Aging in Heart Failure: Embracing Biology Over Chronology: JACC Family Series.

Age is among the most potent risk factors for developing heart failure and is strongly associated with adverse outcomes. As the global population continues to age and the prevalence of heart failure rises, understanding the role of aging in the development and progression of this chronic disease is essential. Although chronologic age is on a fixed course, biological aging is more variable and potentially modifiable in patients with heart failure. This review describes the current knowledge on mechanisms of biological aging that contribute to the pathogenesis of heart failure. The discussion focuses on 3 hallmarks of aging-impaired proteostasis, mitochondrial dysfunction, and deregulated nutrient sensing-that are currently being targeted in therapeutic development for older adults with heart failure. In assessing existing and emerging therapeutic strategies, the review also enumerates the importance of incorporating geriatric conditions into the management of older adults with heart failure and in ongoing clinical trials.

Atrioventricular optimization improves cardiac resynchronization response in patients with long interventricular electrical delays: A pooled analysis of the SMART-AV and SMART-CRT trials.

BACKGROUND: The utility of atrioventricular (AV) optimization (AVO) algorithms remains in question. A substudy of the SMART-AV trial found that patients with prolonged interventricular delays ≥70 ms were more likely to benefit from cardiac resynchronization therapy (CRT) with AVO. The SMART-CRT trial evaluated AVO on the basis of these results, but the study was underpowered. OBJECTIVE: To increase statistical power, data from SMART-AV patients meeting the inclusion criterion of interventricular delay ≥70 ms were pooled with data from SMART-CRT to reassess AVO. METHODS: SMART-CRT and SMART-AV were prospective, randomized, multicenter clinical trials. Patients in both studies were randomized to be programmed with an AVO algorithm (SmartDelay) or fixed AV delay (120 ms). Paired echocardiograms obtained at baseline and 6 months were compared, with CRT response defined as ≥15% reduction in left ventricular end-systolic volume. RESULTS: A total of 451 complete patient data sets were pooled and analyzed. The baseline demographics between studies did not differ statistically in terms of age, sex, left ventricular ejection fraction, or left ventricular end-systolic volume. The AVO group had a greater proportion of CRT responders (SmartDelay, 73.9%; fixed, 63.1%; P = .014) and greater changes in measures of reverse remodeling. SmartDelay patients with a recommended sensed AV delay outside the nominal range (100-120 ms) had 2.3 greater odds of CRT response than fixed AV delay patients. CONCLUSION: Greater CRT response and measures of reverse remodeling were observed in patients with SmartDelay enabled vs a fixed AV delay. This study supports the use of SmartDelay in patients with a CRT indication and interventricular delay ≥70 ms. GOV REGISTRATION: NCT00677014 and NCT03089281.

Health economic evaluation of blended collaborative care for older multimorbid heart failure patients: study protocol.

BACKGROUND: Integrated care, in particular the 'Blended Collaborative Care (BCC)' strategy, may have the potential to improve health-related quality of life (HRQoL) in multimorbid patients with heart failure (HF) and psychosocial burden at no or low additional cost. The ESCAPE trial is a randomised controlled trial for the evaluation of a BCC approach in five European countries. For the economic evaluation of alongside this trial, the four main objectives were: (i) to document the costs of delivering the intervention, (ii) to assess the running costs across study sites, (iii) to evaluate short-term cost-effectiveness and cost-utility compared to providers' usual care, and (iv) to examine the budgetary implications. METHODS: The trial-based economic analyses will include cross-country cost-effectiveness and cost-utility assessments from a payer perspective. The cost-utility analysis will calculate quality-adjusted life years (QALYs) using the EQ-5D-5L and national value sets. Cost-effectiveness will include the cost per hospital admission avoided and the cost per depression-free days (DFD). Resource use will be measured from different sources, including electronic medical health records, standardised questionnaires, patient receipts and a care manager survey. Uncertainty will be addressed using bootstrapping. DISCUSSION: The various methods and approaches used for data acquisition should provide insights into the potential benefits and cost-effectiveness of a BCC intervention. Providing the economic evaluation of ESCAPE will contribute to a country-based structural and organisational planning of BCC (e.g., the number of patients that may benefit, how many care managers are needed). Improved care is expected to enhance health-related quality of life at little or no extra cost. TRIAL REGISTRATION: The study follows CHEERS2022 and is registered at the German Clinical Trials Register (DRKS00025120).

