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Cardiomyopathy is a disease of the heart muscle leading to abnormal structure or function in the absence of coronary artery disease, hypertension, or valvular or congenital heart disease. Currently, cardiomyopathy is the leading diagnosis of heart transplant patients worldwide. Incorporation of next-generation sequencing strategies will likely revolutionize genetic testing in cardiomyopathy. The use of patient-specific pluripotent stem cell-derived cardiomyocytes for disease modeling and therapeutic testing has opened a new avenue for precision medicine in cardiomyopathy. Stem cell therapy, gene therapy, interfering RNA, and small molecules are actively being evaluated in clinical trials.

WH Wilson TangSection of Heart Failure and Cardiac Transplantation Medicine, Department of Cardiovascular Medicine, the Cleveland Clinic, Cleveland, OH, USAAbstract: Anti-adrenergic therapy has been widely accepted as an important therapeutic intervention in patients with chronic heart failure. However, there has been continuing controversy regarding the risks and clinical significance of metabolic effects of different anti-adrenergic drugs. This review summarizes what has been learned from clinical trial evidence regarding the benefits of anti-adrenergic drugs in diabetic patients with chronic heart failure.Keywords: diabetes mellitus, congestive heart failure, anti-adrenergic drugs, carvedilol

With the total cases and economic burden of heart failure continuing to rise, there is an overwhelming need for novel therapies. Several drugs for heart failure have succeeded in preclinical and early-phase clinical trials, but most of them failed to show the real benefit in pivotal clinical trials. Meanwhile, the US Food and Drug Administration recently approved two promising new drugs to treat heart failure: ivabradine and sacubitril/valsartan. Furthermore, some of the newer agents in testing offer the potential for significant progress in addition to these drugs. Patiromer and zirconium cyclosilicate are attractive agents that are expected to prevent hyperkalemia during renin-angiotensin-aldosterone system inhibition, and serelaxin and urodilatin are promising drugs in the treatment of acute heart failure. Future clinical trials with more appropriate study designs, optimal clinical endpoints, and proper patient selection are mandatory to assess the true efficacy of these attractive compounds in clinical practice.

Background: Reduced gas transfer in patients with pulmonary arterial hypertension (PAH) is traditionally attributed to remodeling and progressive loss of pulmonary arterial vasculature that results in decreased capillary blood volume available for gas exchange. Methods: We tested this hypothesis by determination of lung diffusing capacity (DL) and its components, the alveolar capillary membrane diffusing capacity (Dm) and lung capillary blood volume (Vc) in 28 individuals with PAH in comparison to 41 healthy individuals, and in 19 PAH patients over time. Using single breath simultaneous measure of diffusion of carbon monoxide (DLco) and nitric oxide (DLNO), DL and Dm were respectively determined, and Vc calculated. Dm and Vc were evaluated over time in relation to standard clinical indicators of disease severity, including brain natriuretic peptide (BNP), 6-minute walk distance (6MWD) and right ventricular systolic pressure (RVSP) by echocardiography. Results: Both DLCO and DLNO were reduced in PAH as compared to controls and the lower DL in PAH was due to loss of both Dm and Vc (all p < 0.01). While DLCO of PAH patients did not change over time, DLNO decreased by 24 ml/min/mmHg/year (p = 0.01). Consequently, Dm decreased and Vc tended to increase over time, which led to deterioration of the Dm/Vc ratio, a measure of alveolar-capillary membrane functional efficiency without changes in clinical markers. Conclusions: The findings indicate that lower than normal gas transfer in PAH is due to loss of both Dm and Vc, but that deterioration of Dm/Vc over time is related to worsening membrane diffusion. [ABSTRACT FROM AUTHOR]

Given the critical role of skeletal muscle in healthy aging, low muscle mass (myopenia) and quality (myosteatosis) can be used as predictors of poor functional and cardiometabolic outcomes. Myopenia is also a part of sarcopenia and malnutrition diagnostic criteria. However, there is limited evidence for using chest computed tomography (CT) to evaluate muscle health. We aimed to compare chest CT landmarks to the widely used L3 vertebra for single-slice skeletal muscle evaluation in patients with heart failure (HF). Patients admitted for acute decompensated HF between January 2017 and December 2018 were retrospectively analyzed. Body composition measurements were made on CT of the chest and abdomen/pelvis with or without contrast one month before discharge. Skeletal muscle index (SMI) and intermuscular adipose tissue percentage (IMAT%) were calculated at several thoracic levels (above the aortic arch, T8, and T12) and correlated to the widely used L3 level. A total of 200 patients were included, 89 (44.5%) female. The strongest correlation of thoracic SMI (for muscle quantity) and IMAT% (for muscle quality) with L3 was at the T12 level (r = 0.834, p < 0.001 and r = 0.757, p < 0.001, respectively). Cutoffs to identify low muscle mass for T12 SMI (derived from the lowest sex-stratified L3 SMI tertile) were 31.1 cm²/m² in men and 26.3 cm²/m² in women. SMI and IMAT% at T12 had excellent correlations with the widely used L3 level for muscle quantity and quality evaluation in patients with HF., (© 2024. The Author(s).)

