Treatment options in end-stage heart failure: where to go from here?
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ABSTRACT:
SUBMITTER: Haeck ML
PROVIDER: S-EPMC3303031 | biostudies-literature | 2012 Apr
REPOSITORIES: biostudies-literature
Publications
Treatment options in end-stage heart failure: where to go from here?
Haeck M L A ML Hoogslag G E GE Rodrigo S F SF Atsma D E DE Klautz R J RJ van der Wall E E EE Schalij M J MJ Verwey H F HF
Netherlands heart journal : monthly journal of the Netherlands Society of Cardiology and the Netherlands Heart Foundation 20120401 4
Chronic heart failure is a major healthcare problem associated with high morbidity and mortality. Despite significant progress in treatment strategies, the prognosis of heart failure patients remains poor. The golden standard treatment for heart failure is heart transplantation after failure of medical therapy, surgery and/or cardiac resynchronisation therapy. In order to improve patients' outcome and quality of life, new emerging treatment modalities are currently being investigated, including ...[more]
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Project description:Background Transcriptomic studies have contributed to fundamental knowledge of myocardial remodeling in human heart failure (HF). However, the key HF genes reported are often inconsistent between studies, and systematic efforts to integrate evidence from multiple patient cohorts are lacking. Here, we aimed to provide a framework for comprehensive comparison and analysis of publicly available data sets resulting in an unbiased consensus transcriptional signature of human end-stage HF. Methods and Results We curated and uniformly processed 16 public transcriptomic studies of left ventricular samples from 263 healthy and 653 failing human hearts. First, we evaluated the degree of consistency between studies by using linear classifiers and overrepresentation analysis. Then, we meta-analyzed the deregulation of 14 041 genes to extract a consensus signature of HF. Finally, to functionally characterize this signature, we estimated the activities of 343 transcription factors, 14 signaling pathways, and 182 micro RNAs, as well as the enrichment of 5998 biological processes. Machine learning approaches revealed conserved disease patterns across all studies independent of technical differences. These consistent molecular changes were prioritized with a meta-analysis, functionally characterized and validated on external data. We provide all results in a free public resource (https://saezlab.shinyapps.io/reheat/) and exemplified usage by deciphering fetal gene reprogramming and tracing the potential myocardial origin of the plasma proteome markers in patients with HF. Conclusions Even though technical and sampling variability confound the identification of differentially expressed genes in individual studies, we demonstrated that coordinated molecular responses during end-stage HF are conserved. The presented resource is crucial to complement findings in independent studies and decipher fundamental changes in failing myocardium.
| S-EPMC8174362 | biostudies-literature
Project description:AimsDespite signals from clinical trials and mechanistic studies implying different resilience to heart failure (HF) depending on gender, the impact of gender on presentation and outcomes in patients with HF remains unclear. This study assessed the impact of gender on clinical presentation and outcomes in patients with HF referred to a specialised tertiary HF service.Methods and resultsConsecutive patients with HF referred to a specialised tertiary HF service offering advanced therapy options including left ventricular assist devices (LVAD) and heart transplantation were prospectively enrolled from August 2015 until March 2018. We assessed clinical characteristics at baseline and performed survival analyses and age-adjusted Cox regression analyses in men vs. women for all-cause death and a combined disease-related endpoint comprising death, heart transplantation, and LVAD implantation. Analyses were performed for the overall study population and for patients with HF with reduced ejection fraction (HFrEF). Of 356 patients included, 283 (79.5%) were male. The median age was 58 years (interquartile range 50-67). Two hundred and fifty-one (74.5%) patients had HFrEF. HF aetiology, ejection fraction, functional status measures, and most of the cardiac and non-cardiac comorbidities did not differ between men and women. In a median follow-up of 3.2 years, 50 patients died (45 men, 5 women), 15 patients underwent LVAD implantation, and 8 patients heart transplantation. While all-cause death was not significantly different between both genders in the overall population [16.9 vs. 6.0%, P = 0.065, hazard ratio (HR) 2.29 (95% confidence interval 0.91-5.78), P = 0.078], in the HFrEF subgroup, a significant difference between men and women was observed [20.7% vs. 3.9%, P = 0.017, HR 3.67 (95% confidence interval 1.13-11.91), P = 0.031]. The combined endpoint was more often reached in men than in women in both the overall population [21.6% vs. 9.0%, P = 0.053, HR 2.51 (1.08-5.82), P = 0.032] and the HFrEF subgroup [27.1% vs. 7.7%, P = 0.015, HR 3.58 (1.29-9.94), P = 0.014].ConclusionsPatients referred to a specialised tertiary HF service showed a similar clinical profile without relevant gender differences. In the mid-term follow-up, more male than female patients died or underwent heart transplantation and LVAD implantation. These findings call for independent validation and for further research into gender-specific drivers of HF progression.