Trends in use of composite endpoints in clinical trials: A comparison between acute heart failure trials and COVID-19 trials.

Composite endpoints can encode multiple pieces of information and are increasingly adopted in clinical trials. Advocacy for using composite endpoints began decades ago in cardiovascular trials, leading to incorporation of patient-oriented outcomes and consideration of a hierarchical ranking system. The use of composite endpoints in coronavirus disease (COVID-19) trials has evolved similarly. We conducted a literature review to investigate the use of composite endpoints in acute heart failure and COVID-19 clinical trials. The results showed more frequent use of patient-oriented outcomes and ordinal composite endpoints in COVID-19 trials, which might be driven by global consensus on a set of common outcome measures.

Characteristics of Postoperative Heart Failure in Older Hip Fractures Patients Combined with Coronary Heart Disease and Construction of a Prediction Model of Nomogram, a Retrospective Cohort Study.

Introduction: Older patients combined with coronary heart disease (CHD) develop acute heart failure (AHF) after hip fracture surgery is common, and this study aimed to investigate the risk factors of postoperative AHF in older hip fracture patients and to construct a nomogram prediction model. Methods: We retrospectively collected older hip fracture patients with CHD who underwent hip fracture surgery at the Third Hospital of Hebei Medical University from January 2017 to December 2021. We divided them into a training set and a validation set. We collected the demographic data, laboratory indicators and imaging examination results. We identified risk factors for postoperative AHF and used R language software to establish a nomogram prediction model, plot ROC curves, calibration curves and DCA decision curves. Results: We retrospectively collected 1288 older hip fractures patients with CHD. After excluding 214 patients who did not meet the criteria, 1074 patients were included in our research and we divided them into the training set and the validation set. In the training set, a total of 346 (42.8%) patients developing postoperative AHF. Through univariate and multivariate logistic regression analysis, we identified the risk factors for postoperative AHF and constructed a nomogram prediction model. The AUC of the prediction model is 0.778. The correction curve shows that the model has good consistency. The decision curve analysis shows that the model has good clinical practicality. Conclusion: There were 42.8% older patients combined with CHD develop postoperative AHF. Among them, fracture type, age, anemia at admission, combined with COPD, ASA ≥ 3, and preoperative waiting time >3 days are risk factors for postoperative AHF. We constructed a nomogram prediction model that can effectively predict the risk of postoperative AHF in older hip fracture patients combined with CHD.

Associations between waist circumference, central obesity, and the presence of non-valvular atrial fibrillation patients with heart failure.

Background: Reportedly, there is a clear correlation between waist circumference (WC) and atrial fibrillation (AF). However, there is no specific discussion about the relationship between WC and non-valvular AF (NVAF) patients with heart failure. Our main purpose was to study the relationship between WC, central obesity (CO), and NVAF patients with heart failure. Methods: This is a retrospective cohort study. A total of 3,435 patients with NVAF in the First Affiliated Hospital of Xinjiang Medical University from January 2015 to December 2017 were enrolled. The targeted independent variable and the dependent variable were WC and CO and the presence of NVAF with heart failure, respectively. Univariate, multiple regression, and subgroup analyses were used to analyze their relationship. We used the receiver operating characteristic (ROC) curve to choose the better predictor of NVAF with heart failure between WC and CO and calculated the proposed cut-off value of WC in males and female separately. Results: The identified risk factors of NVAF with heart failure were sex, height, WC, CO, body mass index (BMI), fasting blood glucose (FBG), homocysteine (HCY), triglyceride (TG), low-density lipoprotein cholesterol (LDLC), hypertension, diabetes mellitus (DM), stroke, vascular disease, and plaque. Then, a binary logistic regression model indicated that the occurrence of NVAF patients with heart failure increased 10% with WC increasing 1 cm and had a 2.8-fold increased risk with CO compared to those without. The predictive value [area under the ROC curve (AUC)], specificity, sensitivity, and accuracy of WC for the disease risk of NVAF with heart failure were higher than those of CO. The proposed cut-off value of WC was 91.85 cm for males and 93.15 cm for females. The diagnostic value of WC for NVAF with heart failure was higher for females than it was for males. Conclusions: Our research found that WC is related to the presence of heart failure in the patients with NYAF and can predict the presence of NVAF with heart failure. Our findings may help to improve the treatment and care strategies of NVAF individuals with abdominal obesity.

