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Aim: Phenylacetylglutamine (PAGln) is a phenylalanine‐derived metabolite produced by gut microbiota with mechanistic links to heart failure (HF)‐relevant phenotypes. We sought to investigate the prognostic value of PAGln in patients with stable HF. Methods and results: Fasting plasma PAGln levels were measured by stable‐isotope‐dilution liquid chromatography–tandem mass spectrometry (LC‐MS/MS) in patients with stable HF from two large cohorts. All‐cause mortality was assessed at 5‐year follow‐up in the Cleveland cohort, and HF, hospitalization, or mortality were assessed at 3‐year follow‐up in the Berlin cohort. Within the Cleveland cohort, median PAGln levels were 4.2 (interquartile range [IQR] 2.4–6.9) μM. Highest quartile of PAGln was associated with 3.09‐fold increased mortality risk compared to lowest quartile. Following adjustments for traditional risk factors, as well as race, estimated glomerular filtration rate, amino‐terminal pro‐B‐type natriuretic peptide, high‐sensitivity C‐reactive protein, left ventricular ejection fraction, ischaemic aetiology, and HF drug treatment, elevated PAGln levels remained predictive of 5‐year mortality in quartile comparisons (adjusted hazard ratio [HR] [95% confidence interval, CI] for Q4 vs Q1: 1.64 [1.07–2.53]). In the Berlin cohort, a similar distribution of PAGln levels was observed (median 3.2 [IQR 2.0–4.8] μM), and PAGln levels were associated with a 1.92‐fold increase in 3‐year HF hospitalization or all‐cause mortality risk (adjusted HR [95% CI] for Q4 vs Q1: 1.92 [1.02‐3.61]). Prognostic value of PAGln appears to be independent of trimethylamine N‐oxide levels. Conclusion: High levels of PAGln are associated with adverse outcomes independent of traditional cardiac risk factors and cardio‐renal risk markers. [ABSTRACT FROM AUTHOR]

This article discusses the renal perturbations that can occur with the use of sodium-glucose cotransporter 2 (SGLT2) inhibitors in patients with heart failure with preserved ejection fraction (HFpEF). Worsening renal function is commonly observed in patients with heart failure and can have adverse outcomes. SGLT2 inhibitors have emerged as a therapeutic advance in cardio-renal-metabolic diseases, but they can also cause acute changes in estimated glomerular filtration rate (eGFR) and extrarenal haemodynamic shifts. The article emphasizes the need for careful monitoring and individualized management strategies when initiating SGLT2 inhibitor therapy in patients with HFpEF to optimize therapeutic outcomes and mitigate adverse renal events. [Extracted from the article]

[Display omitted] [ABSTRACT FROM AUTHOR]

Nonalcoholic fatty liver disease (NAFLD) and cardiovascular diseases are both highly prevalent conditions around the world, and emerging data have shown an association between them. This review found several longitudinal and cross-sectional studies showing that NAFLD was associated with coronary artery disease, cardiac remodeling, aortic valve remodeling, mitral annulus valve calcifications, diabetic cardiomyopathy, diastolic cardiac dysfunction, arrhythmias, and stroke. Although the specific underlying mechanisms are not clear, many hypotheses have been suggested, including that metabolic syndrome might act as an upstream metabolic defect, leading to end-organ manifestations in both the heart and liver. Management of NAFLD includes weight loss through lifestyle interventions or bariatric surgery, and pharmacological interventions, often targeting comorbidities. Although there are no Food and Drug Administration–approved nonalcoholic steatohepatitis-specific therapies, several drug candidates have demonstrated effect in the improvement in fibrosis or nonalcoholic steatohepatitis resolution. Further studies are needed to assess the effect of those interventions on cardiovascular outcomes, the major cause of mortality in patients with NAFLD. In conclusion, a more comprehensive, multidisciplinary approach to diagnosis and management of patients with NAFLD and cardiovascular diseases is needed to optimize clinical outcomes. [ABSTRACT FROM AUTHOR]

B This article refers to 'Renal profiling based on estimated glomerular filtration rate and spot urine sodium identifies high-risk acute heart failure patients' by J. Biegus I et al i ., published in this issue on pages 729-739. b Every era grapples with a medical riddle and the complexities underlying the interaction between heart and kidney physiology are no exception, as knowledge gaps regarding this complex interaction have persisted throughout much of medical history. Secondly, some patients received intravenous diuretics in the pre-hospital setting or had intensification of oral diuretics prior to admission, which may have affected baseline U SB Na sb values. It is also unclear whether I all i patients will need serial assessment of U SB Na sb (for example, a patient who has >3 L/day of urine output is likely diuretic responsive). [Extracted from the article]

Despite major strides in reducing cardiovascular disease (CVD) burden with modification of classic CVD risk factors, significant residual risks remain. Recent discoveries that linked intestinal microbiota and CVD have broadened our understanding of how dietary nutrients may affect cardiovascular health and disease. Although next-generation sequencing techniques can identify gut microbial community participants and provide insights into microbial composition shifts in response to physiological responses and dietary exposures, provisions of prebiotics or probiotics have yet to show therapeutic benefit for CVD. Our evolving understanding of intestinal microbiota-derived physiological modulators (e.g., short-chain fatty acids) and pathogenic mediators (e.g., trimethylamine N-oxide) of host disease susceptibility have created novel potential therapeutic opportunities for improved cardiovascular health. This review discusses the roles of human intestinal microbiota in normal physiology, their associations with CVD susceptibilities, and the potential of modulating intestinal microbiota composition and metabolism as a novel therapeutic target for CVD. [ABSTRACT FROM AUTHOR]