| S-EPMC8712844 | biostudies-literature
Project description:Little is known about the right ventricular (RV) proteome in human heart failure (HF), including possible differences compared to the left ventricular (LV) proteome. We used 2-dimensional differential in-gel electrophoresis (pH: 4-7, 10-150 kDa), followed by liquid chromatography tandem mass spectrometry, to compare the RV and LV proteomes in 12 explanted human hearts. We used Western blotting and multiple-reaction monitoring for protein verification and RNA sequencing for messenger RNA and protein expression correlation. In all 12 hearts, the right ventricles (RVs) demonstrated differential expression of 11 proteins relative to the left ventricles (LVs), including lesser expression of CRYM, TPM1, CLU, TXNL1, and COQ9 and greater expression of TNNI3, SAAI, ERP29, ACTN2, HSPB2, and NDUFS3. Principal-components analysis did not suggest RV-versus-LV proteome partitioning. In the nonischemic RVs (n = 6), 7 proteins were differentially expressed relative to the ischemic RVs (n = 6), including increased expression of CRYM, B7Z964, desmin, ANXA5, and MIME and decreased expression of SERPINA1 and ANT3. Principal-components analysis demonstrated partitioning of the nonischemic and ischemic RV proteomes, and gene ontology analysis identified differences in hemostasis and atherosclerosis-associated networks. There were no proteomic differences between RVs with echocardiographic dysfunction (n = 8) and those with normal function (n = 4). Messenger RNA and protein expression did not correlate consistently, suggesting a major role for RV posttranscriptional protein expression regulation. Differences in contractile, cytoskeletal, metabolic, signaling, and survival pathways exist between the RV and the LV in HF and may be related to the underlying HF etiology and differential posttranscriptional regulation.
| S-EPMC4556499 | biostudies-literature
Project description:Objectives: Many studies indicate the involvement of transient receptor potential (TRP) channels in the development of heart hypertrophy. However, the data is often conflicted and has originated in animal models. Here, we provide systematic analysis of TRP channels expression in human failing myocardium. Methods and results: Left-ventricular tissue samples were isolated from explanted hearts of NYHA III-IV patients undergoing heart transplants (n = 43). Quantitative real-time PCR was performed to assess the mRNA levels of TRPC, TRPM and TRPV channels. Analysis of functional, clinical and biochemical data was used to confirm an end-stage heart failure diagnosis. Compared to myocardium samples from healthy donor hearts (n = 5), we detected a distinct increase in the expression of TRPC1, TRPC5, TRPM4 and TRPM7, and decreased expression of TRPC4 and TRPV2. These changes were not dependent on gender, clinical or biochemical parameters, nor functional parameters of the heart. We detected, however, a significant correlation of TRPC1 and MEF2c expression. Conclusions: The end-stage heart failure displays distinct expressional changes of TRP channels. Our findings provide a systematic description of TRP channel expression in human heart failure. The results highlight the complex interplay between TRP channels and the need for deeper analysis of early stages of hypertrophy and heart failure development.
