivity Among Patients With Heart Failure Supported With Continuous-Flow Left Ventricular Assist Devices.

Sailer C, Edelmann H, Buchanan C, Giro P, ... Tarumi T, Cornwell WK
Background
Continuous-flow (CF) left ventricular assist devices (LVADs) improve outcomes for patients with advanced heart failure (HF). However, the lack of a physiological pulse predisposes to side-effects including uncontrolled blood pressure (BP), and there are little data regarding the impact of CF-LVADs on BP regulation.
Methods
Twelve patients (10 males, 60±11 years) with advanced heart failure completed hemodynamic assessment 2.7±4.1 months before, and 4.3±1.3 months following CF-LVAD implantation. Heart rate and systolic BP via arterial catheterization were monitored during Valsalva maneuver, spontaneous breathing, and a 0.05 Hz repetitive squat-stand maneuver to characterize cardiac baroreceptor sensitivity. Plasma norepinephrine levels were assessed during head-up tilt at supine, 30o and 60o. Heart rate and BP were monitored during cardiopulmonary exercise testing.
Results
Cardiac baroreceptor sensitivity, determined by Valsalva as well as Fourier transformation and transfer function gain of Heart rate and systolic BP during spontaneous breathing and squat-stand maneuver, was impaired before and following LVAD implantation. Norepinephrine levels were markedly elevated pre-LVAD and improved-but remained elevated post-LVAD (supine norepinephrine pre-LVAD versus post-LVAD: 654±437 versus 323±164 pg/mL). BP increased during cardiopulmonary exercise testing post-LVAD, but the magnitude of change was modest and comparable to the changes observed during the pre-LVAD cardiopulmonary exercise testing.
Conclusions
Among patients with advanced heart failure with reduced ejection fraction, CF-LVAD implantation is associated with modest improvements in autonomic tone, but persistent reductions in cardiac baroreceptor sensitivity. Exercise-induced increases in BP are blunted. These findings shed new light on mechanisms for adverse events such as stroke, and persistent reductions in functional capacity, among patients supported by CF-LVADs. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03078972.



Circ Heart Fail: 30 Dec 2020; 14:e007448
Sailer C, Edelmann H, Buchanan C, Giro P, ... Tarumi T, Cornwell WK
Circ Heart Fail: 30 Dec 2020; 14:e007448 | PMID: 33464953
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Abstract

Defining Shock and Preshock for Mortality Risk Stratification in Cardiac Intensive Care Unit Patients.

Jentzer JC, Burstein B, Van Diepen S, Murphy J, ... Naidu SS, Baran DA
Background
Previous studies have defined preshock as isolated hypotension or isolated hypoperfusion, whereas shock has been variably defined as hypoperfusion with or without hypotension. We aimed to evaluate the mortality risk associated with hypotension and hypoperfusion at the time of admission in a cardiac intensive care unit population.
Methods
We analyzed Mayo Clinic cardiac intensive care unit patients admitted between 2007 and 2015. Hypotension was defined as systolic blood pressure <90 mm Hg or mean arterial pressure <60 mm Hg, and hypoperfusion as admission lactate >2 mmol/L, oliguria, or rising creatinine. Associations between hypotension and hypoperfusion with hospital mortality were estimated using multivariable logistic regression.
Results
Among 10 004 patients with a median age of 69 years, 43.1% had acute coronary syndrome, and 46.1% had heart failure. Isolated hypotension was present in 16.7%, isolated hypoperfusion in 15.3%, and 8.7% had both hypotension and hypoperfusion. Stepwise increases in hospital mortality were observed with hypotension and hypoperfusion compared with neither hypotension nor hypoperfusion (3.3%; all P<0.001): isolated hypotension, 9.3% (adjusted odds ratio, 1.7 [95% CI, 1.4-2.2]); isolated hypoperfusion, 17.2% (adjusted odds ratio, 2.3 [95% CI, 1.9-3.0]); both hypotension and hypoperfusion, 33.8% (adjusted odds ratio, 2.8 [95% CI, 2.1-3.6]). Adjusted hospital mortality in patients with isolated hypoperfusion was higher than in patients with isolated hypotension (P=0.02) and not significant different from patients with both hypotension and hypoperfusion (P=0.18).
Conclusions
Hypotension and hypoperfusion are both associated with increased mortality in cardiac intensive care unit patients. Hospital mortality is higher with isolated hypoperfusion or concomitant hypotension and hypoperfusion (classic shock). We contend that preshock should refer to isolated hypotension without hypoperfusion, while patients with hypoperfusion can be considered to have shock, irrespective of blood pressure.