Background Effective decongestion of heart failure patients predicts improved outcomes, but high dose loop diuretics (HDLD) used to achieve diuresis predict adverse outcomes. In the DOSE trial, randomization to a HDLD intensification strategy (HDLD-strategy) improved diuresis but not outcomes. Our objective was to determine if potential beneficial effects of more aggressive decongestion may have been offset by adverse effects of the HDLD used to achieve diuresis. Methods and results A post hoc analysis of the DOSE trial (n = 308) was conducted to determine the influence of post-randomization diuretic dose and fluid output on the rate of death, rehospitalization or emergency department visitation associated with the HDLD-strategy. Net fluid output was used as a surrogate for beneficial decongestive effects and cumulative loop diuretic dose for the dose-related adverse effects of the HDLD-strategy. Randomization to the HDLD-strategy resulted in increased fluid output, even after adjusting for cumulative diuretic dose (p = 0.006). Unadjusted, the HDLD-strategy did not improve outcomes (p = 0.28). However, following adjustment for cumulative diuretic dose, significant benefit emerged (HR = 0.64, 95% CI 0.43–0.95, p = 0.028). Adjusting for net fluid balance eliminated the benefit (HR = 0.95, 95% CI 0.67–1.4, p = 0.79). Conclusions A clinically meaningful benefit from a randomized aggressive decongestion strategy became apparent after accounting for the quantity of loop diuretic administered. Adjusting for the diuresis resulting from this strategy eliminated the benefit. These hypothesis-generating observations may suggest a role for aggressive decongestion in improved outcomes. [ABSTRACT FROM AUTHOR]

Disparities in cancer screening and outcomes based on factors such as sex, socioeconomic status, and race and ethnicity in the United States are well documented. A blood-based multi-cancer early detection (MCED) test that detects a shared cancer signal across multiple cancer types and also predicts the cancer signal origin was developed and validated in the Circulating Cell-free Genome Atlas study (CCGA; NCT02889978). CCGA is a prospective, multicenter, case-control, observational study with longitudinal follow-up (overall N = 15,254). In this pre-specified, exploratory, descriptive analysis, test performance was evaluated among racial and ethnic groups. Overall, 4077 participants comprised the independent validation set with confirmed cancer status (cancer: n = 2823; non-cancer: n = 1254). Participants were stratified into the following racial/ethnic groups: Black (non-Hispanic), Hispanic (all races), Other (non-Hispanic), Other/unknown and White (non-Hispanic). Cancer and non-cancer participants were predominantly White (n = 2316, 82.0% and n = 996, 79.4%, respectively). Across groups, specificity for cancer signal detection ranged from 98.1% [ n = 103; 95% CI: 93.2–99.5%] to 100% [ n = 85; 95% CI: 95.7–100.0%]. The sensitivity for cancer signal detection across groups ranged from 43.9% [ n = 57; 95% CI: 31.8–56.7%] to 63.0% [ n = 192; 95% CI: 56.0–69.5%] and generally increased with clinical stage. The MCED test had consistently high specificity and similar sensitivity across racial and ethnic groups, though results are limited by sample size for some groups. Results support the broad applicability of this MCED test and clinical implementation on a population scale as a complement to standard screening. • Performance of a blood-based multi-cancer test was assessed by race and ethnicity. • The test specificity was consistently high regardless of race and ethnicity. • Sensitivity of cancer signal detection was similar across racial and ethnic groups. • Sensitivity was comparable among groups for 12 high-mortality cancers. • Results support the potential population-wide use of this blood-based cancer test. [ABSTRACT FROM AUTHOR]

Background/objectives Cystatin-C and beta-2-microglobulin may be superior to serum creatinine, blood urea nitrogen (BUN), or estimated glomerular filtration rate (eGFR) in patients hospitalized with heart failure (HF). We compared these renal markers in ambulatory HF patients. Methods We prospectively evaluated the association of baseline renal markers and eGFR (by 4 different formulas) with (1) the composite of death or HF-related hospitalization and (2) rates of hospitalizations and emergency department (ED) visits in 166 outpatients with HF (57.3 ± 11.6 years; 57.2% white, 38.6% black, median left ventricular ejection fraction 27.5% [17.5, 40.0]). Results After a median of 3.9 years, 63 (38.0%) patients met the composite endpoint. There were 458 hospitalizations (177 [38.6%] for HF) and 209 ED visits (51 [24.4%] for HF). Cystatin-based eGFR most consistently predicted (1) the composite endpoint (highest-to-lowest tertile adjusted hazard ratio [HR] 4.92 [95% CI 2.07–11.7; P < 0.001]); and (2) hospitalization rates, including HF hospitalizations (highest-to-lowest tertile, adjusted relative rate 5.24 [95% CI 1.61–17.01; P = 0.006]). Serum creatinine alone was a strong predictor of the composite endpoint (highest-to-lowest tertile, adjusted HR 3.20 [95% CI, 1.51–6.78; P = 0.002]). Only the highest tertile of BUN was associated with rates of ED visits. Conclusions In outpatients with HF, cystatin-based eGFR provides consistent prognostication across outcomes, except ED visits. Serum creatinine is an adequate prognosticator of death or HF hospitalization. [ABSTRACT FROM AUTHOR]

Background Altered intestinal function is prevalent in patients with heart failure (HF), but its role in adverse outcomes is unclear. Objectives This study investigated the potential pathophysiological contributions of intestinal microbiota in HF. Methods We examined the relationship between fasting plasma trimethylamine- N -oxide (TMAO) and all-cause mortality over a 5-year follow-up in 720 patients with stable HF. Results The median TMAO level was 5.0 μM, which was higher than in subjects without HF (3.5 μM; p < 0.001). There was modest but significant correlation between TMAO concentrations and B-type natriuretic peptide (BNP) levels (r = 0.23; p < 0.001). Higher plasma TMAO levels were associated with a 3.4-fold increased mortality risk. Following adjustments for traditional risk factors and BNP levels, elevated TMAO levels remained predictive of 5-year mortality risk (hazard ratio [HR]: 2.2; 95% CI: 1.42 to 3.43; p < 0.001), as well as following the addition of estimated glomerular filtration rate to the model (HR: 1.75; 95% CI: 1.07 to 2.86; p < 0.001). Conclusions High TMAO levels were observed in patients with HF, and elevated TMAO levels portended higher long-term mortality risk independent of traditional risk factors and cardiorenal indexes. [ABSTRACT FROM AUTHOR]

