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Diabetic Cardiomyopathy (DbCM) is a form of heart failure (HF) in patients with diabetes occurring in the absence of coronary artery disease, clinically relevant arrhythmia, severe valvular heart disease and uncontrolled blood pressure. The ARISE-HF study is a phase 3 clinical trial evaluating the potential benefit of a novel aldose reductase inhibitor (AT-001) for improving cardiac functional capacity in patients with DbCM. The objective of the present analysis was to characterize baseline physical activity levels and cardiac functional capacity in study participants with DbCM enrolled in ARISE-HF. Physical Activity Scale (PASE) is a validated self-administered questionnaire that measures physical activities carried out over the last 7 days. Table 1 details the demographics, medical history, cardiac biomarkers, and cardiopulmonary functional capacity of 594 study participants (∼90% of the study population) as a function of Physical Activity Scale (PASE) quartiles. Mean PASE score was 151, indicative of a sedentary lifestyle. Study participants in the lowest quartile of PASE score were older, had lower level of peak VO 2 (p<0.001), and had highest NT-proBNP concentrations (p=0.02). Lower PASE score was not associated with duration of diabetes or presence of albuminuria. Among those with DbCM substantial impairment in cardiac functional capacity is frequently present, indicating a significant reduction in physical activity. The ARISE-HF trial is evaluating the effect of aldose reductase inhibition with AT-001 on functional capacity in DbCM. [ABSTRACT FROM AUTHOR]

Sarcopenia, or muscle wasting, is prevalent in the aging population and among patients with heart failure (HF) or chronic kidney disease (CKD), leading to worse outcomes. Our team, along with others, has identified a connection between diet-related gut microbial metabolites such as trimethylamine (TMA) and trimethylamine N-oxide (TMAO) and negative clinical outcomes in patients with cardio-renal diseases. However, the role of gut microbial metabolites in muscle loss and the underlying mechanisms in HF or CKD patients remain unclear. TMA and TMAO can promote muscle westing in HF-associated sarcopenia Muscle cell survival and senescence are crucial factors for skeletal muscle regeneration and maintenance. To investigate the impact of TMAO and TMA on muscle wasting, C2C12 cells were exposed to varying concentrations of TMA or TMAO to determine the physiological effects of GMM on cell senescence and survival. A subset of aging and muscle genes were analyzed using qPCR. We observed that cell viability was influenced by TMAO and TMA in a dose-dependent manner. Additionally, TMAO and TMA increased the expression of genes associated with aging (e.g., FOXO genes) and muscle wasting (e.g., Trim 63) in C2C12-differentiated muscle cells. Moreover, both TMA and TMAO-treated muscle cells exhibited a reduction in histone modification related to transcriptional activity and a muscle cell specific epigenetic regular, SMYD1 maybe involved in this process. To examine whether dietary modulation directly affects skeletal muscle wasting in HF-associated sarcopenia, TNFα overexpressing transgenic mice, an inflammatory-mediated HF mouse model, were fed a high-choline diet to increase TMA/TMAO levels. EchoMRI showed that the high-choline diet led to exacerbated muscle wasting and a reduction in lean muscle mass in the HF mouse model. We observed a negative correlation between the percentage of lean muscle mass and TMAO concentration. We have established a mechanistic link between sarcopenia/muscle wasting and TMA and TMAO. These two metabolites may influence HF-associated sarcopenia, in part, by affecting the activity of SMYD1 and its associated epigenome. [ABSTRACT FROM AUTHOR]

