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Background: Transthyretin amyloid cardiomyopathy (ATTR-CM) is a morbid condition, though recent advances in diagnosis and therapy stand to change its natural history. Patients' TTR genotype may guide family screening as more treatments and preventive strategies become available. An efficient, intuitive means of determining pretest genetic risk may better inform patients/clinicians when pursuing genetic testing. Methods: This is a cohort study of 767 consecutive patients diagnosed with ATTR-CM who underwent genetic testing. Classification and regression trees (CART) analysis created a decision tree assessing likelihood of carrying a pathologic TTR gene variant. Age, sex, and race were used as independent variables. Logistic regression was also performed to model probability of pathologic TTR genotype. The primary outcome was the decision tree's accuracy in 2 separate institutions' ATTR-CM registry. Results: In our study cohort, 208 patients (27.1%) had ATTRv. Race has served most efficiently as the root node followed by age and sex in a CART algorithm, and showed 88.2% accuracy (75.3% sensitivity, 93.9% specificity) in the validation cohort. The odds of having a TTR gene variant were greater in Black patients compared with non-Black patients (OR, 34.6 [95% CI, 20.5–58.3]; P <0.001). Non-Black patients with ATTR-CM aged 69 years and older had <4% risk of having a predisposing mutation. Conclusions: This CART algorithm incorporating age, sex, and race was able to determine which patients with ATTR-CM have pathogenic TTR mutations with high specificity. Non-Black patients diagnosed at age 69 years or older with ATTR-CM have a low likelihood to have ATTRv. [ABSTRACT FROM AUTHOR]

Background: Little information is available on the prognostic relevance of cardiac hemodynamic cutoffs in cardiac amyloidosis (CA) and its subtypes. Methods: Consecutive patients diagnose with light chain-CA or transthyretin CA undergoing right heart catheterization were analyzed. Prognostic relevance of classic hemodynamic cutoffs of cardiac index (CI <2.2 L/min per m2), pulmonary capillary wedge pressure (>18 mm Hg), right atrial pressure (>8 mm Hg), and mean pulmonary artery pressure (≥25 mm Hg or pulmonary hypertension) with the combined end point of cardiac transplant/left ventricular assist device and death and heart failure admissions separately was assessed. Results: A total of 469 CA patients underwent right heart catheterization (light chain CA=42% and transthyretin CA=52%) of whom 69%, 64%, and 79% had elevated right atrial pressure, pulmonary capillary wedge pressure, and pulmonary hypertension, respectively. The classic hemodynamic cutoffs for right atrial pressure (hazard ratio, 1.26 [0.98–1.62]) and mean pulmonary artery pressure (hazard ratio, 1.28 [0.96–1.71]) did not identify patients at higher risk for adverse outcome; however, cutoffs of 14 mm Hg for right atrial pressure (hazard ratio, 1.59 [1.26–2.00]) and 35 mm Hg for mean pulmonary artery pressure (hazard ratio, 1.30 [1.01–1.66]) performed better to detect worse outcome (P <0.05 for both). Reduced CI occurred in 55% of patients and was the strongest variable associated with the risk for cardiac transplant/left ventricular assist device and death, heart failure admissions, and reduced functional capacity. Reduced CI independently predicted risk on top of the Mayo-score in light chain CA and National Amyloid Center score in transthyretin CA (P <0.05 for both). Patients with light chain CA had higher pulmonary capillary wedge pressure and lower stroke volume index but maintained CI through a higher heart rate. Conclusions: Hemodynamic variables are grossly abnormal in CA, but elevated filling pressures are prognostic at significantly higher threshold values than classic cutoff values. CI is the hemodynamic variable most strongly associated with outcome and functionality in CA. [ABSTRACT FROM AUTHOR]

