Etiology Of Heart Failure Research Articles

Implantable Cardioverter Defibrillator in Nonischemic Versus Ischemic Cardiomyopathy: Real-World Primary Prevention Study.

The evidence in the primary prevention of sudden cardiac death (SCD) by using implantable cardioverter defibrillators (ICD) in patients with ischemic cardiomyopathy (ICM) is well-established but remains controversial for those with nonischemic cardiomyopathy (NICM). This study evaluates whether prognostic differences exist between ICM and NICM patients after ICD implantation. Patients initially undergoing ICD implantation as primary SCD prevention were retrospectively enrolled from January 2017 to May 2023. Malignant ventricular arrhythmic and/or SCD were set as the primary endpoint, whereas all-cause mortality was the secondary endpoint. Patients were grouped by heart failure etiology (ICM vs. NICM) and then by primary endpoint events occurrence. Outcomes analyses were performed between the NICM and ICM patients. The final cohort had 342 patients, 213 (62.3%) with NICM and 129 (37.7%) with ICM. At a median follow-up of 23.0 (10.7, 33.2) months, 51 patients (14.9%) encountered primary endpoint events. No statistically significant disparities in primary endpoint events (log rank p = 0.413), all-cause death (log rank p = 0.208), cardiovascular mortality (log rank p = 0.218), or appropriate ICD therapy (log rank p = 0.250) between the two groups were indicated by Kaplan-Meier survival analysis. Moreover, the COX-adjusted models further demonstrated the absence of any significant differences between the two groups. In real-world settings, primary prevention of SCD with ICD implantation yields similar outcomes for ICM and NICM patients, including probabilities of SCD and/or malignant ventricular arrhythmias, all-cause mortality, appropriate ICD therapy, and cardiovascular mortality.

Identifying etiologies of heart failure using non-contrast cardiac magnetic resonance imaging: cine imaging, T1 and T2 mapping, and texture analysis for T1 mapping

Identifying etiologies of heart failure using non-contrast cardiac magnetic resonance imaging: cine imaging, T1 and T2 mapping, and texture analysis for T1 mapping

Left ventricular function improvement during angiotensin receptor-neprilysin inhibitor treatment in a cohort of HFrEF/HFmrEF patients.

Heart failure (HF) patients may lack improvement of left ventricular (LV) ejection fraction (LVEF) despite optimal HF medication comprising an angiotensin receptor-neprilysin inhibitor (ARNI). Therefore, we aimed to identify key predictors for LV functional enhancement and prognostic reverse cardiac remodelling in HF patients on ARNI treatment. We retrospectively analysed 294 consecutive patients with HF with reduced (HFrEF) or mildly reduced (HFmrEF) ejection fraction in our 'EnTruth' patient registry. LVEF was determined by echocardiography at initiation of ARNI and at 12months of follow-up. We assessed the predictive value of clinically relevant patient-, HF- and treatment-related parameters in regard to changes in LVEF and all-cause mortality using medoid clustering and the XGBoost machine learning algorithm. Cluster analysis integrating clinically relevant patient characteristics unveiled four characteristic sub-phenotypes of patients with HFrEF and HFmrEF, respectively. Distinct clusters exhibit a strong (P<0.05) therapeutic response to ARNI treatment and enhanced LV function. Key patient criteria, such as duration and aetiology of HF, renal function and de novo ARNI treatment, were significantly (P<0.05) associated with change of LVEF and independently predicted cardiac remodelling. By training various machine learning models on relevant clinical parameters, stratification of LVEF improvement by XGBoost resulted in a high prediction accuracy. The stratification of patients with HFrEF [area under the receiver operating characteristic curve (AUC)=0.77] and HFmrEF (AUC=0.70) led to an increased diagnostic accuracy of LVEF improvement in the validation cohort. Using machine learning, the likelihood of cardiac remodelling following ARNI treatment, as indicated by our newly established EnTruth score, was directly associated with absolute LVEF improvement in both HFrEF (r=0.51, P<0.0001) and HFmrEF (r=0.42, P=0.001). Ultimately, patients with HFrEF and a high EnTruth score have a lower risk of all-cause mortality (P<0.05 in survival analysis). Recognition of essential clinical factors by integrating machine learning and cluster analyses may help to identify HF patients benefiting from improvement of LVEF following ARNI treatment. Early identification of those patients with a high response to ARNI treatment may allow a more refined selection of patients benefiting from an early escalation of HF treatment or interventional therapy.