Despite therapeutic advances, chronic heart failure (HF) is still associated with significant risk of morbidity and mortality. The course of disease and responses to therapies vary widely among individuals with HF, highlighting the need for precision medicine approaches. Gut microbiome stands to be an important aspect of precision medicine in HF. Exploratory clinical studies have revealed shared patterns of gut microbiome dysregulation in this disease, with mechanistic animal studies providing evidence for active involvement of the gut microbiome in development and pathophysiology of HF. Deeper insights into gut microbiome-host interactions in patients with HF promise to deliver novel disease biomarkers, preventative and therapeutic targets, and improve disease risk stratification. This knowledge may enable a paradigm shift in how we care for patients with HF, and pave the path toward improved clinical outcomes through personalized HF care. [Display omitted] • Gut microbiome modulates HF pathophysiology, contributes to disease progression and therapeutic responses, and holds promise as a novel biomarker. • Interactions among the gut microbiome, diet, and medications offer potentially innovative modalities for management of patients with HF. • Interdisciplinary collaboration will facilitate translation of precision gut microbiomics to the clinical evaluation and management of patients with HF. [ABSTRACT FROM AUTHOR]

Chronic kidney disease (CKD) is increasingly prevalent in patients with chronic systolic heart failure. Therefore, evidence-based therapies are more and more being used in patients with some degree of renal dysfunction. However, most pivotal randomized clinical trials specifically excluded patients with (severe) renal dysfunction. The benefit of these evidence-based therapies in this high-risk patient group is largely unknown. This paper reviews data from randomized clinical trials in systolic heart failure and the interactions between baseline renal dysfunction and the effect of randomized treatment. It highlights that most evidence-based therapies show consistent outcome benefit in patients with moderate renal insufficiency (stage 3 CKD), whereas there are very scarce data on patients with severe (stage 4 to 5 CKD) renal insufficiency. If any, the outcome benefit might be even greater in stage 3 CKD compared with those with relatively preserved renal function. However, prescription of therapies should be individualized with consideration of possible harm and benefit, especially in those with stage 4 to 5 CKD where limited data are available. [Copyright &y& Elsevier]

Galectin-3 plays an important role in fibroblast activation and fibrosis in animal models. Increased galectin-3 levels are associated with poor long-term survival in heart failure (HF). We examined the relation between plasma galectin-3 levels and myocardial indexes of systolic HF. We measured plasma galectin-3 in 133 subjects with chronic HF and 45 with advanced decompensated HF using echocardiographic and hemodynamic evaluations. In the chronic HF cohort, median plasma galectin-3 level was 13.9 ng/ml (interquartile range 12.1 to 16.9). Higher galectin-3 was associated with more advanced age (r = 0.22, p = 0.010), poor renal function (estimated glomerular filtration rate, r = −0.24, p = 0.007; cystatin C, r = 0.38, p <0.0001) and predicted all-cause mortality (hazard ratio 1.86, 95% confidence interval 1.36 to 2.54, p <0.001). In multivariate analysis, galectin-3 remained an independent predictor of all-cause mortality after adjusting for age, estimated glomerular filtration rate, left ventricular (LV) ejection fraction, and mitral early diastolic myocardial relaxation velocity at septal mitral annulus (hazard ratio 1.94, 95% confidence interval 1.30 to 2.91, p = 0.001). However, galectin-3 did not predict the combined end point of all-cause mortality, cardiac transplantation, or HF hospitalization (p >0.05). Furthermore, there were no relations between galectin-3 and LV end-diastolic volume index (r = −0.05, p = 0.61), LV ejection fraction (r = 0.10, p = 0.25), or LV diastolic function (mitral early diastolic myocardial relaxation velocity at septal mitral annulus, r = 0.06, p = 0.52; left atrial volume index, r = 0.08, p = 0.41). In the advanced decompensated HF cohort, we did not observe any relation between galectin-3 and echocardiographic or hemodynamic indexes. In conclusion, high plasma galectin-3 levels were associated with renal insufficiency and poorer survival in patients with chronic systolic HF. However, we did not observe a relation between galectin-3 and echocardiographic or hemodynamic indexes. [Copyright &y& Elsevier]

Objectives: We hypothesized that an integrated assessment of arginine with its catabolic products might better predict cardiovascular risks than arginine levels alone. Background: Arginine is the sole nitrogen source for nitric oxide (NO) synthesis. The major catabolic products of arginine are ornithine and citrulline. Methods: Plasma levels of free arginine, ornithine, citrulline, and the endogenous NO synthase inhibitor asymmetric dimethylarginine (ADMA) were measured with liquid chromatography coupled with tandem mass spectrometry. We examined the relationship of global arginine bioavailability ratio (GABR) (defined as arginine/[ornithine + citrulline]) versus arginine and its catabolic metabolites to prevalence of significantly obstructive coronary artery disease (CAD) and incidence of major adverse cardiovascular events (MACE) (death, myocardial infarction, stroke) over a 3-year follow-up in 1,010 subjects undergoing elective cardiac catheterization. Results: Patients with significantly obstructive CAD had significantly lower GABR (median [interquartile range]: 1.06 [0.75 to 1.31] vs. 1.27 [0.96 to 1.73], p < 0.001) and arginine levels [mean: 68 ± 20 μmol/l vs. 74 ± 24 μmol/l, p < 0.001) than those without significantly obstructive CAD. After adjusting for Framingham risk score, C-reactive protein, and renal function, lower GABR (but not arginine levels) and higher citrulline levels remained significantly associated with both the prevalence of significantly obstructive CAD (adjusted odds ratio: 3.93, p < 0.001, and 5.98, p < 0.001, respectively) and 3-year risk for the incidence of MACE (adjusted hazard ratio: 1.98, p = 0.025, and 2.40, p = 0.01, respectively) and remained significant after adjusting for ADMA. Conclusions: GABR might serve as a more comprehensive concept of reduced NO synthetic capacity compared with systemic arginine levels. Diminished GABR and high citrulline levels are associated with both development of significantly obstructive atherosclerotic CAD and heightened long-term risk for MACE. [Copyright &y& Elsevier]