Background: The gut microbiota-dependent metabolite phenylacetylgutamine (PAGln) is both associated with atherothrombotic heart disease in humans, and mechanistically linked to cardiovascular disease pathogenesis in animal models via modulation of adrenergic receptor signaling. Methods: Here we examined both clinical and mechanistic relationships between PAGln and heart failure (HF). First, we examined associations among plasma levels of PAGln and HF, left ventricular ejection fraction, and N-terminal pro-B-type natriuretic peptide in 2 independent clinical cohorts of subjects undergoing coronary angiography in tertiary referral centers (an initial discovery US Cohort, n=3256; and a validation European Cohort, n=829). Then, the impact of PAGln on cardiovascular phenotypes relevant to HF in cultured cardiomyoblasts, and in vivo were also examined. Results: Circulating PAGln levels were dose-dependently associated with HF presence and indices of severity (reduced ventricular ejection fraction, elevated N-terminal pro-B-type natriuretic peptide) independent of traditional risk factors and renal function in both cohorts. Beyond these clinical associations, mechanistic studies showed both PAGln and its murine counterpart, phenylacetylglycine, directly fostered HF-relevant phenotypes, including decreased cardiomyocyte sarcomere contraction, and B-type natriuretic peptide gene expression in both cultured cardiomyoblasts and murine atrial tissue. Conclusions: The present study reveals the gut microbial metabolite PAGln is clinically and mechanistically linked to HF presence and severity. Modulating the gut microbiome, in general, and PAGln production, in particular, may represent a potential therapeutic target for modulating HF. Registration: URL: https://clinicaltrials.gov/; Unique identifier: NCT00590200 and URL: https://drks.de/drks%5fweb/; Unique identifier: DRKS00020915. [ABSTRACT FROM AUTHOR]

Sarcopenia has been established as a predictor of poor outcomes in various clinical settings. It is particularly prevalent in heart failure, a clinical syndrome that poses significant challenges to health care worldwide. Despite this, sarcopenia remains overlooked and undertreated in cardiology practice. Understanding the currently proposed diagnostic process is paramount for the early detection and treatment of sarcopenia to mitigate downstream adverse health outcomes. [ABSTRACT FROM AUTHOR]

Outcomes associated with episodes of hypotension while hospitalized with acute decompensated heart failure are not well understood.Using data from Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND-HF), we assessed factors associated with in-hospital hypotension and subsequent 30-day outcomes. Patients were classified as having symptomatic or asymptomatic hypotension. Multivariable logistic regression was used to determine factors associated with in-hospital hypotension, and Cox proportional hazards models were used to assess the association between hypotension and 30-day outcomes. We also tested for treatment interaction with nesiritide on 30-day outcomes and the association between in-hospital hypotension and renal function at hospital discharge. Overall, 1555 of 7141 (21.8%) patients had an episode of hypotension, of which 73.1% were asymptomatic and 26.9% were symptomatic. Factors strongly associated with in-hospital hypotension included randomization to nesiritide (odds ratio, 1.98; 95% confidence interval [CI], 1.76-2.23; P<0.001), chronic metolazone therapy (odds ratio, 1.74; 95% CI, 1.17-2.60; P<0.001), and baseline orthopnea (odds ratio, 1.31; 95% CI, 1.13-1.52; P=0.001) or S3 gallop (odds ratio, 1.21; 95% CI, 1.06-1.40; P=0.006). In-hospital hypotension was associated with increased hazard of 30-day mortality (hazard ratio, 2.03; 95% CI, 1.57-2.61; P<0.001), 30-day heart failure hospitalization or mortality (hazard ratio, 1.58; 95% CI, 1.34-1.86; P<0.001), and 30-day all-cause hospitalization or mortality (hazard ratio, 1.40; 95% CI, 1.22-1.61; P<0.001). Nesiritide had no interaction on the relationship between hypotension and 30-day outcomes (interaction P=0.874 for death, P=0.908 for death/heart failure hospitalization, P=0.238 death/all-cause hospitalization).Hypotension while hospitalized for acute decompensated heart failure is an independent risk factor for adverse 30-day outcomes, and its occurrence highlights the need for modified treatment strategies.URL: http://www.clinicaltrials.gov. Unique identifier: NCT00475852. [ABSTRACT FROM AUTHOR]