CORONAROGRAPHIE ET ETIOLOGIES DE L'INSUFFISANCE CARDIAQUE A FRACTION D'EJECTION VENTRICULAIRE GAUCHE ALTEREE AU SENEGAL

Heart failure is a major public health problem because of the number and duration of hospitalizations. Patients with heart failure may have mixed etiologies that are not mutually exclusive, and etiologies vary between high-income and developing countries. The aim of our work was to study the contribution of coronary angiography in the etiological investigation of heart failure with impaired LVEF in the cardiology department of HPD. This was a descriptive and analytical cross-sectional study with retrospective data collection on 103 patients hospitalized in the cardiology department of DAKAR's Hospital Principal presenting with heart failure with impaired LVEF and who underwent coronary angiography from January 2019 to December 2022. Our study included 103 patients with a clear male predominance 79.6% and a sex ratio of 3.7. Their mean age was 64±13.5 years. Diabetes was prevalent at 24.3% (p=0.033). All patients had impaired segmental and/or global left ventricular kinetics. Mean ejection fraction was 28.1±6.8. The right radial route was predominantly used 83.7% of the time, and there were no procedural incidents or accidents. Diabetes was significantly associated with coronary involvement (p=0.033). Coronary angiography was normal in 37.8% of patients and showed tri-truncular lesions in 19.4% of patients and bi-truncular lesions in 17.4%. We found 91 significant lesion and 67 non-significant lesion. A total of 41 patients had ischemic heart disease, equivalent to 39.8%. Our study shows that ischemic heart disease plays an important role in the etiology of heart failure with impaired LVEF, and that coronary angiography should be performed routinely.

Sacubitril/valsartan in a wide spectrum of heart failure patients (from mechanisms of action to outcomes in specific populations).

Heart failure (HF) represents a significant global health challenge, characterized by high morbidity and mortality rates, decreased quality of life and a significant financial and economic burden. The prevalence of HF continues to rise, driven by an ageing population and an increasing burden of comorbidities such as hypertension, diabetes and obesity. Understanding the complex pathophysiology and developing effective treatments are critical for improving patient outcomes, yet the range of effective, life-prolonging medication classes has remained mostly constant in the last few decades. The introduction of angiotensin receptor neprilysin inhibitors (ARNI) was a major breakthrough in HF management, for the first time targeting the natriuretic peptide system in addition to the renin-angiotensin-aldosterone pathway to potentiate the effects of older drug classes. ARNI shows superiority in clinical outcomes compared to previous guideline-directed therapies, especially in patients with reduced ejection fraction (EF). It has now been implemented into international guidelines, endorsing its use in patients with HF and reduced ejection fraction (HFrEF) and HF with mildly reduced ejection fraction (HFmrEF). This review summarises the mechanism of action of Sac/Val, presents key clinical trials in a range of patient populations and HF aetiologies and outlines gaps in knowledge and potential novel uses of Sac/Val.

G Protein Regulation by RGS Proteins in the Pathophysiology of Dilated Cardiomyopathy.

Regulators of G protein signaling (RGS) proteins finetune signaling via heterotrimeric G proteins to maintain physiologic homeostasis in various organ systems of the human body including the brain, kidney, heart, and the vasculature. Impaired regulation of G protein signaling by RGS proteins is implicated in the pathogenesis of several human diseases including various forms of cardiomyopathy such as hypertrophic cardiomyopathy and dilated cardiomyopathy (DCM). Both genetic and non-genetic changes that impinge on G protein signaling in cardiomyocytes are implicated in the etiology of DCM, and there is accumulating evidence that such genetic and non-genetic changes affecting G protein signaling in cell types other than cardiomyocytes could serve as a DCM trigger in humans. This review discusses and highlights mammalian RGS proteins and their roles in cardiac physiology and disease, with specific focus on the current understanding of the etiology of DCM and the pathogenic roles of RGS proteins that are prominently expressed in the cardiovascular system. Growing evidence suggests that defects in G protein regulation by RGS proteins in the cardiovascular system likely contribute to cardiomyocyte structural damage and decreased contractile function that hallmark DCM. Further studies that enhance the understanding of the dynamics of G protein regulation by RGS proteins in several cell types in the myocardium and the vasculature are critical to gaining more insight into the etiology of DCM and heart failure, and to the identification of novel therapeutic targets.

Influence of Insertion/Deletion Polymorphism of the Angiotensin Converting Enzyme Gene on Adiposity and Cardiac Function in Patients with Heart Failure.

The angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphism (rs4340) is associated with the pathogenesis of heart failure (HF). This polymorphism may contribute to a greater propensity for severe HF and excess weight. To evaluate adiposity, cardiac function, and their association with ACE I/D polymorphism in HF patients. Cross-sectional study with ambulatory individuals ≥18 years diagnosed with HF. Genetic analysis was performed using polymerase chain reaction followed by agarose gel electrophoresis. Left ventricular ejection fraction (LVEF) was determined by echocardiography. Nutritional status was assessed using body mass index, while adiposity was analyzed using bioelectrical impedance analysis (BIA), waist circumference, waist-to-hip ratio, and waist-to-height ratio. The adopted significance level was 5% (p < 0.05). Seventy-one individuals were included, with a mean age of 55.8 ± 13.0 years, predominantly male (66.2%), with functional class I and II (90.9%), and a median LVEF of 30% (24-40). The prevalence of overweight was 38%, class I obesity was 23.9%, and class II and III obesity was 12.7%, with 50.7% exhibiting excess adiposity as assessed by BIA. A total of 88 D alleles and 54 I alleles of the ACE gene were identified. Regarding ACE genotypes, 38.1% were DD, 47.8% were ID, and 14.1% were II. In the multivariate analysis, the D allele (DD + ID genotypes versus II) was associated with LVEF (PR 0.995; 95% CI 0.991-1.000; p = 0.048) and with the etiology of HF (dilated cardiomyopathy: PR 1.283; 95% CI 1.039-1.583; p = 0.021). No independent association was found with adiposity. The presence of the D allele of the ACE polymorphism is associated with LVEF and HF etiology. Despite overweight being prevalent in the sample, no independent associations were found.