| S-EPMC6681334 | biostudies-literature
Project description:BackgroundA rising number of patients are surgically treated for heart failure at the more advanced stage, thanks to the increasing use of left ventricular assist device (LVAD) as a reliable alternative to heart transplantation (HTx). However, it is still unknown whether differences exist between the two surgical approaches in the efficacy of rehabilitation programmes. Therefore, aim of this study was to evaluate whether functional capacity and rehabilitative outcomes differ between HTx and implantation of LVAD.Methods and resultsWe enrolled 51 patients with HTx and 46 with LVAD upon admission to our rehabilitation-unit. We evaluated six-minute walking test (6MWT), resting oxygen saturation (SaO2) and nutritional assessment before and after a standardised cardiovascular rehabilitation programme. HTx and LVAD groups differed in age, anthropometric variables, gender distribution. Upon enrolment, 6MWT distance was similar in the two groups, whereas malnutrition was less frequent and the waist circumference/height ratio (WHtR) was greater in LVAD patients. SaO2 was greater in HTx patients. Rehabilitation improved SaO2, 6MWT distance and nutritional status. The difference in malnutrition disappeared, but WHtR remained higher in the LVAD and SaO2 higher in the HTx patients; the 6MWT distance improved more in the HTx patients. Multivariate linear regression analysis confirmed that the type of intervention was independent predictor of 6MWT distance after rehabilitation.ConclusionsHTx patients improve more rapidly and perform better after rehabilitation, suggesting the need for more tailored rehabilitation training for LVAD patients.
| S-EPMC5626463 | biostudies-literature
Project description:We are developing a novel treatment for heart failure by increasing myocardial 2 deoxy-ATP (dATP). Our studies in rodent models have shown that substitution of dATP for adenosine triphosphate (ATP) as the energy substrate in vitro or elevation of dATP in vivo increases myocardial contraction and that small increases in the native dATP pool of heart muscle are sufficient to improve cardiac function. Here we report, for the first time, the effect of dATP on human adult cardiac muscle contraction. We measured the contractile properties of chemically-demembranated multicellular ventricular wall preparations and isolated myofibrils from human subjects with end-stage heart failure. Isometric force was increased at both saturating and physiologic Ca(2+) concentrations with dATP compared to ATP. This resulted in an increase in the Ca(2+) sensitivity of force (pCa50) by 0.06 pCa units. The rate of force redevelopment (ktr) in demembranated wall muscle was also increased, as was the rate of contractile activation (kACT) in isolated myofibrils, indicating increased cross-bridge binding and cycling compared with ATP in failing human myocardium. These data suggest that dATP could increase dP/dT and end systolic pressure in failing human myocardium. Importantly, even though the magnitude and rate of force development were increased, there was no increase in the time to 50% and 90% myofibril relaxation. These data, along with our previous studies in rodent models, show the promise of elevating myocardial dATP to enhance contraction and restore cardiac pump function. These data also support further pre-clinical evaluation of this new approach for treating heart failure.
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Project description:Heart Failure (HF) is a complex clinical disease and leading cause of hospitalization in the United States. Although precision-based treatment options are ultimately preferred, understanding the common underlying features of HF is also needed to develop universal therapies that address its pathogenesis. Among the etiology-independent molecular changes known to occur in HF is a global shift in the heart’s metabolic substrate preference. Transcriptional reprogramming of the heart has been shown to mediate this metabolic switch towards glycolytic metabolism; however, the molecular machinery that reactivate dormant genes remain largely unknown. In the current study, we hypothesized that the cardiac epigenome regulates metabolism via alterations in DNA methylation.