Chagas heart disease is associated with decreased physical activity levels: A cross-sectional analysis.

Background: Studies evaluating physical activity (PA) levels in individuals with Chagas disease (CD) are still scarce. The present study aimed to evaluate PA levels in CD individuals and examine their association with Chagas heart disease (ChHD). Methods: We included patients with CD regularly followed in a reference center for treatment of infectious diseases. PA levels were assessed using the short version of the International Physical Activity Questionnaire (IPAQ). ChHD was determined following the Brazilian Consensus on Chagas Disease. The association between ChHD and levels of PA (total, walking, moderate, and vigorous) as a continuous variable was fitted using generalized linear models. Logistic regression models were fitted to evaluate the association between ChHD and meeting WHO's PA recommendations. Results: Among the 361 participants included in the analysis (60.7 ± 10.7 years; 56.2 % women), 58.1 % (n = 210) complied with the WHO's PA recommendations. After adjustments for potential confounders, regression analyses revealed that ChHD without heart failure was significantly associated with reduced vigorous PA (Exp ß 0.32 95 % CI 0.10 to 0.98). ChHD with heart failure had significantly lower levels of total (Exp ß 0.61 95 % CI 0.44 to 0.84) and moderate (Exp ß 0.59 95 % CI 0.39 to 0.89) PA. ChHD with heart failure had a lower odd of meeting the PA recommendation in comparison to those with no cardiac involvement (OR 0.48 95 % CI 0.24 to 0.97). Conclusions: We found low levels of PA among individuals with CD. Presence of ChHD (mainly with HF) was associated with decreased levels of PA.

Catheter Ablation Versus Medical Therapy for Atrial Fibrillation in Patients with Heart Failure with Preserved Ejection Fraction: A Systematic Review and Meta-analysis.

BACKGROUND: The benefit of catheter ablation in patients with atrial fibrillation (AF) for patients with heart failure with preserved ejection fraction (HFpEF) remains uncertain. OBJECTIVE: We conducted a systematic review and meta-analysis to compare catheter ablation and medical therapy (antiarrhythmics for rhythm or rate control) in patients with AF and HFpEF. METHODS: We searched PubMed, Embase and Cochrane Central. Outcomes were the composite endpoints of death or heart failure (HF) hospitalization, all-cause-death, cardiovascular death, all-cause-rehospitalization and HF hospitalization. Statistical analysis was performed using the R program (version 4.3.2). Heterogeneity was assessed with I2 statistics. RESULTS: We included 20,257 patients from 8 studies. Of those, 3 were derived from RCTs, either through post-hoc analysis or subgroup analysis, and 5 were observational studies. The median follow-up ranged from 24.6 to 61.2 months. As compared to medical therapy, catheter ablation was associated with a statistically significant lower risk of death or HF hospitalization (HR 0.62; 95% CI 0.47 - 0.83; p=0.001; I2 =66%), all-cause-death (HR 0.68; 95% CI 0.46 - 0.99; p=0.047; I2 =61%), cardiovascular death (HR 0.42; 95% CI 0.21 - 0.84; p=0.014; I2 =22%) and HF hospitalization (HR 0.43; 95% CI 0.23 - 0.82; p=0.011; I2 =87%). CONCLUSION: In this meta-analysis, catheter ablation was associated with lower risk of the all-cause mortality, cardiovascular death, HF hospitalization and all-cause-rehospitalization in comparison to medical of patients with AF and HFpEF.

Association between Visit Frequency, Continuity of Care, and Pharmacy Fill Adherence in Heart Failure Patients.