Abstract: Diabetic cardiomyopathy is the presence of myocardial dysfunction in the absence of coronary artery disease and hypertension. Hyperglycemia seems to be central to the pathogenesis of diabetic cardiomyopathy and to trigger a series of maladaptive stimuli that result in myocardial fibrosis and collagen deposition. These processes are thought to be responsible for altered myocardial relaxation characteristics and manifest as diastolic dysfunction on imaging. Sophisticated imaging technologies also have permitted the detection of subtle systolic dysfunction in the diabetic myocardium. In the early stages, these changes appear reversible with tight metabolic control, but as the pathologic processes become organized, the changes are irreversible and contribute to an excess risk of heart failure among diabetic patients independently of common comorbidities, such as coronary artery disease and hypertension. Therapeutic agents specifically targeting processes that lead to these pathophysiologic changes are in the early stages of development. Although glycemic control and early administration of neurohormonal antagonists remain the cornerstones of therapeutic approaches, newer treatment targets are currently being explored. [Copyright &y& Elsevier]

Objectives: We sought to determine whether circulating soluble angiotensin-converting enzyme 2 (sACE2) is increased in the plasma of patients with heart failure (HF). Background: Angiotensin-converting enzyme 2 (ACE2) is an integral membrane protein that antagonizes the actions of angiotensin II and prevents the development of HF in animal models. However, because of the need for invasive cardiac tissue sampling, little is known about whether ACE2 is involved in the pathophysiology of HF in humans. Methods: We developed a sensitive and specific assay to measure sACE2 activity in human plasma and screened a heterogeneous group of patients suspected of having clinical HF. Results: Increasing sACE2 plasma activity strongly correlated with a clinical diagnosis of HF (p = 0.0002), worsening left ventricular ejection fraction (p < 0.0001), and increasing B-type natriuretic peptide levels (p < 0.0001). Similar to B-type natriuretic peptide, sACE2 activity reflected the severity of HF, with increasing levels associated with worsening New York Heart Association functional class (p < 0.0001). These associations were independent of other disease states and medication use. We found that sACE2 activity was increased in patients with both ischemic and nonischemic cardiomyopathies and also in patients with clinical HF but a preserved left ventricular ejection fraction. Conclusions: Soluble ACE2 activity is increased in patients with HF and correlates with disease severity, suggesting that a cardioprotective arm of the renin-angiotensin-aldosterone system is active in HF. [Copyright &y& Elsevier]

Objectives: This study sought to determine the characteristics and long-term prognosis of anemia in ambulatory patients with chronic heart failure. Background: Anemia is prevalent in heart failure, and may portend poor outcomes. Methods: We reviewed 6,159 consecutive outpatients with chronic stable heart failure at baseline, short-term (3-month) follow-up, and long-term (6-month) follow-up between 2001 and 2006. Clinical, demographic, laboratory, and echocardiographic data were reviewed from electronic medical records. Mortality rates were determined from 6-month follow-up to end of study period. Results: Prevalence of anemia (hemoglobin [Hb] <12 g/dl for men, <11 g/dl for women) was 17.2% in our cohort. Diabetes, B-natriuretic peptide, left ventricular ejection fraction, and estimated glomerular filtration rate were independent predictors of baseline anemia. Documented evaluation of anemia was found in only 3% of all anemic patients, and better in internal medicine than in cardiology clinics. At 6-month follow-up, new-onset anemia developed in 16% of patients without prior anemia, whereas 43% patients with anemia at baseline had resolution of their hemoglobin levels. Higher total mortality rates were evident in patients with persistent anemia (58% vs. 31%, p < 0.0001) or with incident anemia (45% vs. 31%, p < 0.0001) compared with those with without anemia at 6 months. Conclusions: These observations in a broad unselected outpatient cohort suggest that anemia in patients with heart failure is under-recognized and underevaluated. However, resolution of anemia was evident in up to 43% of patients who presented initially with anemia, and did not pose greater long-term risk for all-cause mortality. However, the presence of persistent anemia conferred poorest survival in patients with heart failure when compared with that of incident, resolved, or no anemia. [Copyright &y& Elsevier]

High-sensitivity C-reactive protein (hs-CRP) is a hepatocyte-derived inflammatory cytokine shown to be increased in the setting of acute heart failure (HF), particularly with increased intracardiac filling pressures. In the chronic HF setting, the relation between hs-CRP and echocardiographic indexes of left ventricular (LV) diastolic performance has not been examined. We measured plasma hs-CRP levels using a particle-enhanced immunonephelometry assay (Dade Behring, Inc., Deerfield, Illinois) in 136 subjects with chronic HF (LV ejection fraction [EF] ≤35%, New York Heart Association functional classes II to IV). We performed echocardiography, including color M-mode and tissue Doppler methods. We prospectively examined subjects’ death, cardiac transplantation, and HF hospitalization status over 33 ± 17 months. In our study cohort (mean LVEF 26 ± 6%, median plasma hs-CRP 3.19 mg/L), plasma hs-CRP levels progressively increased with worsening LV diastolic dysfunction. In particular, plasma hs-CRP levels correlated with mitral E/A wave ratio (Spearman r = 0.25, p = 0.004), mitral deceleration time (r = −0.28, p = 0.002), pulmonary vein systolic wave/diastolic wave ratio (r = −0.32, p <0.001), mitral E wave/color M-mode velocity of propagation ratio (r = 0.28, p = 0.001), and mitral E wave/tissue Doppler septal E′ wave ratio (r = 0.28, p = 0.001). Plasma hs-CRP levels independently predicted adverse clinical events even after adjustment for LVEF and mitral E wave/tissue Doppler septal E′ wave ratio (hazard ratio 2.28, 95% confidence interval 1.18 to 4.39). In conclusion, in patients with chronic systolic HF, expression of circulating CRP was associated with increasing echocardiographic indexes of diastolic dysfunction. High plasma hs-CRP levels portend poor long-term outcomes, particularly in those with severe concomitant systolic and diastolic dysfunctions. [Copyright &y& Elsevier]