Circ Heart Fail: 30 Dec 2020; 14:e007678
Jentzer JC, Burstein B, Van Diepen S, Murphy J, ... Naidu SS, Baran DA
Circ Heart Fail: 30 Dec 2020; 14:e007678 | PMID: 33464952
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Abstract

Cardiac Microvascular Endothelial Cells in Pressure Overload-Induced Heart Disease.

Trenson S, Hermans H, Craps S, Pokreisz P, ... Luttun A, Janssens S
Background
Chronic pressure overload predisposes to heart failure, but the pathogenic role of microvascular endothelial cells (MiVEC) remains unknown. We characterized transcriptional, metabolic, and functional adaptation of cardiac MiVEC to pressure overload in mice and patients with aortic stenosis (AS).
Methods
In Tie2-Gfp mice subjected to transverse aortic constriction or sham surgery, we performed RNA sequencing of isolated cardiac Gfp+-MiVEC and validated the signature in freshly isolated MiVEC from left ventricle outflow tract and right atrium of patients with AS. We next compared their angiogenic and metabolic profiles and finally correlated molecular and pathological signatures with clinical phenotypes of 42 patients with AS (50% women).
Results
In mice, transverse aortic constriction induced progressive systolic dysfunction, fibrosis, and reduced microvascular density. After 10 weeks, 25 genes predominantly involved in matrix-regulation were >2-fold upregulated in isolated MiVEC. Increased transcript levels of Cartilage Intermediate Layer Protein (Cilp), Thrombospondin-4, Adamtsl-2, and Collagen1a1 were confirmed by quantitative reverse transcription polymerase chain reaction and recapitulated in left ventricle outflow tract-derived MiVEC of AS (P<0.05 versus right atrium-MiVEC). Fatty acid oxidation increased >2-fold in left ventricle outflow tract-MiVEC, proline content by 130% (median, IQR, 58%-474%; P=0.008) and procollagen secretion by 85% (mean [95% CI, 16%-154%]; P<0.05 versus right atrium-MiVEC for all). The altered transcriptome in left ventricle outflow tract-MiVEC was associated with impaired 2-dimensional-vascular network formation and 3-dimensional-spheroid sprouting (P<0.05 versus right atrium-MiVEC), profibrotic ultrastructural changes, and impaired diastolic left ventricle function, capillary density and functional status, especially in female AS.
Conclusions
Pressure overload induces major transcriptional and metabolic adaptations in cardiac MiVEC resulting in excess interstitial fibrosis and impaired angiogenesis. Molecular rewiring of MiVEC is worse in women, compromises functional status, and identifies novel targets for intervention.



Circ Heart Fail: 30 Dec 2020; 14:e006979
Trenson S, Hermans H, Craps S, Pokreisz P, ... Luttun A, Janssens S
Circ Heart Fail: 30 Dec 2020; 14:e006979 | PMID: 33464950
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Impact:
Abstract

Extracardiac Abnormalities of Preload Reserve: Mechanisms Underlying Exercise Limitation in Heart Failure with Preserved Ejection Fraction, Autonomic Dysfunction, and Liver Disease.

Fudim M, Sobotka PA, Dunlap ME
While many of the cardiac limitations to exercise performance are now well-characterized, extracardiac limitations to exercise performance have been less well recognized but are nevertheless important. We propose that abnormalities of cardiac preload reserve represents an under-recognized but common cause of exercise limitations. We further propose that mechanistic links exist between conditions as seemingly disparate as heart failure with preserved ejection fraction, nonalcoholic fatty liver disease, and pelvic venous compression/obstruction syndromes (eg, May-Thurner). We conclude that extracardiac abnormalities of preload reserve serve as a major pathophysiologic mechanism underlying these and other disease states.



Circ Heart Fail: 30 Dec 2020; 14:e007308
Fudim M, Sobotka PA, Dunlap ME
Circ Heart Fail: 30 Dec 2020; 14:e007308 | PMID: 33464948
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Impact:

This program is still in alpha version.