Mutations to the co-chaperone protein BAG3 (B-cell lymphoma-2-associated athanogene-3) are a leading cause of dilated cardiomyopathy (DCM). These mutations often impact the C-terminal BAG domain ...(residues 420-499), which regulates heat shock protein 70-dependent protein turnover via autophagy. While mutations in other regions are less common, previous studies in patients with DCM found that co-occurrence of 2
variants (P63A, P380S) led to worse prognosis. However, the underlying mechanism for dysfunction is not fully understood.
In this study, we used proteomics, Western blots, and myofilament functional assays on left ventricular tissue from patients with nonfailing, DCM, and DCM with
to determine how these mutations impact protein quality control and cardiomyocyte contractile function. We found dysregulated autophagy and increased protein ubiquitination in patients with
compared with nonfailing and DCM, suggesting impaired protein turnover. Expression and myofilament localization of BAG3-binding proteins were also uniquely altered in the
including abolished localization of the small heat shock protein CRYAB (alpha-crystallin B chain) to the sarcomere. To determine whether these variants impacted sarcomere function, we used cardiomyocyte force-calcium assays and found reduced maximal calcium-activated force in DCM and
. Interestingly, myofilament calcium sensitivity was increased in DCM but not with
, which was not explained by differences in troponin I phosphorylation.
Together, our data support that the disease-enhancing mechanism for
variants outside of the BAG domain is through disrupted protein turnover leading to compromised sarcomere function. These findings suggest a shared mechanism of disease among pathogenic
variants, regardless of location.
Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are a powerful platform for biomedical research. However, they are immature, which is a barrier to modeling adult-onset ...cardiovascular disease. Here, we sought to develop a simple method that could drive cultured hiPSC-CMs toward maturity across a number of phenotypes, with the aim of utilizing mature hiPSC-CMs to model human cardiovascular disease. hiPSC-CMs were cultured in fatty acid-based medium and plated on micropatterned surfaces. These cells display many characteristics of adult human cardiomyocytes, including elongated cell morphology, sarcomeric maturity, and increased myofibril contractile force. In addition, mature hiPSC-CMs develop pathological hypertrophy, with associated myofibril relaxation defects, in response to either a pro-hypertrophic agent or genetic mutations. The more mature hiPSC-CMs produced by these methods could serve as a useful in vitro platform for characterizing cardiovascular disease.
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•Standard (glucose) cultured hiPSC-CMs demonstrate a blunted hypertrophic response•A maturation method induces hiPSC-CM maturation and suppresses HIF1A expression•Mature hiPSC-CMs demonstrate improved sarcomeric morphology and contractility•Mature hiPSC-CMs respond to agonist- or mutation-induced hypertrophy
In this article, Song and colleagues show that a combination of fatty acid medium and micropatterned surfaces induces maturation in human induced pluripotent stem cell-derived cardiomyocytes. Matured cells display improved sarcomere morphology, metabolic maturation, and contractility. These cells also show increased sensitivity to hypertrophic stimuli, including hypertrophic agonist and genetic mutations, representing an ideal system to model cardiovascular disease.
Introduction:
There are no randomized controlled trial data that evaluate mortality and hospitalization rates in cardiac resynchronization therapy (CRT) recipients based on left ventricular (LV) lead ...location. We analyzed the event‐driven outcomes of mortality and hospitalization as well as functional outcomes including Functional Class, Quality‐of‐Life, and 6‐minute walk distance in 1,520 patients enrolled in the COMPANION study of CRT versus optimal medical therapy.
Methods and Results:
Over a mean follow‐up after implantation of 16.2 months, patients randomized to CRT, regardless of lead location, experienced benefit compared with optimized pharmacologic therapy (OPT), with respect to all‐cause mortality or heart failure hospitalization. All but a posterior location showed benefit with respect to the all‐cause mortality or all‐cause hospitalization outcome. Mortality benefit in CRT‐D patients was indifferent to LV lead position. All functional outcomes including 6‐minute walk distance, Quality‐of‐Life (QOL) and Functional Class improved with CRT, regardless of LV lead location.