Perturbations in blood composition and blood cell function are seen in both acute and chronic inflammatory conditions. We have previously developed a comprehensive peroxidase-based hematologic profiling model (PEROX) for the prediction of short-term (1-year) adverse clinical outcomes in stable cardiac patients. In stable cardiac patients undergoing coronary angiography, PEROX risk score is associated with risk for prevalent heart failure (HF) and all-cause mortality, myocardial infarction, and stroke at 3-years. We performed complete blood count with differential analyses using a high-throughput peroxidase-based hematology analyzer (Advia 120, Siemens, New York NY) in 7,128 patients. We stratified PEROX score in quartiles and performed Cox proportional hazard analysis using death or myocardial infarction and stroke in 3-years as primary outcome. In our study cohort (mean age 67±11 years, 70% male), the mean±SD and median(IQR) PEROX score was 44±9.6 and 50(42,57) respectively. Higher PEROX scores were associated with increased likelihood of prevalent HF (Quartiles 4 vs 1; odds ratio 3.15 [95%CI 2.42-4.11], p<0.001), and increased risk of death, non-fatal myocardial infarction, and non-fatal stroke in 3-years even after adjusting for traditional cardiac risk factors (Quartiles 4 vs 1; Hazard ratio 3.2 [95%CI 1.92-5.43], p<0.001). Elevated PEROX score is associated with increased likelihood of prevalent HF and increased risk of death, myocardial infarction, and stroke in 3-years independent of traditional risk factors. [ABSTRACT FROM AUTHOR]

Natriuretic peptides have been recommended as biomarkers for the diagnosis and prognosis of patients with HF, and are often elevated the setting of acute kidney injury (AKI). However, the prognostic value of NT-proBNP in patients with AKI with or without HF remains unclear. Increased NT-proBNP on admission was associated with adverse renal outcomes (need for dialysis, dialysis dependence, and in-hospital mortality) in patients with AKI regardless of HF diagnosis. We retrospectively reviewed electronic medical records of consecutive patients with AKI stage 2 and 3 admitted to the Cleveland Clinic between September 2011 and December 2021. Patients with NT-proBNP levels collected before renal consultation or dialysis initiation were included. We excluded patients without baseline creatinine prior to index hospitalization, or with ESRD, kidney transplant or long-tern dialysis. Outcomes were dialysis requirement and dialysis dependence defined as patients undergoing dialysis within 72 hours prior to hospital discharge, or in-hospital mortality. Multivariable logistic regression analysis was used to determine prognostic value of NT-proBNP levels with adjustment for cardio-renal risk factors including age, race, sex, baseline CKD stage, CAD, HF, hypertension, diabetes, presence of LV systolic dysfunction (EF ≤ 40%), cirrhosis, cancer, surgery during index hospitalization, mechanical ventilation, sepsis, and type of AKI (community- or hospital-acquired). In our study cohort (n=3,811, median [IQR] age 66 [56-74] years, baseline Cr 1.06 [0.80-1.49] mg/dL, peak Cr 3.66 [2.76-4.86], and NT-proBNP 6,418 [2,002-18,215] pg/mL), 2,521 (66%) patients underwent dialysis, and 1,619 (42%) patients became dialysis dependent, and 1,325 (35%) patients had in-hospital mortality. After adjusting for cardio-renal risk factors, the highest quartile of NT-proBNP (≥18,215 pg/ml) was associated with increased likelihood of dialysis requirement (quartile [Q] 4 vs 1; odds ratio [OR]: 2.36; 95% CI: 1.87 to 2.99), becoming dialysis dependence (Q4 vs 1; OR: 1.46; 95% CI: 1.08 to 2.00), and had mortality (Q4 vs 1; OR: 1.34; 95% CI: 1.01 to 1.34). Prognostic value of NT-proBNP levels remained robust for dialysis requirement and dependence in subgroups of patients with HF (n=1,966) and without HF (n=1,845) with P for interaction 0.780 and 0.200, respectively (Figure 1), but not for mortality in patients with HF (P for interaction 0.007, Figure 1A). Increased NT-proBNP was independently associated with an increased risk of dialysis requirement and becoming dialysis dependence and in-hospital mortality in patients with moderate to severe AKI with or without HF. [ABSTRACT FROM AUTHOR]