The urinary composition, including sodium (Na+) and chloride (Cl-) concentrations, might provide useful information in addition to urine output during decongestive treatment in heart failure.Consecutive patients with heart failure (n=61), ejection fraction 45%, worsening symptoms, and scheduled treatment with intravenous loop diuretics were included. Patients received protocol-driven therapy until complete decongestion, assessed clinically and by echocardiography. Three consecutive 24-hour urinary collections were performed. With 2 mg (1-4 mg), 1 mg (0-2 mg), and 1 mg (0-1 mg) bumetanide administered in bolus during consecutive 24-hour intervals, in addition to combinational diuretic therapy in ≈70% and both oral spironolactone and vasodilators in ≈90%, euvolemia was reached, often within 24 hours. Urine output was higher during the first when compared with the second or third 24-hour interval (2700 versus 1550 or 1375 mL, respectively; P<0.001), but this was no longer significant after correction for diuretic dose (P=0.263), indicating preserved diuretic efficiency during the study. In contrast, urinary Na+ and Cl- excretion both decreased significantly, even after correction for diuretic dose (P=0.040 and 0.004, respectively), leading to decreasing urinary concentrations with progressive decongestion. After reaching euvolemia, lower urinary Na+/Cr and Cl-/Cr ratios were both associated with urine output 1500 mL (area under the curve, 0.830 and 0.826, respectively; P<0.001 for both), in contrast to plasma N-terminal pro-B-type natriuretic peptide levels that were not (area under the curve, 0.515; P=0.735)The urinary composition during progressive decongestion in heart failure with reduced ejection fraction is characterized by a drop in urinary Na+ and Cl- concentrations. The urinary Na+/Cr or Cl-/Cr ratio might provide insightful information to titrate diuretic therapy. [ABSTRACT FROM AUTHOR]

We hypothesized that S100A1 is regulated during human hypertrophy and heart failure and that it may be implicated in remodeling after left ventricular assist device. S100A1 is decreased in animal and human heart failure, and restoration produces functional recovery in animal models and in failing human myocytes. With the potential for gene therapy, it is important to carefully explore human cardiac S100A1 regulation and its role in remodeling.We measured S100A1, the sarcoplasmic endoplasmic reticulum Ca2+ATPase, phospholamban, and ryanodine receptor proteins, as well as β-adrenergic receptor density in nonfailing, hypertrophied (left ventricular hypertrophy), failing, and failing left ventricular assist device-supported hearts. We determined functional consequences of protein alterations in isolated contracting muscles from the same hearts. S100A1, sarcoplasmic endoplasmic reticulum Ca2+ATPase and phospholamban were normal in left ventricular hypertrophy, but decreased in failing hearts, while ryanodine receptor was unchanged in either group. Baseline muscle contraction was not altered in left ventricular hypertrophy or failing hearts. β-Adrenergic receptor and inotropic response were decreased in failing hearts. In failing left ventricular assist device-supported hearts, S100A1 and sarcoplasmic endoplasmic reticulum Ca2+ATPase showed no recovery, while phospholamban, β-adrenergic receptor, and the inotropic response fully recovered.S100A1 and sarcoplasmic endoplasmic reticulum Ca2+ATPase, both key Ca2+-regulatory proteins, are decreased in human heart failure, and these changes are not reversed after left ventricular assist device. The clinical significance of these findings for cardiac recovery remains to be addressed. [ABSTRACT FROM AUTHOR]