BACKGROUND: Despite advances in medical therapy for heart failure with reduced ejection fraction (HFrEF), major gaps in medication adherence to guideline-directed medical therapies (GDMT) remain. Greater continuity of care may impact medication adherence and reduced hospitalizations. METHODS: We conducted a cross-sectional study of adults with a diagnosis of HF and EF≤40% with ≥2 outpatient encounters between 1/1/2017 and 10/1/2021, prescribed ≥1 of the following GDMT: 1) Beta Blocker, 2) Angiotensin Converting Enzyme Inhibitor/Angiotensin Receptor Blocker/Angiotensin Receptor Neprilysin Inhibitor, 3) Mineralocorticoid Receptor Antagonist, 4) Sodium Glucose Cotransporter-2 Inhibitor. Continuity of care was calculated using the Bice-Boxerman Continuity of Care Index (COC) and the Usual Provider of Care (UPC) index, categorized by quantile. The primary outcome was adherence to GDMT, defined as average proportion of days covered ≥80% over one year. Secondary outcomes included all-cause and HF hospitalization at 1-year. We performed multivariable logistic regression analyses adjusted for demographics, insurance status, comorbidity index, number of visits and neighborhood SES index. RESULTS: Overall, 3,971 individuals were included (mean age 72 years (SD 14), 71% male, 66% White race). In adjusted analyses, compared to individuals in the highest COC quartile, individuals in the third COC quartile had higher odds of GDMT adherence (OR 1.26, 95% CI 1.03-1.53, p=0.024). UPC tertile was not associated with adherence (all p>0.05). Compared to the highest quantiles, the lowest UPC and COC quantiles had higher odds of all-cause (UPC: OR 1.53, 95% CI 1.23-1.91; COC: OR 2.54, 95% CI 1.94-3.34) and HF (UPC: OR 1.81, 95% CI 1.23-2.67; COC: OR 1.77, 95% CI 1.09-2.95) hospitalizations. CONCLUSIONS: Continuity of care was not associated with GDMT adherence among patients with HFrEF but lower continuity of care was associated with increased all-cause and HF-hospitalizations.

Methods to predict heart failure in diabetes patients.

INTRODUCTION: Type 2 diabetes mellitus (T2DM) is one of the leading causes of cardiovascular disease and powerful predictor for new-onset heart failure (HF). AREAS COVERED: We focus on the relevant literature covering evidence of risk stratification based on imaging predictors and circulating biomarkers to optimize approaches to preventing HF in DM patients. EXPERT OPINION: Multiple diagnostic algorithms based on echocardiographic parameters of cardiac remodeling including global longitudinal strain/strain rate are likely to be promising approach to justify individuals at higher risk of incident HF. Signature of cardiometabolic status may justify HF risk among T2DM individuals with low levels of natriuretic peptides, which preserve their significance in HF with clinical presentation. However, diagnostic and predictive values of conventional guideline-directed biomarker HF strategy may be non-optimal in patients with obesity and T2DM. Alternative biomarkers affecting cardiac fibrosis, inflammation, myopathy, and adipose tissue dysfunction are plausible tools for improving accuracy natriuretic peptides among T2DM patients at higher HF risk. In summary, risk identification and management of the patients with T2DM with established HF require conventional biomarkers monitoring, while the role of alternative biomarker approach among patients with multiple CV and metabolic risk factors appears to be plausible tool for improving clinical outcomes.

Serum metabolomics improves risk stratification for incident heart failure.

AIMS: Prediction and early detection of heart failure (HF) is crucial to mitigate its impact on quality of life, survival, and healthcare expenditure. Here, we explored the predictive value of serum metabolomics (168 metabolites detected by proton nuclear magnetic resonance [1H-NMR] spectroscopy) for incident HF. METHODS AND RESULTS: Leveraging data of 68 311 individuals and >0.8 million person-years of follow-up from the UK Biobank cohort, we (i) fitted per-metabolite Cox proportional hazards models to assess individual metabolite associations, and (ii) trained and validated elastic net models to predict incident HF using the serum metabolome. We benchmarked discriminative performance against a comprehensive, well-validated clinical risk score (Pooled Cohort Equations to Prevent HF [PCP-HF]). During a median follow-up of ≈12.3 years, several metabolites showed independent association with incident HF (90/168 adjusting for age and sex, 48/168 adjusting for PCP-HF). Performance-optimized risk models effectively retained key predictors representing highly correlated clusters (≈80% feature reduction). Adding metabolomics to PCP-HF improved predictive performance (Harrel's C: 0.768 vs. 0.755, ΔC = 0.013, [95% confidence interval [CI] 0.004-0.022], continuous net reclassification improvement [NRI]: 0.287 [95% CI 0.200-0.367], relative integrated discrimination improvement [IDI]: 17.47% [95% CI 9.463-27.825]). Models including age, sex and metabolomics performed almost as well as PCP-HF (Harrel's C: 0.745 vs. 0.755, ΔC = 0.010 [95% CI -0.004 to 0.027], continuous NRI: 0.097 [95% CI -0.025 to 0.217], relative IDI: 13.445% [95% CI -10.608 to 41.454]). Risk and survival stratification was improved by integrating metabolomics. CONCLUSION: Serum metabolomics improves incident HF risk prediction over PCP-HF. Scores based on age, sex and metabolomics exhibit similar predictive power to clinically-based models, potentially offering a cost-effective, standardizable, and scalable single-domain alternative.