Objectives: The purpose of this study was to explore the relationship between myeloperoxidase (MPO) and cardiac structure, performance, and prognosis. Background: Myeloperoxidase is an inflammatory marker that is elevated in patients with heart failure (HF) and cardiac dysfunction, with mechanistic links to plaque vulnerability and left ventricular (LV) remodeling. Methods: We evaluated plasma MPO levels (CardioMPO, PrognostiX, Inc., Cleveland, Ohio) in 140 patients with chronic systolic HF (LV ejection fraction <35%) and examined the plasma MPO levels’ relationships with echocardiographic indexes of systolic and diastolic performance, as well as long-term clinical outcomes (death, cardiac transplantation, or HF hospitalization). Results: Within the overall cohort, increasing plasma MPO levels were associated with increasing likelihood of more advanced HF (restrictive diastolic stage, right ventricular systolic dysfunction ≥3+, and tricuspid regurgitation area ≥1.8 cm2). Plasma MPO levels were predictive of long-term clinical outcomes (risk ratio [95% confidence interval] = 3.35 [1.52 to 8.86]), even after adjustment for age, LV ejection fraction, plasma B-type natriuretic peptide (BNP), creatinine clearance, or diastolic stage. In receiver-operator characteristic curve analyses, addition of MPO to BNP testing augmented the predictive accuracy of future adverse clinical events (area under the curve 0.66 for BNP only [chi-square test = 12.9, p = 0.0003], and 0.70 for BNP plus MPO [chi-square test = 15.87, p = 0.0004]). Conclusions: In chronic systolic HF, elevated plasma MPO levels are associated with an increased likelihood of more advanced HF. Moreover, elevated plasma MPO levels within a HF subject seem to be predictive of increased adverse clinical outcomes. [Copyright &y& Elsevier]

Increased oxidative stress and endothelial dysfunction are commonly observed in patients with chronic heart failure (HF). The relation between myeloperoxidase (MPO), an inflammatory marker with mechanistic links to plaque vulnerability and abnormal ventricular remodeling, and degrees of severity in chronic HF has not been reported. Plasma MPO levels were measured in 105 normal controls (no history of HF or left ventricular dysfunction) and 102 patients with chronic systolic HF (left ventricular ejection fraction <50%), and the relations among plasma MPO levels, plasma B-type natriuretic peptide levels, and the left ventricular ejection fraction were examined. Plasma MPO levels in patients with chronic systolic HF were significantly elevated compared with those of healthy controls (1,158 ± 2,965 vs 204 ± 139 pM, p <0.0001). Plasma MPO levels increased in parallel with increasing New York Heart Association class (p <0.0001) and were correlated with plasma B-type natriuretic peptide levels (Spearman’s r = 0.39, p <0.0001). Levels of MPO were strongly associated with the prevalence of HF (unadjusted odds ratio 30.3, 95% confidence interval 11.1 to 94.5) and remained significant when adjusted for age and B-type natriuretic peptide (odds ratio 27.7, 95% confidence interval 3.6 to 371.1). In conclusion, in a cohort of patients with chronic HF, plasma MPO levels were elevated compared with those of normal controls and were associated with worsening functional class. [Copyright &y& Elsevier]

Objectives: This study was designed to quantify the prevalence of abnormal glucose tolerance and insulin resistance in patients with idiopathic dilated cardiomyopathy (IDCM).Background: Insulin resistance is an independent risk factor for mortality in patients with heart failure (HF) and is a known risk factor for ischemic cardiomyopathy. Though potential physiologic links between insulin resistance and HF have been hypothesized, the relationship between insulin resistance and IDCM remains unclear.Methods: A total of 230 consecutive patients from a university HF clinic were screened for IDCM, the absence of diabetes mellitus, and the lack of significant co-morbid conditions. Oral glucose tolerance tests were performed in the 43 patients with IDCM who met these criteria, and their plasma glucose and insulin responses were compared with those of 40 healthy volunteers, matched for age, gender, and body mass index.Results: Plasma glucose responses were higher during the oral glucose tolerance tests in patients with IDCM (p < 0.01), associated with significantly higher plasma insulin concentrations following the oral glucose challenge (p < 0.01). In addition, abnormalities of glucose tolerance were significantly (p < 0.05) more common in patients with IDCM (49% vs. 23%).Conclusions: Insulin resistance and abnormal glucose tolerance are more prevalent in patients with IDCM and represent potentially reversible metabolic derangements in these individuals. [Copyright &y& Elsevier]

: ObjectivesWe sought to define the characteristics of fluid retention after thiazolidinedione (TZD) initiation in patients with established heart failure (HF).: BackgroundFluid retention associated with the use of TZD is commonly attributed to exacerbation of HF, which has led to the proscription of these potentially useful agents in patients with chronic HF.: MethodsWe examined 111 consecutive diabetic patients with chronic systolic HF who were treated with TZD from January 1999 to June 2001. A retrospective chart review was performed to determine the incidence of fluid retention in this cohort. Physical signs of fluid retention were compared between TZD users and an age- and gender-matched control group of diabetic, non-TZD users with chronic HF who had fluid retention. Baseline clinical and echocardiographic data were compared between TZD users with and without fluid retention.: ResultsNineteen TZD users (17.1%) developed fluid retention, which reversed after drug withdrawal and presented predominantly as peripheral and not central edema. Comparing patients in the upper and lower tertiles of weight gain, more female patients and insulin users developed TZD-related fluid retention. However, there were no differences in the baseline New York Heart Association functional class or echocardiographic severity of cardiac dysfunction.: ConclusionsAlthough fluid retention after treatment with TZD in diabetic patients with chronic systolic HF occurs, the mechanism is undefined. Fluid retention related to TZD tends to be peripheral and is usually reversible after drug withdrawal. No direct association between the risk of fluid retention and the baseline degree of severity of HF was observed. [Copyright &y& Elsevier]

Patients with renal insufficiency may have increased serum troponins even in the absence of clinically suspected acute myocardial ischemia. While cardiovascular disease is the most common cause of death in patients with renal failure, we are just beginning to understand the clinical meaning of serum troponin elevations. Serum troponin T is increased more frequently than troponin I in patients with renal failure, leading clinicians to question its specificity for the diagnosis of myocardial infarction. Many large-scale trials demonstrating the utility of serum troponins in predicting adverse events and in guiding therapy and intervention in acute coronary syndromes have excluded patients with renal failure. Despite persistent uncertainty about the mechanism of elevated serum troponins in patients with reduced renal function, data from smaller groups of renal failure patients have suggested that troponin elevations are associated with added risk, including an increase in mortality. It is possible that increases in serum troponin from baseline in patients with renal insufficiency admitted to hospital with acute coronary syndrome may signify myocardial necrosis. Further studies are needed to clarify this hypothesis. [Copyright &y& Elsevier]

Examines the role of angiotensin receptor blockers (ARB) in the management of chronic heart disease (CHD) in clinical trial settings. Emerging evidence that angiotensin-converting enzyme (ACE) provides incomplete long-term suppression of angiotensin II and aldosterone; Effect of losartan in aged with CHD; Comparison of the effect of ARB versus ACE inhibitors.