Conclusion:
LV lead location was not a major determinant of multiple measures of response to CRT therapy in the COMPANION Trial. While acute data indicate that a left lateral LV lead location results in the most favorable hemodynamic response, these chronic data suggest that positioning an LV lead in an anterior rather than a lateral or posterior LV location has similar benefit.
Organ fibrosis due to excessive production of extracellular matrix by resident fibroblasts is estimated to contribute to >45% of deaths in the Western world, including those due to cardiovascular ...diseases such as heart failure. Here, we screened for small molecule inhibitors with a common ability to suppress activation of fibroblasts across organ systems.
High-content imaging of cultured cardiac, pulmonary, and renal fibroblasts was used to identify nontoxic compounds that blocked induction of markers of activation in response to the profibrotic stimulus, transforming growth factor-β1. SW033291, which inhibits the eicosanoid-degrading enzyme, 15-hydroxyprostaglandin dehydrogenase, was chosen for follow-up studies with cultured adult rat ventricular fibroblasts and human cardiac fibroblasts (CF), and for evaluation in mouse models of cardiac fibrosis and diastolic dysfunction. Additional mechanistic studies were performed with CFs treated with exogenous eicosanoids.
Nine compounds, including SW033291, shared a common ability to suppress transforming growth factor-β1-mediated activation of cardiac, pulmonary, and renal fibroblasts. SW033291 dose-dependently inhibited transforming growth factor-β1-induced expression of activation markers (eg, α-smooth muscle actin and periostin) in adult rat ventricular fibroblasts and normal human CFs, and reduced contractile capacity of the cells. Remarkably, the 15-hydroxyprostaglandin dehydrogenase inhibitor also reversed constitutive activation of fibroblasts obtained from explanted hearts from patients with heart failure. SW033291 blocked cardiac fibrosis induced by angiotensin II infusion and ameliorated diastolic dysfunction in an alternative model of systemic hypertension driven by combined uninephrectomy and deoxycorticosterone acetate administration. Mechanistically, SW033291-mediated stimulation of extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase signaling was required for the compound to block CF activation. Of the 12 exogenous eicosanoids that were tested, only 12(S)-hydroxyeicosatetraenoic acid, which signals through the G protein-coupled receptor, GPR31, recapitulated the suppressive effects of SW033291 on CF activation.
Inhibition of degradation of eicosanoids, arachidonic acid-derived fatty acids that signal through G protein-coupled receptors, is a potential therapeutic strategy for suppression of pathological organ fibrosis. In the heart, we propose that 15-hydroxyprostaglandin dehydrogenase inhibition triggers CF-derived autocrine/paracrine signaling by eicosanoids, including 12(S)-hydroxyeicosatetraenoic acid, to stimulate extracellular signal-regulated kinase 1/2 and block conversion of fibroblasts into activated cells that secrete excessive amounts of extracellular matrix and contribute to heart failure pathogenesis.
Aims
Cardiac resynchronization therapy (CRT) reduces morbidity and mortality for patients with heart failure, reduced left ventricular ejection fraction, QRS duration >130 ms and in sinus rhythm. The ...aim of this study was to identify patient characteristics that predict the effect, specifically, of CRT pacemakers (CRT‐P) on all‐cause mortality or the composite of hospitalization for heart failure or all‐cause mortality.