Reporting quality of heart failure randomized controlled trials 2000-2020: Temporal trends in adherence to CONSORT criteria.

AIM: Heart failure (HF) is a major cause of morbidity and mortality in older adults. Randomized controlled trials (RCTs) inform HF policy and practice, but the accurate interpretation of results is contingent on clear and transparent reporting. The CONsolidated Standards Of Reporting Trials (CONSORT) statement serves as a guide to RCT reporting. We evaluated the quality of reporting in HF RCTs in high-impact journals by assessing their adherence to CONSORT. METHODS AND RESULTS: We searched MEDLINE, EMBASE and CINAHL for HF RCTs published in high-impact journals 2000-2020. We assessed the proportion of CONSORT criteria that individual HF RCTs adhered to, and used the Jonckheere-Terpstra test to examine temporal trends in adherence. Multivariable linear regression explored the association between trial characteristics and adherence to CONSORT. Primary analysis assessed adherence to CONSORT 2010 update. A sensitivity analysis assessed adherence to the original (1996) CONSORT criteria. Among 221 RCTs analysed, the mean (standard deviation [SD]) adherence was suboptimal overall (mean [SD] adherence 69.7 [11.5]%) (5513/7913 criteria), with a temporal increase in adherence over the 20-year period (p < 0.001). Factors associated with adherence included publication after versus during/before 2010 (ß = 10.17, 95% confidence interval [CI] 7.64-12.70; p < 0.001); two-group parallel individual-level randomization versus other (including multi-group or cluster randomization) (ß = 5.81, 95% CI 2.88-8.73; p < 0.001); and multicentre versus single-centre trials (ß = 7.26, 95% CI 3.25-11.27; p < 0.001). There was no difference in trial adherence to the updated CONSORT (2010) versus the original (1996) CONSORT criteria, and temporal trends in adherence to both sets of criteria were similar, likely due to overlap between the two sets of criteria. Trials with greater adherence to CONSORT were published in higher impact factor journals, with a positive correlation (r = 0.312; p < 0.001). CONCLUSION: The quality of reporting in HF RCTs, as measured by CONSORT adherence, has improved over time but remains suboptimal.

Incremental value of diastolic wall strain in predicting heart failure events in patients with atrial fibrillation.

Diastolic wall strain (DWS), an echocardiographic index based on linear elasticity theory, has been identified as a predictor of heart failure (HF) in patients with sinus rhythm. However, its effectiveness in atrial fibrillation (AF) patients remains uncertain. This study aims to assess DWS as a predictor of HF in AF patients with preserved ejection fraction. We analysed a prospective database of AF patients undergoing transthoracic echocardiography. AF patients with reduced left ventricular ejection fraction (< 50%), posterior wall motion abnormality, hypertrophic cardiomyopathy, valvular heart disease, pericardial disease, congenital heart disease, or history of pacemaker/implantable cardioverter-defibrillator implantation or cardiac surgery were excluded. The study followed patients until HF development, death, or last visit. Follow-up for patients who underwent catheter ablation was censored on the date of their procedure. HF was ascertained based on the Framingham criteria. DWS was calculated using a validated formula: DWS = (PWs -PWd)/PWs, where PWs is the posterior wall thickness at end-systole and PWd is the posterior wall thickness at end-diastole. Among 411 study patients (mean age 69.6 years, 66% men), 20 (5%) was underwent catheter ablation and 57 (14%) developed HF during a mean follow-up of 82 months. Cox-proportional hazards demonstrated that low DWS (≤ 0.33) significantly predicted HF events (hazard ratio [HR] 3.28, 95% confidence interval [CI]) 1.81-5.94, P < 0.0001), independent of age (per 10 years; HR 1.99, 95% CI 1.35-2.93, P < 0.001), indexed left ventricular mass (per 10 g/m2; HR 1.16, 95% CI 1.05-1.27, P < 0.01), and indexed left atrial volume (per 10 mL/m2; HR 1.14, 95% CI 1.04-1.24, P < 0.01). Additionally, global log-likelihood ratio chi-square statistics indicated that DWS incrementally predicts HF development beyond age, indexed left ventricular mass, and left atrial volume (P < 0.001).