The risk of death according to left ventricular ejection fraction and right ventricular dilatation in 17 321 adults with heart failure from 40 high-, middle- and low-income countries-A Global Congestive Heart Failure (G-CHF) study.

The aim of this study was to describe the prognostic importance of left ventricular ejection fraction (LVEF) versus right ventricular (RV) dilatation and dysfunction in patients with heart failure (HF) from countries of different income levels. We enrolled 17 321 participants with HF from 40 countries. Participants were followed for a median (25th-75th percentile) of 2.1 (2.0-4.6) years. Cox proportional hazards models were performed with adjustment for age, sex, HF aetiology, diabetes, atrial fibrillation, chronic obstructive pulmonary disease, tobacco and alcohol use, functional class, and the use of HF medications, blood pressure, serum creatinine and HF duration. During follow-up, 5738 (33%) participants died and 3569 (21%) were hospitalized for HF. Compared with LVEF ≥50%, the hazard ratios (HR) for death were 0.88 (95% confidence interval [CI] 0.80-0.97, p = 0.009) in patients with LVEF 40-49%, 0.96 (95% CI 0.88-1.05, p = 0.40) for LVEF 30-39%, and 1.18 (95% CI 1.08-1.29, p < 0.0001) for LVEF <30%. RV enlargement was associated with an increased risk of death (HR 1.35, 95% CI 1.26-1.44, p < 0.0001). The relationship between LVEF and death differed according to HF aetiology (interaction p = 0.0010). In ischaemic HF and idiopathic dilated cardiomyopathy, there was a continuous inverse association between LVEF and the risk of death, but in hypertensive, valvular and other HF types, there was no association between LVEF and the risk of mortality. Reduced LVEF was associated with worse prognosis in ischaemic and idiopathic dilated cardiomyopathy but not in HF of other causes. RV enlargement was associated with a more marked increase in the risk of death.

Investigation of left ventricular ejection fraction in a Swiss heart failure population: Insights into mortality and sex differences.

Understanding heart failure (HF) characteristics is essential to improve patient outcomes. Categorizing HF beyond left ventricular ejection fraction (LVEF) is challenging due to heterogeneous clinical presentation and aetiologies. Despite global studies on HF, the role of LVEF on mortality remains controversial. We explored the association of LVEF with mortality, considering sex differences and comorbidities in a cohort from the largest tertiary cardiovascular centre in Switzerland. HF patients admitted to the University Hospital of Bern from January 2015 to December 2019 were evaluated. LVEF was used to classify patients into HF with preserved ejection fraction (HFpEF), HF with mid-range ejection fraction (HFmrEF) and HF with reduced preserved ejection fraction (HFrEF) categories. Cox proportional hazard models and time-stratified analyses adjusted for potential confounders were employed. A total of 5824 HF patients were included, and 2912 died over a median follow-up time of 3.39years. Mortality rates across LVEF categories showed no significant differences, while overall, women showed significantly higher mortality; 30day mortality was lower in the HFpEF category [hazard ratio (HR) 0.67, 95% confidence interval (CI): 0.52-0.88, P=0.003], with persistent effects upon stratification in males (HR 0.59, 95% CI: 0.42-0.81, P<0.001) and non-diabetics (HR 0.62, 95% CI: 0.44-0.87, P=0.005). An isolated reduction in HFpEF mortality was observed in females after 1year (HR 0.72, 95% CI: 0.53-0.98, P=0.035). The prognostic role of LVEF on all-cause mortality remains unclear, while differences in mortality rate distribution between women and men mirror established HF pathophysiological sex differences. Future HF studies should focus on HF aetiology and include measures beyond LVEF for comprehensive characterization.

Elevated Donor-Derived Cell-Free DNA Levels Are Associated With Reduced Myocardial Blood Flow but Not Angiographic Cardiac Allograft Vasculopathy: The EVIDENT Study.