Sarcopenia is associated with worse outcomes in patients with chronic heart failure (HF). In chronic HF from cardiac amyloid (CA), malnutrition, frailty, and exercise capacity are important prognostic factors. Loss of muscle mass and low subcutaneous adipose tissue are associated with poor prognosis in patients with CA. We identified consecutive patients between January 2001 and August 2021 with CA, either transthyretin (ATTR) or light-chain (AL), who had chest computed tomography (CT) within one year before the date of diagnosis. Chest CT scans were used to measure chest circumference and quantify skeletal muscle index (SMI) and subcutaneous adipose tissue index (SATI) at the T12 vertebral level. Sarcopenia was defined as the lowest sex-stratified SMI tertile, and higher SATI was the highest sex-stratified SATI tertile. A total of 160 patients with either ATTR- or AL-CA were identified. Of these, 33% (N=53) were deemed sarcopenic. Adjusted for age, the presence of sarcopenia predicted worse survival in CA (Figure 1A). Higher SMI (cm2/m2; HR 0.96, CI 0.93-0.98, P=0.008) and larger chest circumference (mm; HR 0.98, CI 0.96-0.99, P=0.04) independently predicted better survival in CA. Adjusted for age, those with CA and higher SATI had better survival than those with CA and lower SATI (Figure 1B; HR 0.62, CI 0.40-0.95, P=0.03). On subgroup analysis, ATTR-CA with higher SATI had better overall survival and fewer hospitalizations than ATTR-CA with lower SATI; this did not apply to patients with AL-CA divided based on SATI. When adjusted for age, sarcopenia predicted worse survival in CA. Furthermore, higher SMI and larger chest circumference were independent predictors of better survival. Patients with higher SATI had better survival which remained significant on subgroup analysis of patients with ATTR-CA but not AL-CA. [ABSTRACT FROM AUTHOR]

The aim of this study was to explore the relationship between serum soluble angiotensin converting enzyme 2 (sACE2), parameters of cardiopulmonary exercise testing and plasma asymmetric dimethylarginine (ADMA), a marker of oxidative stress-induced endothelial dysfunction. This has not been previously evaluated. We assessed 50 consecutive ambulatory patients with chronic systolic heart failure and left ventricular ejection fraction (LVEF) ≤45%. Their blood samples were collected for sACE2 and ADMA tests before they underwent symptom-limited cardiopulmonary exercise testing and transthoracic echocardiography. The majority of our study subjects had New York Heart Association functional class II (74%) and III (18%) presentation, and 42% of patients had ischemic etiology. Median sACE2 activity was 10.36 (7.00-14.47) ng/mL and mean ADMA was 0.90 ± 0.22. sACE2 activity was inversely correlated with pVO2 (r = -0.42, P = 0.00283), exercise time (r = -0.35, P = 0.0138) and LVEF (r = -0.548, P < 0.001), and positively correlated with VE/VCO2 slope (r = 0.294, P = 0.0405), ΔDBP (r = 0.315, P = 0.0278), mitral E/Ea ratio (r = 0.442, P = 0.00158) and ADMA levels (r = 0.351, P = 0.0134). Meanwhile, we observed a negative correlation between ADMA and pVO2 (r = -0.424, P = 0.00227) and positive correlations between ADMA and VE/VCO2 slope (r = 0.515, P < 0.001), ΔDBP (r = 0.391, P = 0.00568), mitral E/Ea ratio (r = 0.426, P = 0.00219). In multivariate logistic regression analysis, sACE2 was independently associated with peak oxygen uptake (% predicted) after adjusting for body mass index (BMI) and mitral E/Ea ratio (odds ratio [OR] 0.81 (0.58-0.94), P = 0.041) and associated with oxygen pulse (VO2/HR) (%) after adjusting for age, gender, BMI and mitral E/Ea ratio (OR 0.83 [0.68-0.95], P = 0.025). Therefore in stable chronic systolic heart failure patients, higher sACE2 activity is independently associated with diminished exercise capacity and correlates with elevated systemic oxidative stress-mediated endothelial dysfunction. [ABSTRACT FROM AUTHOR]