Bile acids (BAs) are cholesterol-derived compounds that regulate glucose, lipid, and energy metabolism. Despite their significance in glucose homeostasis, the association between specific BA molecular species and their synthetic pathways with diabetes is unclear. Here, we used a recently validated, stable-isotope dilution, high-performance liquid chromatography with tandem mass spectrometry method to quantify a panel of BAs in fasting plasma from 2,145 study participants and explored structural and genetic determinants of BAs linked to diabetes, insulin resistance, and obesity. Multiple 12α-hydroxylated BAs were associated with diabetes (adjusted odds ratio [aOR] range, 1.3–1.9; P < 0.05 for all) and insulin resistance (aOR range, 1.3–2.2; P < 0.05 for all). Conversely, multiple 6α-hydroxylated BAs and isolithocholic acid (iso-LCA) were inversely associated with diabetes and obesity (aOR range, 0.3–0.9; P < 0.05 for all). Genome-wide association studies revealed multiple genome-wide significant loci linked with 9 of the 14 diabetes-associated BAs, including a locus for iso-LCA (rs11866815). Mendelian randomization analyses showed genetically elevated deoxycholic acid levels were causally associated with higher BMI, and iso-LCA levels were causally associated with reduced BMI and diabetes risk. In conclusion, comprehensive, large-scale, quantitative mass spectrometry and genetics analyses show circulating levels of multiple structurally specific BAs, especially DCA and iso-LCA, are clinically associated with and genetically linked to obesity and diabetes. Article Highlights: The association between specific circulating bile acid (BA) molecular species and diabetes in humans is not extensively studied. In the present study, we found that multiple 12α-hydroxylated BAs are positively associated with diabetes and insulin resistance, whereas multiple 6α-hydroxylated BAs are inversely associated with diabetes and obesity. Mendelian randomization analyses show isolithocholic acid levels are causally associated with reduced risk for diabetes and obesity, and deoxycholic acid levels are causally associated with obesity risk. The findings of this study provide new avenues for investigating the role of BAs in metabolic diseases and may have substantial therapeutic implications. [ABSTRACT FROM AUTHOR]

Aims Methods and results Conclusions The clinical utility of pulmonary hypertension (PH) risk scores in non‐group 1 PH with pulmonary vascular disease (PVD) remains unresolved.We utilized the prospective multicenter PVDOMICS cohort with group 2, 3, 4 or 5 PH‐related PVD and calculated group 1 PH risk scores (REVEAL 2.0, REVEAL Lite 2, French registry score and COMPERA 2). The c‐statistic to predict death was compared separately in (i) pre‐capillary PH groups 3/4/5, and (ii) combined post‐ and pre‐capillary PH group 2. Exercise right heart catheterization reserve, ventricular interdependence and right ventricular–pulmonary artery (RV‐PA) coupling were compared across risk categories. Among 449 individuals with group 3/4/5 PH, the REVEAL 2.0 risk score had the highest c‐statistic for predicting death (0.699, 95% confidence interval [CI] 0.660–0.737, p < 0.0001) with comparable performance using the simpler REVEAL Lite 2 score (0.695, 95% CI 0.656–0.734, p < 0.0001). The French and COMPERA 2 risk scores were also predictive of mortality, but performance of both was statistically inferior to REVEAL 2.0 (c‐statistic difference −0.072, 95% CI −0.123 to −0.020, p = 0.006, and −0.043, 95% CI −0.067 to −0.018, p = 0.0007, respectively). RV function and RV‐PA coupling measures were prognostic in isolation, but did not add incremental value to REVEAL (p > 0.50 for all). Findings were similar in patients with group 2 PH (n = 239). Stratification by the REVEAL Lite 2 score non‐invasively identified non‐group 1 PH with more advanced PVD with worse exercise capacity, RV‐PA uncoupling, ventricular interdependence and impaired cardiac output reserve (p < 0.05 for all).Non‐invasive REVEAL risk predicts mortality in non‐group 1 PH without incremental prognostic value from detailed RV function or RV‐PA coupling assessment. Baseline REVEAL Lite 2 risk stratification non‐invasively identifies greater pulmonary vascular dysfunction and right heart‐related exercise limitation, which may help guide patient selection for targeted pulmonary vascular therapies in non‐group 1 PH. [ABSTRACT FROM AUTHOR]

Diabetic cardiomyopathy (DbCM) increases risk of overt heart failure in individuals with diabetes mellitus. Racial and ethnic differences in DbCM remain unexplored. The authors sought to identify racial and ethnic differences among individuals with type 2 diabetes mellitus, structural heart disease, and impaired exercise capacity. The ARISE-HF (Aldolase Reductase Inhibitor for Stabilization of Exercise Capacity in Heart Failure) trial is assessing the efficacy of an aldose reductase inhibitor for exercise capacity preservation in 691 persons with DbCM. Baseline characteristics, echocardiographic parameters, and functional capacity were analyzed and stratified by race and ethnicity. The mean age of the study participants was 67.4 years; 50% were women. Black and Hispanic patients had lower use of diabetes mellitus treatments. Black patients had poorer baseline ventricular function and more impaired global longitudinal strain. Overall, health status was preserved, based on Kansas City Cardiomyopathy Questionnaire scores, but reduced exercise capacity was present as evidenced by reduced Physical Activity Scale for the Elderly (PASE) scores. When stratified by race and ethnicity and compared with the entire cohort, Black patients had poorer health status, more reduced physical activity, and a greater impairment in exercise capacity during cardiopulmonary exercise testing, whereas Hispanic patients also displayed compromised cardiopulmonary exercise testing functional capacity. White patients demonstrated higher physical activity and functional capacity. Racial and ethnic differences exist in baseline characteristics of persons affected by DbCM, with Black and Hispanic study participants demonstrating higher risk features. These insights inform the need to address differences in the population with DbCM. (Safety and Efficacy of AT-001 in Patients With Diabetic Cardiomyopathy [ARISE-HF]; NCT04083339) [ABSTRACT FROM AUTHOR]