Cardiac allograft vasculopathy (CAV) leads to impaired myocardial blood flow (MBF), increasing the risk of cardiovascular death or retransplant among heart transplantation (HT) recipients. Data on elevation in donor-derived cell-free DNA (dd-cfDNA) and CAV in the absence of rejection are mixed. We sought to test the hypothesis that CAV with reduced MBF (RMBF) is associated with elevated dd-cfDNA. A retrospective review was conducted on HT recipients at a high-volume center who underwent dd-cfDNA testing between September 2019 and November 2022. Inclusion criteria included undergoing CAV screening with cardiac positron emission tomography scans and coronary angiograms. Patients were grouped by the presence of angiographic CAV diagnosis and MBF reserve evaluated through cardiac positron emission tomography. The latter was subdivided into normal MBF or RMBF, with RMBF defined as an MBF reserve ≤2. Elevated dd-cfDNA was defined as ≥0.12%. Two hundred fifty-six HT recipients were included (median age, 55 years; 27.6% female; median, 8 years [interquartile range (IQR), 5-14] post-HT). Ischemic etiology of heart failure was more prevalent in the RMBF group (36%) compared with the normal MBF group (20%; P=0.02). The prevalence and magnitude of a positive dd-cfDNA test with angiographic CAV (29%; median, 0.26% [IQR, 0.15%-0.62%]) were not significantly different from those without CAV (30%; P=0.94; median, 0.31% [IQR, 0.17%-0.71%]; P=0.38). However, RMBF patients exhibited significantly higher dd-cfDNA prevalence and levels (51%; median, 0.81% [IQR, 0.48%-1.11%]) compared with normal MBF patients (27%; P<0.001; median, 0.25% [IQR, 0.15%-0.52%]; P<0.001). HT recipients with angiographic CAV had similar dd-cfDNA levels and rates as those without. Notably, dd-cfDNA levels and rates were significantly elevated in patients with RMBF assessed by positron emission tomography compared with those with normal MBF.

Heart failure: innovative understanding from traditional Chinese medicine (TCM) and treatment with classic TCM formulas

The prevalence of cardiovascular diseases in China has shown a rising trend. With the patient number of about 8.9 million, heart failure has brought a heavy burden to public health and wellness. Despite the modern medical research progress in the pathogenesis and clinical treatment of heart failure, the patients with heart failure still suffer from recurrent episodes of dyspnea(requiring repeated hospital admissions), diuretic resistance, elevated creatinine levels due to prolonged diuretic use, and poor prognosis, among other major clinical and scientific issues. In traditional Chinese medicine(TCM), heart failure belongs to the category of &quot;heart water&quot;. The research team has found that because of the changes in the modern disease spectrum, the differences between ancient and modern physical constitutions, and the use of anti-heart failure drugs in modern medicine, the pathological process of heart failure has been altered, and the symptoms of some patients have become unobvious. As a result, the etiology and pathogenesis of heart failure have undergone major changes. The disease causes include external pathogen attack, emotional disorders, excessive labor injury, medication-induced damage, dietary disorders, water-dampness stagnation, and endowment insufficiency. These causes are closely related to the infection aggravation-induced heart failure, cardiac and psychological diseases, and heart volume overload in modern medicine. The pathogeneses of heart failure include edema due to Yang deficiency and water retention turning into heat in the acute stage and liver depression and Qi stagnation, heart Qi deficiency, kidney Yang deficiency, Qi deficiency in lung and spleen, phlegm and water retention, and internal obstruction due to blood stasis in the remission stage. The corresponding treatment strategies were recommended as follows: Zhenwu Decoction for edema due to Yang deficiency, Mufangji Decoction for water retention turning into heat, Chaihu Longgu Muli Decoction for liver depression and Qi stagnation, Guizhi Decoction for heart Qi insufficiency, Shenqi Pills and Yougui Pills for kidney Yang deficiency, Yupingfeng Powder, Lizhong Decoction, Buzhong Yiqi Decoction, and Guipi Decoction for Qi deficiency in lung and spleen, Fangji Huangqi Decoction, Wuling Powder, Linggui Zhugan Decoction, and Tingli Dazao Xiefei Decoction for internal obstruction due to phlegm and water retention, Guizhi Fuling Pills and Danggui Shaoyao Powder for internal obstruction due to blood stasis. The clinical treatment should follow the principle of considering both pathogenesis and pathology as well as both medicine nature and mechanism. The TCM concept of secondary prevention with TCM formulas for replenishing deficiency should be adopted. The treatment based on the principle and concept above will improve the patients' quality of life, reduce the number of hospital admissions, ameliorate diuretic resistance, and improve the clinical outcomes.

Genetic Biomarkers in Heart Failure: From Gene Panels to Polygenic Risk Scores.