Methods and results
We conducted an individual patient data meta‐analysis of the Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) and Cardiac Resynchronization‐Heart Failure (CARE‐HF) trials. Only patients assigned to CRT‐P or control (n = 1738) were included in order to avoid confounding from concomitant defibrillator therapy. The influence of baseline characteristics on treatment effects was investigated. Median age was 67 (59–73) years, most patients were men (70%), 68% had a QRS duration of 150–199 ms and 80% had left bundle branch block. Patients assigned to CRT‐P had lower rates for all‐cause mortality (hazard ratio HR 0.68, 95% confidence interval CI 0.56–0.81; p < 0.0001) and the composite outcome (HR 0.67, 95% CI 0.58–0.78; p < 0.0001). No pre‐specified characteristic, including sex, aetiology of ventricular dysfunction, QRS duration (within the studied range) or morphology or PR interval significantly influenced the effect of CRT‐P on all‐cause mortality or the composite outcome. However, CRT‐P had a greater effect on the composite outcome for patients with lower body surface area and those prescribed beta‐blockers.
Conclusions
Cardiac resynchronization therapy‐pacemaker reduces morbidity and mortality in appropriately selected patients with heart failure. Benefits may be greater in smaller patients and in those receiving beta‐blockers. Neither QRS duration nor morphology independently predicted the benefit of CRT‐P.
Clinical Trial Registration: COMPANION, NCT00180258; CARE‐HF, NCT00170300.
Potential substrates for and mechanisms of action for cardiac resynchronization therapy pacemakers (CRT‐P). Kaplan–Meier estimates for all‐cause mortality (hazard ratio 0.68, 95% confidence interval CI 0.56–0.81; p < 0.0001) and time to composite of first hospitalization for heart failure or all‐cause mortality (hazard ratio 0.67, 95% CI 0.58–0.78; p < 0.0001). No heterogeneity was identified in the effect of CRT‐P on mortality amongst trial participants. CRT‐P had greater effects on the composite outcome (hospitalization for heart failure or all‐cause mortality) for those taking beta‐blockers and patients of smaller stature. Although women are, on average, smaller than men, no interaction between CRT‐P and sex was observed. Similar trends were observed when only men were included in the analysis. These analyses suggest that stature rather than sex is associated with the effect of CRT‐P on outcome. LBBB, left bundle branch block.
The purpose of this study was to assess the phenotype of Filamin C (FLNC) truncating variants in dilated cardiomyopathy (DCM) and understand the mechanism leading to an arrhythmogenic phenotype.
...Mutations in FLNC are known to lead to skeletal myopathies, which may have an associated cardiac component. Recently, the clinical spectrum of FLNC mutations has been recognized to include a cardiac-restricted presentation in the absence of skeletal muscle involvement.
A population of 319 U.S. and European DCM cardiomyopathy families was evaluated using whole-exome and targeted next-generation sequencing. FLNC truncation probands were identified and evaluated by clinical examination, histology, transmission electron microscopy, and immunohistochemistry.
A total of 13 individuals in 7 families (2.2%) were found to harbor 6 different FLNC truncation variants (2 stopgain, 1 frameshift, and 3 splicing). Of the 13 FLNC truncation carriers, 11 (85%) had either ventricular arrhythmias or sudden cardiac death, and 5 (38%) presented with evidence of right ventricular dilation. Pathology analysis of 2 explanted hearts from affected FLNC truncation carriers showed interstitial fibrosis in the right ventricle and epicardial fibrofatty infiltration in the left ventricle. Ultrastructural findings included occasional disarray of Z-discs within the sarcomere. Immunohistochemistry showed normal plakoglobin signal at cell–cell junctions, but decreased signals for desmoplakin and synapse-associated protein 97 in the myocardium and buccal mucosa.
We found FLNC truncating variants, present in 2.2% of DCM families, to be associated with a cardiac-restricted arrhythmogenic DCM phenotype characterized by a high risk of life-threatening ventricular arrhythmias and a pathological cellular phenotype partially overlapping with arrhythmogenic right ventricular cardiomyopathy.