2019-07-25 | GSE123976 | GEO
Project description:Exploring the mechanisms of valvular heart disease (VHD) at the cellular level may be useful to identify new therapeutic targets; however, the comprehensive cellular landscape of non-diseased human cardiac valve leaflets remains unclear. The cellular landscapes of non-diseased human cardiac valve leaflets (five aortic valves, five pulmonary valves, five tricuspid valves, and three mitral valves) from end-stage heart failure patients undergoing heart transplantation were explored using single-cell RNA sequencing (scRNA-seq)
2022-09-13 | GSE213128 | GEO
Project description:Heart failure (HF) is a leading cause of morbidity and mortality in the United States and worldwide. As a multifactorial syndrome with unpredictable clinical outcomes, identifying the common molecular underpinnings that drive HF pathogenesis remains a major focus of investigation. Disruption of cardiac gene expression has been shown to mediate a common final cascade of pathological hallmarks wherein the heart reactivates numerous developmental pathways. Although the central regulatory mechanisms that drive this cardiac transcriptional reprogramming remain unknown, epigenetic contributions are likely. In the current study, we examined whether the epigenome, specifically DNA methylation, is reprogrammed in HF to potentiate a pathological shift in cardiac gene expression. To accomplish this, we used paired-end whole genome bisulfite sequencing and next-generation RNA sequencing of left ventricle tissue obtained from seven patients with end-stage HF and three nonfailing donor hearts. We found that differential methylation was localized to promoter-associated cytosine-phosphate-guanine islands, which are established regulatory regions of downstream genes. Hypermethylated promoters were associated with genes involved in oxidative metabolism, whereas promoter hypomethylation enriched glycolytic pathways. Overexpression of plasmid-derived DNA methyltransferase 3A in vitro was sufficient to lower the expression of numerous oxidative metabolic genes in H9c2 rat cardiomyoblasts, further supporting the importance of epigenetic factors in the regulation of cardiac metabolism. Last, we identified binding-site competition via hypermethylation of the nuclear respiratory factor 1 (NRF1) motif, an established upstream regulator of mitochondrial biogenesis. These preliminary observations are the first to uncover an etiology-independent shift in cardiac DNA methylation that corresponds with altered metabolic gene expression in HF.NEW & NOTEWORTHY The failing heart undergoes profound metabolic changes because of alterations in cardiac gene expression, reactivating glycolytic genes and suppressing oxidative metabolic genes. In the current study, we discover that alterations to cardiac DNA methylation encode this fetal-like metabolic gene reprogramming. We also identify novel epigenetic interference of nuclear respiratory factor 1 via hypermethylation of its downstream promoter targets, further supporting a novel contribution of DNA methylation in the metabolic remodeling of heart failure.
| S-EPMC6843013 | biostudies-literature
Project description:Heart failure with reduced ejection fraction (HFrEF) impacts approximately 20% of dialysis patients and is associated with high mortality rates. Key issues discussed in this review of HFrEF management in dialysis include dialysis modality choice, vascular access, dialysate composition, pharmacological therapies, and strategies to reduce sudden cardiac death, including the use of cardiac devices. Peritoneal dialysis and more frequent or longer duration of hemodialysis may be better tolerated due to slower ultrafiltration rates, leading to less intradialytic hypotension and better volume control; dialysate cooling and higher dialysate calcium may also have benefits. While high-quality evidence exists for many drug classes in the non-dialysis population, dialysis patients were excluded from major trials, and only limited data exist for many medications in kidney failure patients. Despite limited evidence, beta blocker and angiotensin-converting enzyme inhibitor or angiotensin receptor blocker use is common in dialysis. Similarly, devices such as implantable cardiac defibrillators (ICDs) and cardiac resynchronization therapy that have proven benefits in non-dialysis HFrEF patients have not consistently been beneficial in the limited dialysis studies. The use of leadless pacemakers and subcutaneous ICDs can mitigate future hemodialysis access limitations. Additional research is critical to address knowledge gaps in treating maintenance dialysis patients with HFrEF.
| S-EPMC7597416 | biostudies-literature