This review aims to provide a comprehensive overview of the current understanding of genetic markers associated with heart failure (HF) and its underlying causative diseases, such as cardiomyopathies. It highlights the relevance of genetic biomarkers in diagnosing HF, predicting prognosis, potentially identifying its preclinical stages and identifying targets to enable the implementation of individualized medicine approaches. The prevalence of HF is increasing due to an aging population but with greater access to disease-modifying therapies. Advanced diagnostic tools such as cardiac magnetic resonance, nuclear imaging, and AI-enabled diagnostic testing are now being utilized to further characterize HF patients. Additionally, the importance of genetic testing in HF diagnosis and management is increasingly being recognized. Genetic biomarkers, including single nucleotide polymorphisms (SNPs) and rare genetic variants, are emerging as crucial tools for diagnosing HF substrates, determining prognosis and increasingly directing therapy. These genetic insights are key to optimizing HF management and delivering personalized treatment tailored to individual patients. HF is a complex syndrome affecting millions globally, characterized by high mortality and significant economic burden. Understanding the underlying etiologies of HF is essential for improving management and clinical outcomes. Recent advances highlight the use of multimodal assessments, including AI-enabled diagnostics and genetic testing, to better characterize and manage HF. Genetic biomarkers are particularly promising in identifying preclinical HF stages and providing personalized treatment options. The genetic contribution to HF is heterogeneous, with both monogenic and polygenic bases playing a role. These developments underscore the shift towards personalized medicine in HF management.

Interpreting Population Mean Treatment Effects in the Kansas City Cardiomyopathy Questionnaire

The Kansas City Cardiomyopathy Questionnaire (KCCQ) is a commonly used outcome in heart failure trials. While comparing means between treatment groups improves statistical power, mean treatment effects do not necessarily reflect the clinical benefit experienced by individual patients. To evaluate the association between mean KCCQ treatment effects and the proportions of patients experiencing clinically important improvements across a range of clinical trials and heart failure etiologies. A patient-level analysis of 11 randomized clinical trials, including 9977 patients, was performed to examine the association between mean treatment effects and the KCCQ Overall Summary Score (OSS) and the absolute differences in the proportions of patients experiencing clinically important (≥5 points) and moderate to large (≥10 points) improvements. There was no target date range, and included studies were those for which patient-level data were available. Validation was performed in 7 additional trials. The data were analyzed between July 1 and September 15, 2023. Proportion of patients experiencing an improvement of 5 or more and 10 or more points in their KCCQ score (with each domain transformed to a range of 0 to 100 points, where higher scores represent better health status). Group mean KCCQ-OSS differences were strongly correlated with absolute differences in clinically important changes (Spearman correlations 0.76-0.92). For example, a mean KCCQ-OSS treatment effect of 2.5 points (half of a minimally important difference for an individual patient) was associated with an absolute difference of 6.0% (95% prediction interval [PI], 4.0%-8.1%) in the proportion of patients improving 5 or more points and 5.0% (95% PI, 3.1%-7.0%) in the proportion improving 10 or more points, corresponding to a number needed to treat of 17 (95% PI, 12-25) and 20 (95% PI, 14-33), respectively. Inferences about clinical impacts based on population-level mean treatment effects may be misleading, since even small between-group differences may reflect clinically important treatment benefits for individual patients. Results of this study suggest that clinical trials should explicitly describe the distributions of KCCQ change at the patient level within treatment groups to support the clinical interpretation of their results.

Abstract 4135127: Traveling more than a 20-mile radius to a Heart Failure Center can affect the quality of Heart Failure Care.

Introduction: We recognized the profound importance of access to care among patients with heart failure (HF). The geographical location of HF centers may significantly impact health outcomes, especially for those with limited transportation. This social determinant of health (SDOH) aspect is critical in bridging the gap in achieving HF care. Hypothesis/Methods: This was a single-center observational study conducted at a tertiary heart failure center in central Pennsylvania. We assessed the impact of travel distance by comparing patients who travel within a 20-mile radius to those who travel beyond a 20-mile radius. A total of 322 patients were referred to the HF clinic and enrolled in a guideline-directed medical therapy (GDMT) optimization program. Data collected included distance to Hershey Medical Center (HMC), health insurance coverage, HF etiology, onset, and echocardiogram. The distance was calculated based on the patient’s zip code. Results: Among patients enrolled in the HF-GDMT program, 194 travel within 20 miles, and 128 travel beyond a 20-mile radius to HMC. The mean travel distance to HMC was 9.1 miles (within) and 40.9 miles beyond 20 miles. The majority of patients were 81.3% white, 67% male, and the average age was 64. Most patients had heart failure with reduced ejection fraction (HFrEF) at 92.9%, 63% nonischemic, and 57.5% new onset. The comorbidities in both groups were similar, including hypertension, hyperlipidemia, and coronary artery disease (CAD). When comparing both groups, those who traveled beyond the 20-mile radius to HMC had more chronic HF at 55.5% vs. 34% in patients who traveled within the 20-mile radius. Upon enrollment, most patients were on suboptimal doses of either 1 or 2 of the four pillars of GDMT for HFrEF. Conclusions: The findings of this study revealed that patients with HF who travel beyond a 20-mile radius to HMC are more likely to have chronic HF, suggesting a delay in seeking care. A delay in referral may affect the timely initiation of appropriate GDMT and will likely lead to worse health outcomes. This underscores the urgent need for interventions to address barriers like transportation to improve HF care, offering a potential avenue for better patient outcomes.

Abstract 4135113: Referral to a Heart Failure Clinic Substantially Increases the Use of Angiotensin Receptor Neprilysin Inhibitor (ARNi) and Sodium-glucose cotransporter-2 Inhibitor (SGLT2i) in Heart Failure Patients.