Associations between cardiovascular diseases and cancer mortality: insights from a retrospective cohort analysis of NHANES data.

BACKGROUND: This study explored the association of cardiovascular disease (CVD) with cancer mortality risk in individuals with or without a history of cancer, to better understand the interplay between CVD and cancer outcomes. METHODS: Utilizing data from the National Health and Nutrition Examination Survey (NHANES) spanning 1999 to 2018, a retrospective cohort analysis was conducted. This analysis accounted for the survey's complex design to ensure national representativeness. The association of CVD with cancer mortality was assessed through multivariable Cox proportional hazards models. RESULTS: The present study included 59,653 participants, of whom 54,095 did not have cancer and 5558 had a history of cancer. In individuals without cancer, heart failure (HF) was associated with an increased risk of mortality from cancer (HR, 1.36; 95% CI, 1.09-1.69; P = 0.005). In participants with cancer, HF correlated with a higher risk of mortality from cancer (HR, 1.76; 95% CI, 1.32-2.34; P < 0.001). Diabetes (DM), hypertension (HBP) and coronary heart disease (CHD) were not significantly associated with an increased risk of mortality from cancer. Significant differences were observed in the interaction between cancer and CHD (HR, 0.68; 95% CI, 0.53-0.87; P = 0.002). For cancer and HBP, a similar trend was noted (HR, 0.75; 95% CI, 0.62-0.91; P = 0.003). No significant differences were found in interactions between HF, DM and cancer. CONCLUSIONS: HF was associated with an increased risk of mortality from cancer, regardless of cancer history, while HBP, CHD and DM showed no significant association. These findings underscore the importance of understanding the mechanisms behind the increased risk of cancer mortality following HF.

Identifying subgroups in heart failure patients with multimorbidity by clustering and network analysis.

This study presents a workflow for identifying and characterizing patients with Heart Failure (HF) and multimorbidity utilizing data from Electronic Health Records. Multimorbidity, the co-occurrence of two or more chronic conditions, poses a significant challenge on healthcare systems. Nonetheless, understanding of patients with multimorbidity, including the most common disease interactions, risk factors, and treatment responses, remains limited, particularly for complex and heterogeneous conditions like HF. We conducted a clustering analysis of 3745 HF patients using demographics, comorbidities, laboratory values, and drug prescriptions. Our analysis revealed four distinct clusters with significant differences in multimorbidity profiles showing differential prognostic implications regarding unplanned hospital admissions. These findings underscore the considerable disease heterogeneity within HF patients and emphasize the potential for improved characterization of patient subgroups for clinical risk stratification through the use of EHR data.

Beat-to-beat alterations of acoustic intensity and frequency at the maximum power of heart sounds are associated with NT-proBNP levels.