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Cost Effectiveness of Cardiac Resynchronization Therapy in the Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) Trial
Arthur M. Feldman, Gregory de Lissovoy, ...Michael R. Bristow, Leslie A. Saxon, Teresa De Marco, David A. Kass, John Boehmer, Steven Singh, David J. Whellan, Peter Carson, Audra Boscoe, Timothy M. Baker, Matthew R. Gunderman
We analyzed survival, hospitalization costs, and incremental cost-effectiveness ratios (ICERs) of the Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) trial patients who received cardiac resynchronization therapy (CRT) via either a pacemaker (CRT-P) or a pacemaker-defibrillator (CRT-D) in combination with optimal pharmacological therapy (OPT) relative to patients with OPT alone. In the seven-year base-case analysis, CRT-P had an ICER of $19,600 per quality-adjusted life-year (QALY) gained, and CRT-D had an ICER of $43,000 per QALY gained. Our analysis shows that for the COMPANION trial patients, the resultant cost-effectiveness ratios for CRT-P and CRT-D relative to OPT were within the accepted range for effective therapy.
The analysis goal was to estimate incremental cost-effectiveness ratios (ICERs) for the Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) trial patients who received cardiac resynchronization therapy (CRT) via pacemaker (CRT-P) or pacemaker-defibrillator (CRT-D) in combination with optimal pharmacological therapy (OPT) relative to patients with OPT alone.
In the COMPANION trial, CRT-P and CRT-D reduced the combined risk of all-cause mortality or first hospitalization among patients with advanced heart failure and intraventricular conduction delays, but the cost effectiveness of the therapy remains unknown.
In this analysis, intent-to-treat trial data were modeled to estimate the cost effectiveness of CRT-D and CRT-P relative to OPT over a base-case seven-year treatment episode. Exponential survival curves were derived from trial data and adjusted by quality-of-life trial results to yield quality-adjusted life-years (QALYs). For the first two years, follow-up hospitalizations were based on trial data. The model assumed equalized hospitalization rates beyond two years. Initial implantation and follow-up hospitalization costs were estimated using Medicare data.
Over two years, follow-up hospitalization costs were reduced by 29% for CRT-D and 37% for CRT-P. Extending the cost-effectiveness analysis to a seven-year base-case time period, the ICER for CRT-P was $19,600 per QALY and the ICER for CRT-D was $43,000 per QALY relative to OPT.
For the COMPANION trial patients, the use of CRT-P and CRT-D was associated with a cost-effectiveness ratio below generally accepted benchmarks for therapeutic interventions of $50,000 per QALY to $100,000 per QALY. This suggests that the clinical benefits of CRT-P and CRT-D can be achieved at a reasonable cost.
Controlled clinical trial data are lacking for cardiac resynchronization therapy (CRT) outcomes in patients with advanced heart failure (HF) from reduced left ventricular ejection fraction (HFrEF) ...and intermittent atrial fibrillation or flutter (IAF/AFL).
The purpose of this study was to describe CRT outcomes in patients with IAF/AFL and advanced HF.
HF outcomes in patients in the COMPANION (Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure) trial with New York Heart Association class III or IV HFrEF, left ventricular ejection fraction ≤0.35, sinus rhythm at randomization, and no history of baseline arrhythmia were compared with those with a history of IAF/AFL.
In those with no history of baseline arrhythmia (n = 887), compared with optimal pharmacological therapy (OPT) with no CRT, the CRT + OPT arms exhibited a significant reduction in the end points of death or any hospitalization (hazard ratio HR 0.73 95% Confidence Interval (CI): 0.60 to 0.89; P = .002) and death or HF hospitalization (HR 0.53 95% CI: 0.41 to 0.68; P < .001). In contrast, in the IAF/AFL subgroup (n = 293), CRT did not result in improved outcomes compared with OPT (death or any hospitalization: HR 1.16 95% CI: 0.83 to 1.63; P = .38; death or HF hospitalization: HR 0.97 95% CI: 0.64 to 1.46; P = .88). The interaction between history of AF/AFL and CRT was statistically significant for both outcomes (P < .05).
In the COMPANION trial, patients with moderate to severe HFrEF and a history of IAF/AFL had no benefit from CRT.
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