Introduction: Addressing access to life-saving therapy is crucial in influencing health outcomes. The stark reality of limited access to pharmacological therapy for heart failure with reduced ejection fraction (HFrEF), particularly novel drugs such as angiotensin receptor neprilysin inhibitors (ARNi) and sodium-glucose cotransporter-2 inhibitors (SGLT2i) for patients with heart failure (HF), underscores the challenges we face. Hypothesis: We analyze the impact of referring patients diagnosed with HF to our HF clinic by evaluating access to the 4 pillars of HFrEF, emphasizing cost-prohibiting pharmacological therapy, and assessing the efficacy of these medications when applied. Methods: This study compared 314 patients who live in counties within and outside the Penn State Health System. The data collected included healthcare insurance coverage, HF etiology, comorbidities, onset, initial and within six months post titration of guideline-directed medical therapy (GDMT) echocardiogram, and medication dose. Results: Among patients referred to our HF clinic, 184 live in counties within, and 130 live outside the Penn State Health System. The average age was 64, 69.4% were male, and a significant number of patients had HFrEF (92.7%). The prevailing comorbidities between the 2 groups were hypertension, hyperlipidemia, and diabetes. Upon completion, there was a significant increase in ARNi (83.1%) and SGLT2i (65.3%) use in both groups. They both (within vs. outside) reached almost similar percentages of triple therapy (77.9% vs. 79.2%; p-value=0.78), except for quadruple therapy (36.4% vs. 44.6%; p-value=0.16) and maximum tolerated dose (83.3% vs. 75%; p-value=0.11). The overall mean ejection fraction (EF) in both groups demonstrated significant improvement from pre-EF (30.5%) to post-EF (45.9%). Conclusion: Despite their location, patients referred to the HF clinic experienced intensified use of cost-prohibiting medications such as ARNi and SGLT2i, compared to the current gap in GDMT use. After optimizing GDMT, both groups had markedly improved EF. These findings suggest that referral to a HF clinic is a promising strategy for addressing the use of life-saving therapy and potentially reducing adverse health outcomes.

Abstract 4136785: Interpreting Population Mean Treatment Effects in the Kansas City Cardiomyopathy Questionnaire

Introduction: The Kansas City Cardiomyopathy Questionnaire (KCCQ) is a common outcome in heart failure trials. While comparing means between treatment groups improves statistical power, mean effects do not necessarily reflect the clinical benefit experienced by patients. Objectives: To evaluate the relationship between mean KCCQ treatment effects in clinical trials and the proportions of patients experiencing clinically important improvements across a range of heart failure etiologies and interventions. Methods: We performed a patient-level meta-analysis of 11 randomized trials (9,977 patients) to examine the relationship between mean KCCQ Overall Summary Score (OSS) treatment effects and the absolute differences in the proportions of patients experiencing clinically important (≥5 points) and moderate or larger (≥10 points) improvements. Validation was performed in 7 additional trials. Results: Group mean KCCQ-OSS differences were strongly correlated with absolute differences in clinically important changes (Spearman correlations 0.76-0.92). For example, a mean KCCQ-OSS treatment effect of 2.5 points (half of a minimally important difference for an individual patient) was associated with an absolute difference of 6.0% (95% prediction interval [PI] 4.0-8.1) in the proportion of patients improving ≥5 points and 5.0% (95% PI 3.1-7.0) in the proportion improving ≥10 points, corresponding to NNTs of 17 (95% PI 12-25) and 20 (95% PI 14-33), respectively. Similar relationships were observed in the validation studies. Conclusions: Inferences on clinical impact based on population-level mean treatment effects are misleading since even small between group differences may reflect clinically important treatment benefits at the patient level. Clinical trials should explicitly describe the distributions of patient-level KCCQ changes to support clinical interpretation of their results.

Impact of HF etiology on the sustainability of favorable response after LVAD weaning: A VAD Wean Registry analysis

Abstract Background A subset of heart failure (HF) patients can experience significant improvement of their cardiac structure and function while on left ventricular assist device (LVAD) support. Purpose We sought to investigate the impact of HF etiology on the durability of cardiac improvement and favorable outcomes after LVAD weaning. Methods We studied 324 HF patients enrolled in the international multicenter VAD Wean Registry who received a durable continuous-flow LVAD and underwent device support weaning (Figure 1). Indications for VAD weaning included: structural/functional cardiac improvement meeting institutional criteria for "myocardial recovery" (responders) or LVAD-related complications accompanied by variable degrees of cardiac improvement (partial responders). Patients were divided into seven categories based on HF etiology: ischemic cardiomyopathy (CM) (n=30), post-myocarditis CM (n=65), peripartum CM (n=53), valvular CM (n=12), chemotherapy-induced CM (n=14) and idiopathic CM (n=150). The primary outcome was 2-year survival free of transplant or LVAD re-implantation. The secondary outcome was the LVEF, measured by echocardiography at 3, 6, 12 and 24 months post-LVAD weaning. Results Patients with idiopathic, peripartum and post-myocarditis CM had higher rate of 2-year survival free of transplant or LVAD re-implantation compared to patients with chemotherapy-induced CM (Figure 2-Panel A) (p-values: 0.009, 0.004, 0.001, respectively). Patients with post-myocarditis CM were also more likely to achieve the primary outcome compared to those with ischemic CM (ICM) (p-value, 0.009). The LVEF changes over time are depicted in the Figure 2-Panel B. Conclusions In this multicenter analysis the etiology of HF appears to impact the durability of favorable response after LVAD weaning. The degree of reverse remodeling achieved before VAD weaning and its impact on the durability of response in different HF etiologies warrants further investigation in studies with larger patient population and power.