Background: Auscultatory features of heart sounds (HS) in patients with heart failure (HF) have been studied intensively. Recent developments in digital and electrical devices for auscultation provided easy listening chances to recognize peculiar sounds related to diastolic HS such as S3 or S4. This study aimed to quantitatively assess HS by acoustic measures of intensity (dB) and audio frequency (Hz). Methods: Forty consecutive patients aged between 46 and 87 years (mean age, 74 years) with chronic cardiovascular disease (CVD) were enrolled in the present study after providing written informed consent during their visits to the Kitasato University Outpatient Clinic. HS were recorded at the fourth intercostal space along the left sternal border using a highly sensitive digital device. Two consecutive heartbeats were quantified on sound intensity (dB) and audio frequency (Hz) at the peak power of each spectrogram of S1-S4 using audio editing and recording application software. The participants were classified into three groups, namely, the absence of HF (n = 27), HF (n = 8), and high-risk HF (n = 5), based on the levels of NT-proBNP < 300, ≥300, and ≥900 pg/ml, respectively, and also the levels of ejection fraction (EF), such as preserved EF (n = 22), mildly reduced EF (n = 12), and reduced EF (n = 6). Results: The intensities of four components of HS (S1-S4) decreased linearly (p < 0.02-0.001) with levels of body mass index (BMI) (range, 16.2-33.0 kg/m2). Differences in S1 intensity (ΔS1) and its frequency (ΔfS1) between two consecutive beats were non-audible level and were larger in patients with HF than those in patients without HF (ΔS1, r = 0.356, p = 0.024; ΔfS1, r = 0.356, p = 0.024). The cutoff values of ΔS1 and ΔfS1 for discriminating the presence of high-risk HF were 4.0 dB and 5.0 Hz, respectively. Conclusions: Despite significant attenuations of all four components of HS by BMI, beat-to-beat alterations of both intensity and frequency of S1 were associated with the severity of HF. Acoustic quantification of HS enabled analyses of sounds below the audible level, suggesting that sound analysis might provide an early sign of HF.

Intravenous iron therapy for patients with iron deficiency and heart failure: a systematic review and meta-analysis of randomized controlled trials.

Introduction: Heart failure (HF) presents a significant health challenge, with intravenous (IV) iron therapy considered a potential treatment avenue. Method: We assessed IV iron therapy's efficacy in HF patients with concurrent iron deficiency versus standard of care. Primary outcomes included the composite of HF hospitalizations or cardiovascular-related mortality, HF hospitalizations, and all-cause, HF, and cardiovascular mortality rates. Secondary measures encompassed improvements in New York Heart Association functional classification, quality of life, 6-minute walk test, left ventricular ejection fraction, and adverse events. We used a random-effects model to compute relative risk (RR) or mean difference (MD) with 95% confidence intervals (CIs). Results: Based on an analysis of 14 randomized controlled trials involving 6614 patients, IV iron therapy significantly reduced composite outcome (RR: 0.84, 95% CI: 0.73, 0.96; P = 0.01) and HF hospitalizations (RR: 0.74, 95% CI: 0.61, 0.89; P = 0.002) compared to standard of care. Mortality rates showed no significant difference. IV iron therapy improved New York Heart Association functional classification, quality of life, and 6-minute walk test, with no major impact on left ventricular ejection fraction. Adverse events remained stable. Conclusions: IV iron therapy holds promise for diminishing HF hospitalizations and enhancing quality of life and 6-minute walk test in HF patients. Yet, its effect on all-cause or cardiovascular mortalities appears limited.

Neuronal nitric oxide synthase required for erythropoietin modulation of heart function in mice.

Introduction: Erythropoietin (EPO) acts primarily in regulating red blood cell production mediated by high EPO receptor (EPOR) expression in erythroid progenitor cells. EPO activity in non-erythroid tissue is evident in mice with EPOR restricted to erythroid tissues (ΔEPORE) that become obese, glucose-intolerant, and insulin-resistant. In animal models, nitric oxide synthase (NOS) contributes to EPO activities including erythropoiesis, neuroprotection, and cardioprotection against ischemia-reperfusion injury. However, we found that extended EPO treatment to increase hematocrit compromised heart function, while the loss of neuronal NOS (nNOS) was protective against the deleterious activity of EPO to promote heart failure. Methods: Wild-type (WT) mice, ΔEPORE mice, and nNOS-knockout mice (nNOS-/-) were placed on a high-fat diet to match the ΔEPORE obese phenotype and were treated with EPO for 3 weeks. Hematocrit and metabolic response to EPO treatment were monitored. Cardiac function was assessed by echocardiography and ultrasonography. Results: ΔEPORE mice showed a decrease in the left ventricular outflow tract (LVOT) peak velocity, ejection fraction, and fractional shortening, showing that endogenous non-erythroid EPO response is protective for heart function. EPO treatment increased hematocrit in all mice and decreased fat mass in male WT, demonstrating that EPO regulation of fat mass requires non-erythroid EPOR. EPO treatment also compromised heart function in WT mice, and decreased the pulmonary artery peak velocity (PA peak velocity), LVOT peak velocity, ejection fraction, and fractional shortening, but it had minimal effect in further reducing the heart function in ΔEPORE mice, indicating that the adverse effect of EPO on heart function is not related to EPO-stimulated erythropoiesis. ΔEPORE mice had increased expression of heart failure-associated genes, hypertrophic cardiomyopathy-related genes, and sarcomeric genes that were also elevated with EPO treatment in WT mice. Male and female nNOS-/- mice were protected against diet-induced obesity. EPO treatment in nNOS-/- mice increased the hematocrit that tended to be lower than WT mice and decreased the PA peak velocity but did not affect the LVOT peak velocity, ejection fraction, and fractional shortening, suggesting that nNOS is required for the adverse effect of EPO treatment on heart function in WT mice. EPO treatment did not change expression of heart failure-associated gene expression in nNOS-/- mice. Discussion: Endogenous EPO has a protective effect on heart function. With EPO administration, in contrast to the protective effect to the cardiac injury of acute EPO treatment, extended EPO treatment to increase hematocrit in WT mice adversely affected the heart function with a corresponding increase in expression of heart failure-associated genes. This EPO activity was independent of EPO-stimulated erythropoiesis and required EPOR in non-erythroid tissue and nNOS activity, while nNOS-/- mice were protected from the EPO-associated adverse effect on heart function. These data provide evidence that nNOS contributes to the negative impact on the heart function of high-dose EPO treatment for anemia.