Progression to symptomatic heart failure is a complication of type 2 diabetes; heart failure onset in this setting is commonly preceded by deterioration in exercise capacity. This study sought to determine whether AT-001, a highly selective aldose reductase inhibitor, can stabilize exercise capacity among individuals with diabetic cardiomyopathy (DbCM) and reduced peak oxygen uptake (V o 2). A total of 691 individuals with DbCM meeting inclusion and exclusion criteria were randomized to receive placebo or ascending doses of AT-001 twice daily. Stratification at inclusion included region of enrollment, cardiopulmonary exercise test results, and use of sodium-glucose cotransporter 2 inhibitors or glucagon-like peptide-1 receptor agonists. The primary endpoint was proportional change in peak V o 2 from baseline to 15 months. Subgroup analyses included measures of disease severity and stratification variables. The mean age was 67.5 ± 7.2 years, and 50.4% of participants were women. By 15 months, peak V o 2 fell in the placebo-treated patients by −0.31 mL/kg/min (P = 0.005 compared to baseline), whereas in those receiving high-dose AT-001, peak V o 2 fell by −0.01 mL/kg/min (P = 0.21); the difference in peak V o 2 between placebo and high-dose AT-001 was 0.30 (P = 0.19). In prespecified subgroup analyses among those not receiving sodium-glucose cotransporter 2 inhibitors or glucagon-like peptide-1 receptor agonists at baseline, the difference between peak V o 2 in placebo vs high-dose AT-001 at 15 months was 0.62 mL/kg/min (P = 0.04; interaction P = 0.10). Among individuals with DbCM and impaired exercise capacity, treatment with AT-001 for 15 months did not result in significantly better exercise capacity compared with placebo. (Safety and Efficacy of AT-001 in Patients With Diabetic Cardiomyopathy [ARISE-HF]; NCT04083339) [Display omitted] [ABSTRACT FROM AUTHOR]

Aims: Patients with pulmonary hypertension (PH) are grouped based upon clinical and haemodynamic characteristics. Groups 2 (G2, left heart disease [LHD]) and 3 (G3, lung disease or hypoxaemia) are most common. Many patients display overlapping characteristics of heart and lung disease (G2–3), but this group is not well‐characterized. Methods and results: Patients with PH enrolled in the prospective, NHLBI‐sponsored PVDOMICS network underwent intensive clinical, biomarker, imaging, gas exchange and exercise phenotyping. Patients with pure G2, pure G3, or overlapping G2–3 PH were compared across multiple phenotypic domains. Of all patients with predominant G2 (n = 136), 66 (49%) were deemed to have secondary lung disease/hypoxaemia contributors (G2/3), and of all patients categorized as predominant G3 (n = 172), 41 (24%) were judged to have a component of secondary LHD (G3/2), such that 107 had G2–3 (combined G2/3 and G3/2). As compared with G3, patients with G2 and G2–3 were more obese and had greater prevalence of hypertension, atrial fibrillation, and coronary disease. Patients with G2 and G2–3 were more anaemic, with poorer kidney function, more cardiac dysfunction, and higher N‐terminal pro‐B‐type natriuretic peptide than G3. Lung diffusion was more impaired in G3 and G2–3, but commonly abnormal even in G2. Exercise capacity was severely and similarly impaired across all groups, with no differences in 6‐min walk distance or peak oxygen consumption, and pulmonary vasoreactivity to nitric oxide did not differ. In a multivariable Cox regression model, patients with G2 had lower risk of death or transplant compared with G3 (hazard ratio [HR] 0.51, 95% confidence interval [CI] 0.30–0.86), and patients with G2–3 also displayed lower risk compared with G3 (HR 0.57, 95% CI 0.38–0.86). Conclusions: Overlap is common in patients with a pulmonary or cardiac basis for PH. While lung structure/function is clearly more impaired in G3 and G2–3 than G2, pulmonary abnormalities are common in G2, even when clinically judged as isolated LHD. Further study is required to identify optimal systematic evaluations to guide therapeutic innovation for PH associated with combined heart and lung disease. Clinical Trial Registration: ClinicalTrials.gov NCT02980887. [ABSTRACT FROM AUTHOR]

This document, published in the journal Circulation, discusses the development of a novel biomarker for transthyretin amyloidosis (ATTR), a disease characterized by the deposition of amyloid fibrils composed of misfolded transthyretin (TTR). The researchers developed a probe called transthyretin aggregate detector 1 (TAD1) to detect ATTR fibrils and aggregates in patient tissues and blood. They validated the probe's ability to bind to ATTR fibrils and found that it displayed high sensitivity and specificity. The researchers also tested TAD1 on plasma samples from patients with ATTR and found that it could detect a unique biomarker that decreased in response to treatment. The study suggests that TAD1 may be a useful tool for early detection and monitoring of ATTR. However, the study has limitations, including a limited sample size and the need for independent validation. The work was supported by various funding sources, and the authors disclose potential conflicts of interest. [Extracted from the article]

Aim: Among patients discharged after hospitalization for heart failure (HF), a strategy of torsemide versus furosemide showed no difference in all‐cause mortality or hospitalization. Clinicians have traditionally favoured torsemide in the setting of kidney dysfunction due to better oral bioavailability and longer half‐life, but direct supportive evidence is lacking. Methods and results: The TRANSFORM‐HF trial randomized patients hospitalized for HF to a long‐term strategy of torsemide versus furosemide, and enrolled patients across the spectrum of renal function (without dialysis). In this post‐hoc analysis, baseline renal function during the index hospitalization was assessed as categories of estimated glomerular filtration rate (eGFR; <30, 30–<60, ≥60 ml/min/1.73 m2). The interaction between baseline renal function and treatment effect of torsemide versus furosemide was assessed with respect to mortality and hospitalization outcomes, and the change in Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ‐CSS). Of 2859 patients randomized, 336 (11.8%) had eGFR <30 ml/min/1.73 m2, 1138 (39.8%) had eGFR 30–<60 ml/min/1.73 m2, and 1385 (48.4%) had eGFR ≥60 ml/min/1.73 m2. Baseline eGFR did not modify treatment effects of torsemide versus furosemide on all adverse clinical outcomes including individual components or composites of all‐cause mortality and all‐cause (re)‐hospitalizations, both when assessing eGFR categorically or continuously (p‐value for interaction all >0.108). Similarly, no treatment effect modification by eGFR was found for the change in KCCQ‐CSS (p‐value for interaction all >0.052) when assessing eGFR categorically or continuously. Conclusion: Among patients discharged after hospitalization for HF, there was no significant difference in clinical and patient‐reported outcomes between torsemide and furosemide, irrespective of renal function. [ABSTRACT FROM AUTHOR]