Phosphoproteomics of PLN R14del heart tissue reveals major myocyte degenerate phenotype, and is attenuated by PLN antisense treatment in vitro

Abstract Background/Purpose: Phospholamban (PLN) p.Arg14del (R14del, R14Δ/+) is a pathogenic variant that can cause cardiomyopathy, characterized by PLN protein aggregation, ultimately leading to heart failure (HF). The exact pathophysiology is unknown, we aim to uncover R14Δ/+ disease mechanisms and study potential treatment using PLN antisense oligonucleotides (PLN-ASOs). Methods Phosphoproteomics was performed on human heart tissue from end-stage R14Δ/+ patients (N=6) versus other etiologies of HF (N=10) as a control. CRISPR-Cas9 engineered R14Δ/+ and isogenic control (WT) induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) were extensively characterized, including the phosphoproteome, calcium transients (FLUO 4-AM), mitochondrial respiration (Seahorse Mito Stress Test) and contractility in dynamic engineered heart tissues (dyn-EHTs) before and after PLN-ASO treatment, and the results were validated in R14Δ/+ iPSC-CMs derived from R14Δ/+ patients. Results Phosphoproteomics of heart tissue from R14Δ/+ vs. other etiologies of HF identified 138 differentially expressed proteins (DEPs) and 317 differentially expressed phosphoproteins (DEPPs), therewith establishing a disease-specific signature. Phosphoproteomics of WT vs. R14Δ/+ iPSC-CMs identified 451 DEPs and 1046 DEPPs. Gene ontology analysis of end-stage R14Δ/+ heart tissue and iPSC-CMs revealed a large overlap. Here, R14Δ/+ showed to have great impact on contraction (e.g. SYNPO2L, MYH10, TTN) and calcium (e.g. AHNAK, HRC, RYR2). In line with this, functional characterization revealed that R14Δ/+ iPSC-CMs have an increased Ca2+ systolic velocity and accelerated calcium transient (decreased T50 and T90), that associated with altered calcium-related DEPPs (e.g. RYR2). In dyn-EHTs, R14Δ/+ dyn-EHTs have a decreased contraction duration, time-to-peak and ability to pace, associated with altered contractility-related DEPPs (e.g. SYNPO2L, MYH7, TTN). PLN-ASOs dose-dependently altered PLN mRNA expression and protein levels in iPSC-CMs, and 62 DEPs and 372 DEPPs were identified. PLN-ASOs increased Ca2+ diastolic velocity, which associated with altered calcium-related DEPPs (e.g. PLN, AHNAK, HRC). PLN-ASOs increased the ability of dyn-EHTs to pace and therewith improved contractility, which associated with altered contractility-related DEPPs (e.g. SYNPO2L, MYH7, TTN). PLN-ASOs dose-dependently increased basal respiration and ATP production, which associated with altered mitophagy-related DEPs (GABARAPL2 and MAP1LC3). These functional characteristics were validated in R14Δ/+ patient iPSC-CMs. Discussion: R14Δ/+ cardiomyocytes have a degenerative phenotype characterized by altered calcium transients and reduced contractility and PLN-ASOs attenuate these characteristics and improve metabolism.

Hemodynamic profiles and survival in chronic advanced heart failure patients evaluated for heart replacement therapy