Rather than the absolute dose of diuretic or urine output, the primary signal of interest when evaluating diuretic responsiveness is the efficiency with which the kidneys can produce urine after a given dose of diuretic. As a result, we hypothesized that a metric of diuretic efficiency (DE) would capture distinct prognostic information beyond that of raw fluid output or diuretic dose.We independently analyzed 2 cohorts: (1) consecutive admissions at the University of Pennsylvania (Penn) with a primary discharge diagnosis of heart failure (n=657) and (2) patients in the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE) data set (n=390). DE was estimated as the net fluid output produced per 40 mg of furosemide equivalents, then dichotomized into high versus low DE based on the median value. There was only a moderate correlation between DE and both intravenous diuretic dose and net fluid output (r20.26 for all comparisons), indicating that DE was describing unique information. With the exception of metrics of renal function and preadmission diuretic therapy, traditional baseline characteristics, including right heart catheterization variables, were not consistently associated with DE. Low DE was associated with worsened survival even after adjusting for in-hospital diuretic dose, fluid output, in addition to baseline characteristics (Penn: hazards ratio [HR], 1.36; 95% confidence interval [CI], 1.04-1.78; P=0.02; ESCAPE: HR, 2.86; 95% CI, 1.53-5.36; P=0.001).Although in need of validation in less-selected populations, low DE during decongestive therapy portends poorer long-term outcomes above and beyond traditional prognostic factors in patients hospitalized with decompensated heart failure. [ABSTRACT FROM AUTHOR]

Ceruloplasmin (Cp) decreases nitric oxide bioavailability in blood and has been associated with cardiovascular disease (CVD) in clinical studies. We assessed the associations between Cp and incident heart failure (HF), death, and CVD in the Atherosclerosis Risk in Communities (ARIC) study.Cp was measured at ARIC visit 4 (1996-1998). We studied 9240 individuals without HF or CVD at ARIC visit 4 and followed them for a mean of 10.5 years. Genome-wide association study was performed to identify genetic determinants of Cp levels and evaluate their association with incident HF in ARIC participants. Cp levels (mean±SD) were higher in women versus men (335±79 versus 258±44 mg/L; P<0.0001), women on versus not on hormone-replacement therapy (398±89 versus 291±60 mg/L; P<0.0001), and African Americans versus whites (299±63 versus 293±74 mg/L; P=0.0005). After adjusting for traditional risk factors, high-sensitivity C-reactive protein, N-terminal pro-B-type natriuretic peptide, and high-sensitivity cardiac troponin T, higher levels of Cp were associated with HF (hazard ratio, 1.44; 95% confidence interval, 1.13-1.83) and mortality (hazard ratio, 1.38; 95% confidence interval, 1.11-1.63). A locus on the ceruloplasmin gene on chromosome 3 was significantly associated with Cp levels (normal 295.56±77.60 mg/L; heterozygote 316.72±88.02 mg/L; homozygote 331.04±85.40 mg/L; P=8.3×10-13) but not with incident HF. After adjustment for traditional risk factors, Cp levels were also weekly associated with CVD.Cp was associated with incident HF, mortality, and CVD in the ARIC population. A single locus on chromosome 3 was associated with Cp levels but not with HF. [ABSTRACT FROM AUTHOR]