Tricuspid Regurgitation and Kidney Transplant Recipient Outcomes.

Rationale & Objective: Kidney function can be adversely affected by significant tricuspid regurgitation (TR) owing to effects on cardiac output and systemic venous congestion. However, the impact of significant TR on short- and long-term kidney function following a kidney transplant remains uncertain. Study Design: Retrospective observational cohort. Setting & Participants: Kidney transplant recipients from a single center between 2016 and 2019. Exposure: Significant TR, defined by at least moderate regurgitation, on echocardiogram before kidney transplantation. Outcomes: Primary end points included the estimated glomerular filtration rate (eGFR) at the following 3 time points: 2 weeks, 3 months, and 1 year after transplantation. Secondary end points included major adverse cardiac events including nonfatal myocardial infarction, all-cause mortality, and hospitalization owing to cardiovascular disease. Analytical Approach: Propensity score matching was performed in 1:3 ratio between patients treated with significant TR and controls, within a caliper 0.05 standard deviation of the propensity score, to analyze for the primary end point. Results: Among 557 kidney transplant recipients, 26 (5%) exhibited significant TR pretransplantation. According to propensity score matching analysis, with 1:3 ratio between 24 patients with significant TR and 72 controls, the presence of significant TR was associated with a lower eGFR posttransplantation. Specifically, the mean eGFR was 41.2 mL/min/1.73 m2 compared to 53.3 mL/min/1.73 m2 at 2 weeks (P < 0.01), 50.0 mL/min/1.73 m2 versus 60.3 mL/min/1.73 m2 at 3 months (P < 0.01), and 49.4 mL/min/1.73 m2 versus 61.2 mL/min/1.73 m2 at 1 year (P < 0.01). Delayed graft function was observed in 41.7% of the patients with significant TR compared to 12.5% of those without significant TR (P < 0.01). No patients with significant TR required dialysis after 1 year. 1-year major adverse cardiac events were nonsignificantly higher among patients with significant TR (20.8% vs 8.1%; P = 0.16). Limitations: Retrospective design and relatively small TR population. Conclusions: The presence of significant TR among kidney transplant recipients was associated with a lower eGFR at 2 weeks, 3 months, and 1 year following transplant, although all remained dialysis independent at 1 year.

Significant tricuspid regurgitation (TR) is associated with increased mortality rates and kidney failure, but its impact on kidney transplant recipients is poorly investigated. We examined how significant TR diagnosed pretransplantation affects kidney function within the first posttransplant year in a retrospective cohort study. Among 24 patients with significant TR, there was a consistent pattern of lower kidney function at 2 weeks, 3 months, and 1 year following transplantation, compared to 72 matched controls based on a propensity score. Results were statistically significant at all time points within the first year after transplant. These findings suggest that selected individuals with significant TR are able to undergo successful kidney transplantation, although with worse kidney function following transplantation.