Abstract Background Advanced heart failure (HF) is associated with dismal prognosis despite optimal medical therapy. Invasive assessment with right heart catheterization (RHC) is a valuable tool to assess transplant candidates and hemodynamic profiling is crucial to stratify prognosis and select patients for advanced therapies. Purpose This study aims to examine the relationship between hemodynamic profiles based on cardiac index (CI) and filling pressures and survival in ambulatory patients with advanced HF evaluated for heart replacement therapy (HRT) such as heart transplantation (HT) and left ventricular assist device (LVAD) implant. Methods We analyzed adult ambulatory advanced HF patients evaluated for HRT with an available baseline RHC from 2003 to 2022. Hemodynamic data were classified using a CI &amp;lt; 2.2 l/min/m2 as marker of reduced cardiac output ("cold" profile opposed to the "warm" profile) and increased filling pressure, defined as right atrial pressure ≥ 10 mmHg and/or pulmonary capillary wedge pressure (PCWP) ≥ 15 mmHg as a marker for congestion ("wet" profile opposed to the "dry" profile). Study endpoint was death or urgent HT or LVAD implant at 5 years. Results Study population included 610 patients (mean age 53±10 years, 79% males). According to hemodynamic criteria, 332 patients (55%) exhibited a "wet cold" hemodynamic profile, 117 (19%) a "cold dry", 91 (15%) a "warm wet" and 66 (11%) a "warm dry" phenotype. The "wet" patients showed a significantly higher prevalence of pulmonary hypertension (96% wet cold, 94% wet warm vs 21% dry warm, 19% dry cold; p&amp;lt;0,001), a lower pulmonary artery pulsatility index (4,0 wet cold, 4,1 wet warm vs 7,4 dry warm, 6,9 dry cold; p&amp;lt;0,001). No differences were found in etiology of HF. Both reduced CI [OR 1,6 (1-2,4), p=0.003] and increased filling pressures [OR 1,9, (1,2-2,8) p=0.007] were associated with worse outcomes. Survival differed significantly among hemodynamic profiles, with a survival rate of 48% in the "cold wet" profile compared to 68% in the "cold dry" [OR 1,9 (1,2-3,1) p=0,007] and 65% in the "warm dry" [OR 2,2 (1,1-4,2), p=0.01]. The difference between "cold wet" and "warm wet" was borderline significant (p=0.07). Further stratification between right and left ventricular filling pressures showed that isolated right ventricular congestion was rare and associated with low event rate, while in patients with preserved CI, biventricular congestion was associated with borderline worse survival as compared to isolated left ventricular increased filling pressures (p=0.06). Conclusions Hemodynamic profiles assessed with RHC stratify prognosis in ambulatory patients with advanced HF referred for HRT. Evaluation of hemodynamic phenotype may help identify subgroups of patients at high risk and guide therapeutic decisions. Further studies are needed to confirm these findings and develop personalized management strategies to improve clinical outcomes in this population.Survival-hemodynamic phenotypeSurvival-filling pressures

Elevated cancer biomarkers in patients with severe heart failure could be a potential predictor of mortality during LVAD support

Abstract Introduction Owing to increasing numbers of heart failure patients a search for new biomarkers predicting prognosis is desirable. Background The purpose of this study was to analyze levels of cancer biomarkers in patients with severe heart failure before or after left ventricular assist device (LVAD) implantation and estimate its impact on survival during LVAD support. Methods We retrospectively analyzed data of all consecutive 168 LVAD recipients (92.8%- male, mean age 53.3 years ( median - 56.6, SD 12.0 ), median INTERMACS profile- 3.0, ischemic etiology of heart failure- 52.4%, 41.0% post CRT-D and 54.8% post ICD implantation, 36.9 post IABP, 5.4% post ECMO%, 11.9% post CABG and 8.9% post other cardiac surgery before LVAD implantation) implanted with continuous-flow LVAD (59.5%-HeartMate3, 35.1%- HeartWare, 5.4%-Heart Mate II) in our institution within years 2009-2023. Among comorbidities 63% of patients had atrial fibrillation or flutter, 41.6%- diabetes, 37.5%- arterial hypertension, 48.8%-renal failure, 7.1% pulmonary obstructive disease, 56.5% had pulmonary hypertension with mean pulmonary artery pressure above 25 mm Hg in right heart catheterization and 47% of patients had a history of cardiac arrest or sustained ventricular arrythmia before LVAD implantation. The overall mortality was 44.0 %. 31% patients were transplanted during LVAD support and in 4 patients (2.3%) LVAD was explanted or deactivated. Patient were followed to death, heart transplantation, LVAD explantation or the end of observation in our institution. Mean time of LVAD support was 885 days (1-2570). 23% of patients had right ventricular failure (RVF) early post LVAD implantation while 7.7% had late form of RVF. Results Serum concentrations of cancer biomarkers: carcinoembryonic antigen (CEA), carbohydrate antigen (CA)19-9, carbohydrate antigen(CA)-125 and alpha fetoprotein (AFP) taken before (56 patients -33.3%) or after (24 patients-14.3%) LVAD implantation were analyzed. Mean values, rate of abnormal results and correlation of abnormal results of CEA, CA19-9, CA-125, AFP with mortality during LVAD support were depicted in Table 1. No statistically significant correlations were found between levels of abovementioned cancer biomarkers and mortality though a trend towards increased mortality could be observed for abnormal results of CEA and Ca 19-9 taken before LVAD implantation. No malignant neoplasms were found in all analyzed patients except of one in whom a recurrence of lymphoma was found 2 months after LVAD implantation. Conclusions Patients with severe heart failure before and after LVAD implantation may present abnormal values of cancer biomarkers despite no found neoplasms. Our observation suggests that elevated cancer biomarker levels could predict mortality in heart failure patients after LVAD implantation. Further research is needed to confirm this thesis and investigate mechanisms of this phenomenon.