Supplemental Digital Content is available in the text. Background: Many patients with amyloid cardiomyopathy (ACM) develop advanced heart failure, and durable mechanical circulatory support (MCS) may be a consideration. However, data describing clinical outcomes after MCS in this population are limited. Methods: Adult patients in the Interagency Registry for Mechanically Assisted Circulatory Support with dilated cardiomyopathy (DCM, n=19 921), nonamyloid restrictive cardiomyopathy (RCM, n=248), or ACM (n=46) between 2005 and 2017 were included. Patient and device characteristics were compared between cardiomyopathy groups. The primary end point was the cumulative incidence of death with heart transplantation as a competing risk. Results: Patients with ACM (n=46) were older (61 years [interquartile range, 55–69 years] versus 58 years [interquartile range, 49–66 years] for DCM and 55 years [interquartile range, 46–62 years] for nonamyloid RCM, P <0.001) and were more commonly Interagency Registry for Mechanically Assisted Circulatory Support profile 1 (30.4% versus 17.9% for DCM and 21.0% for nonamyloid RCM, P =0.04) at device implantation. Use of biventricular support (biventricular assist device or total artificial heart) was the highest for patients with ACM (41.3% versus 6.7% and 19.4% for patients with DCM and nonamyloid RCM, respectively, P =0.014). The cumulative incidence of death was highest for patients with ACM relative to those with DCM or nonamyloid RCM (P <0.001) but did not differ significantly between groups for those who required biventricular MCS. Conclusions: Compared with patients with DCM or nonamyloid RCM who received durable MCS, those with ACM experienced the highest use of biventricular support and the worst survival. These data highlight concerns with the use of durable MCS for patients with ACM. [ABSTRACT FROM AUTHOR]

Supplemental Digital Content is available in the text. Background: Black patients have higher rates of hospitalization for acute heart failure than other race/ethnic groups. We sought to determine whether diuretic efficiency is associated with racial differences in risk for rehospitalization after acute heart failure. Methods: A post hoc analysis was performed on 721 subjects (age, 68±13 years; 22% black) enrolled in 3 acute heart failure clinical trials: ROSE-AHF (Renal Optimization Strategies Evaluation in Acute Heart Failure), DOSE-AHF (Diuretic Optimization Strategy Evaluation in Acute Decompensated Heart Failure), and CARRESS-HF (Cardiorenal Rescue Study in Acute Decompensated Heart Failure). Repeated-measures ANOVA was used to test for a race×time effect on measures of decongestion. Diuretic efficiency was calculated as net fluid balance per total furosemide equivalents. In a subset of subjects, Cox regression was used to examine the association between race and rehospitalization according to plasma renin activity (PRA). Results: Compared with nonblack patients, black patients were younger and more likely to have nonischemic heart failure. During the first 72 to 96 hours, there was greater fluid loss (P =0.001), decrease in NT-proBNP (N-terminal pro-B-type natriuretic peptide; P =0.002), and lower levels of PRA (P <0.0001) in black patients. Diuretic efficiency was higher in black than in nonblack patients (403 [interquartile range, 221–795] versus 325 [interquartile range, 154–698]; P =0.014). However, adjustment for baseline PRA attenuated the association between black race and diuretic efficiency. Over a median follow-up of 68 (interquartile range, 56–177) days, there was an increased risk of all-cause and heart failure–specific rehospitalization in nonblack patients with increasing levels of PRA, while the risk of rehospitalization was relatively constant across levels of PRA in black patients. Conclusions: Higher diuretic efficiency in black patients with acute heart failure may be related to racial differences in activity of the renin-angiotensin-aldosterone system. [ABSTRACT FROM AUTHOR]

Supplemental Digital Content is available in the text. Background: The relationship between intensive volume removal in acute decompensated heart failure patients with preexisting worsening renal function (WRF) and renal tubular injury, postdischarge renal function, and clinical outcomes is unknown. Methods and Results: We used data from the multicenter CARRESS-HF trial (Cardiorenal Rescue Study in Acute Decompensated Heart Failure) that randomized patients with acute decompensated heart failure and preexisting WRF to intensive volume removal with stepped pharmacological therapy or fixed rate ultrafiltration. Patients in the urinary renal tubular injury biomarker substudy (NAG [N-acetyl-b-D-glucosaminidase], KIM-1 [kidney injury molecule-1], and NGAL [neutrophil gelatinase-associated lipocalin]) were evaluated (N=105). The severity of prerandomization WRF was unrelated to baseline renal tubular injury biomarkers (r =0.14; P =0.17). During randomized intensive volume removal, creatinine further worsened in 53% of patients. Despite a small to moderate magnitude increase in creatinine in most of these patients, postrandomization WRF was strongly associated with worsening in renal tubular injury biomarkers (odds ratio, 12.6; P =0.004). This observation did not differ by mode of volume removal (stepped pharmacological therapy versus ultrafiltration, P interaction=0.46). Increase in renal tubular injury biomarkers was associated with a higher incidence of hemoconcentration (odds ratio, 3.1; P =0.015), and paradoxically, better recovery of creatinine at 60 days (P =0.01). Conclusions: In acute decompensated heart failure patients with preexisting WRF, intensive volume removal resulted in a further worsening of creatinine approximately half of the time, a finding associated with a rise in tubular injury biomarkers. However, decongestion and renal function recovery at 60 days were superior in patients with increased tubular injury markers. These data suggest that the benefits of decongestion may outweigh any modest or transient increases in serum creatinine or tubular injury markers that occur during intensive volume removal. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00608491. [ABSTRACT FROM AUTHOR]