Aims: Sodium restriction was not associated with improved outcomes in heart failure patients in recent trials. The skin might act as a sodium buffer, potentially explaining tolerance to fluctuations in sodium intake without volume overload, but this is insufficiently understood. Therefore, we studied the handling of an increased sodium load in patients with heart failure with reduced ejection fraction (HFrEF). Methods and results: Twenty‐one ambulatory, stable HFrEF patients and 10 healthy controls underwent a 2‐week run‐in phase, followed by a 4‐week period of daily 1.2 g (51 mmol) sodium intake increment. Clinical, echocardiographic, 24‐h urine collection, and bioelectrical impedance data were collected every 2 weeks. Blood volume, skin sodium content, and skin glycosaminoglycan content were assessed before and after sodium loading. Sodium loading did not significantly affect weight, blood pressure, congestion score, N‐terminal pro‐brain natriuretic peptide, echocardiographic indices of congestion, or total body water in HFrEF (all p > 0.09). There was no change in total blood volume (4748 ml vs. 4885 ml; p = 0.327). Natriuresis increased from 150 mmol/24 h to 173 mmol/24 h (p = 0.024), while plasma renin decreased from 286 to 88 μU/L (p = 0.002). There were no significant changes in skin sodium content, total glycosaminoglycan content, or sulfated glycosaminoglycan content (all p > 0.265). Healthy controls had no change in volume status, but a higher increase in natriuresis without any change in renin. Conclusions: Selected HFrEF patients can tolerate sodium loading, with increased renal sodium excretion and decreased neurohormonal activation. [ABSTRACT FROM AUTHOR]

Gut microbiome (GMB) has been increasingly recognized as a contributor to development and progression of heart failure (HF), immune-mediated subtypes of cardiomyopathy (myocarditis and anthracycline-induced cardiotoxicity), response to certain cardiovascular drugs, and HF-related comorbidities, such as chronic kidney disease, cardiorenal syndrome, insulin resistance, malnutrition, and cardiac cachexia. Gut microbiome is also responsible for the "gut hypothesis" of HF, which explains the adverse effects of gut barrier dysfunction and translocation of GMB on the progression of HF. Furthermore, accumulating evidence has suggested that gut microbial metabolites, including short chain fatty acids, trimethylamine N-oxide (TMAO), amino acid metabolites, and bile acids, are mechanistically linked to pathogenesis of HF, and could, therefore, serve as potential therapeutic targets for HF. Even though there are a variety of proposed therapeutic approaches, such as dietary modifications, prebiotics, probiotics, TMAO synthesis inhibitors, and fecal microbial transplant, targeting GMB in HF is still in its infancy and, indeed, requires further preclinical and clinical evidence. In this review, we aim to highlight the role gut microbiome plays in HF pathophysiology and its potential as a novel therapeutic target in HF. [ABSTRACT FROM AUTHOR]

The LHFRS is a simple score derived from three factors (history of hypertension, history of coronary artery disease/myocardial infarction, and red blood cell distribution width) deployed for the risk stratification of AHF in Greek population. This study aimed to validate the Larissa Heart Failure Risk Score (LHFRS) in patients with acute heart failure (AHF) in a Japanese population. We performed post-hoc analysis of 1670 consecutive patients enrolled in the REALITY-AHF. In all, 964 patients were finally enrolled. Exclusion criteria included patients with anemia, malignancies and sepsis. The primary outcome was defined as a composite of all-cause mortality and/or heart failure readmission, and the secondary outcome was defined as all-cause mortality. The median admission LHFRS value was 1 (interquartile range [IQR]: 0–2). During a median follow-up of 365 (IQR: 161–365) days, the primary and secondary outcomes were observed in 321 and 157 patients, respectively. LHFRS was an independent predictor of both the primary (adjusted hazard ratio per 1-point increase, 95% confidence interval: 1.17 [1.04–1.32], p = 0.011), and the secondary outcomes (1.31 [1.12–1.55], p = 0.001). Patients with higher LHFRS scores (≥2) exhibited significantly worse outcomes than those with lower scores (<2) both for the primary outcome (1.40 [1.07–1.83], p = 0.014) and the secondary outcome (1.60 [1.09–2.34], p = 0.015). Additionally, LHFRS revealed an excellent goodness of fit (observed versus predicted outcomes) for predicting both the primary and the secondary outcomes (p > 0.99 and p = 0.99, respectively). The simple LHFRS was proved as a reliable predictor of outcomes in patients with AHF. • Risk stratification is important during hospitalization for acute heart failure (AHF). • The Larissa Heart Failure Risk Score (LHFRS) is a simple score that easily and reliably risk stratifies AHF patients. • Close monitoring of high risk AHF patients is warranted. [ABSTRACT FROM AUTHOR]

This article examines the use of comprehensive heart failure (HF) medical therapy in a large, diverse health system. The study utilized an electronic health record (EHR)-based patient registry to evaluate factors that impact the use of guideline-directed medical therapy (GDMT) for HF. The findings showed that cardiology engagement within the last 12 months was strongly associated with higher GDMT scores. HF hospitalization and all-cause hospitalizations were associated with worse GDMT use, although HF hospitalization was linked to an increased likelihood of prescription for certain medications. The study also found no difference in GDMT scores based on patient race or sex when certain medications were excluded from the analysis. The authors suggest that this EHR-based approach can be used to evaluate GDMT opportunities in other health systems, but acknowledge the limitations of the study and the need for further research. [Extracted from the article]