Supplemental Digital Content is available in the text. Background: Acute and chronic effects of cardiac resynchronization therapy (CRT) on pulmonary pressures, right ventricular function, and ventricular-vascular coupling during exercise are insufficiently understood. Yet, these factors are strongly associated with functional status and outcome. Methods and Results: Heart failure patients with reduced ejection fraction indicated for CRT were prospectively included to undergo exercise echocardiography simultaneously with cardiopulmonary exercise testing before (pre_CRT), 1 day after (post_CRT), and 6 months (post6_CRT) after CRT implant. Right ventricular-arterial coupling was assessed by the tricuspid annular plane systolic excursion (TAPSE)/systolic pulmonary artery pressure (SPAP) ratio. A total of 31 heart failure patients with reduced ejection fraction (age=66±13 years) were prospectively included. CRT resulted in an immediate reduction in rest SPAP (pre_CRT=32±16 versus post_CRT=23±16 mm Hg; P =0.006) and rest effective regurgitant orifice (pre_CRT=0.32±0.1 versus post_CRT=0.18±0.2; P =0.001) without changes in exercise mitral regurgitation or exercise SPAP indexed for cardiac output. Six months after CRT, in parallel with left ventricular reverse remodeling and a reduction in exercise mitral regurgitation and exercise E/e′ ratio, the exercise SPAP/cardiac output significantly improved (post_CRT=5.6±3.1 versus post6_CRT=4.3±2.9 mm Hg·L−1·min−1; P =0.039), which was also illustrated by a reduced slope of ΔSPAP/Δcardiac output (post_CRT=5.2±3.7 versus post6_CRT=2.9±2.7 mm Hg·L−1·min−1; P =0.002). CRT did not result in an acute or chronic effect on TAPSE or TAPSE/SPAP ratio at rest. However, exercise revealed the presence of right ventricular-arterial uncoupling which was not affected by an acute CRT effect (P =0.396) but only improved by a chronic CRT effect (P <0.001; TAPSE/SPAP ratio: pre_CRT= 0.39±0.6 mm/mm Hg; post_CRT=0.42±0.5 mm/mm Hg; post6_CRT =0.84±0.12 mm/mm Hg). Of all exercise echocardiography variables, the TAPSE/SPAP ratio demonstrated the strongest correlation with V o 2 peak (r =0.475), VE/V co 2 (r =−0.585), and workload (r =0.476) during cardiopulmonary exercise testing (P <0.05 all). Multivariate predictors affecting exercise ventricular-arterial coupling after CRT included metrics of residual exercise mitral regurgitation and systolic and diastolic left ventricular function. Conclusions: Chronic CRT beneficially influences pulmonary pressures and right ventricular-arterial coupling during exercise, which strongly relates to functional status. These findings are mechanistically linked to reverse remodeling with improved interventricular dependence and reduction in exercise mitral regurgitation. [ABSTRACT FROM AUTHOR]