The combinatorial effect of genetic variants is often assumed to be additive. Although genetic variation can clearly interact non-additively, methods to uncover epistatic relationships remain in their infancy. We develop low-signal signed iterative random forests to elucidate the complex genetic architecture of cardiac hypertrophy. We derive deep learning-based estimates of left ventricular mass from the cardiac MRI scans of 29,661 individuals enrolled in the UK Biobank. We report epistatic genetic variation including variants close to CCDC141 , IGF1R , TTN , and TNKS. Several loci where variants were deemed insignificant in univariate genome-wide association analyses are identified. Functional genomic and integrative enrichment analyses reveal a complex gene regulatory network in which genes mapped from these loci share biological processes and myogenic regulatory factors. Through a network analysis of transcriptomic data from 313 explanted human hearts, we found strong gene co-expression correlations between these statistical epistasis contributors in healthy hearts and a significant connectivity decrease in failing hearts. We assess causality of epistatic effects via RNA silencing of gene-gene interactions in human induced pluripotent stem cell-derived cardiomyocytes. Finally, single-cell morphology analysis using a novel high-throughput microfluidic system shows that cardiomyocyte hypertrophy is non-additively modifiable by specific pairwise interactions between CCDC141 and both TTN and IGF1R . Our results expand the scope of genetic regulation of cardiac structure to epistasis.

Background: Diabetic cardiomyopathy (DbCM) is a form of Stage B heart failure (HF) at high risk for progression to overt disease. Using baseline characteristics of study participants from the Aldose Reductase Inhibition for Stabilization of Exercise Capacity in Heart Failure (ARISE-HF) Trial we sought to characterize clinical characteristics of individuals with findings consistent with DbCM., Methods: Among study participants meeting inclusion criteria, clinical characteristics, laboratory testing, imaging, Kansas City Cardiomyopathy Questionnaire (KCCQ), Physical Activity Scale of the Elderly (PASE) and cardiopulmonary exercise testing (CPET) results were tabulated. Cluster phenogroups were identified., Results: Among 691 study participants (mean age 67.4 years; 50% were female), mean duration of type 2 diabetes mellitus (T2DM) was 14.5 years. The median (Q1, Q3) N-terminal pro-B type natriuretic peptide and high sensitivity cardiac troponin T were 71 (35, 135) ng/L and 9 [6, 12] ng/L. The most common echocardiographic abnormalities were reduced global longitudinal strain in 25.3% and impaired diastolic relaxation in 17.7%. Despite rather well-preserved KCCQ scores the average PASE score was markedly impaired at 155 accompanied by an average maximal oxygen consumption of 15.7 mL/Kg/minute on CPET. In K-means clustering, 4 phenogroups were identified including a higher-risk group with more advanced age, greater elevation of cardiac biomarkers, and more prevalent evidence for diastolic dysfunction and left ventricular hypertrophy., Conclusions: Baseline data from the ARISE-HF Trial provide clinical characterization of individuals with T2DM and features of stage B HF, and may help clarify the diagnosis of DbCM., Trial Registration: ARISE-HF, NCT04083339., (© 2024. The Author(s).)

Aims: Cardiovascular risk assessment beyond traditional risk factors in subjects with prediabetes is not well-established. Here, we evaluated the utility of N-terminal pro-B-type natriuretic peptide (NT-proBNP) in predicting incident adverse cardiovascular outcomes in prediabetic subjects., Methods: NT-proBNP was analyzed in 3,235 stable subjects with prediabetes undergoing cardiovascular risk evaluation and followed for both 3-year major adverse cardiac events (MACE; death, myocardial infarction, stroke), and 5-year all-cause mortality., Results: Using Cox proportional hazard models, we found that plasma NT-proBNP was associated with incident (3-year) MACE risk (Q4 vs Q1, HR 6.04 [95%CI 4.17-8.76], P < 0.001) and 5-year mortality risk (HR 8.64 [95%CI 5.78-12.9], P < 0.001). These associations remained significant after adjustments for traditional cardiovascular risk factors, multiple indices of glycemic control, cardiovascular disease (CVD), left ventricular ejection fraction (LVEF), and medication (e.g. diuretic) use (adjusted HR for 3-year MACE 2.65 [95% CI 1.16-6.05], P < 0.05; and adjusted HR for 5-year mortality 3.45 [95% CI 1.42-8.39], P < 0.01). NT-proBNP significantly improved the clinical prognostic value (C-statistic, NRI, IDI) for both 3-year MACE and 5-year death when added to models., Conclusions: NT-proBNP independently predicts increased long-term MACE and mortality risks in prediabetic subjects, and may help identify those for whom more aggressive global preventive efforts are indicated., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Hazen reports being named as co-inventor on pending and issued patents held by the Cleveland Clinic relating to cardiovascular diagnostics and therapeutics. Dr. Hazen also reports being a paid consultant for Zehna Therapeutics, Inc., having received research funds from Zehna Therapeutics, Inc., and Roche Diagnostics, and being eligible to receive royalty payments for inventions or discoveries related to cardiovascular diagnostics or therapeutics from Cleveland HeartLab, a fully owned subsidiary of Quest Diagnostics, Zehna Therapeutics, Inc., and Procter & Gamble. Dr. Tang has served as a paid consultant for Sequana Medical AG, Cardiol Therapeutics Inc, Genomics plc, Zehna Therapeutics, Renovacor, WhiteSwell, Kiniksa, Boston Scientific, and CardiaTec Biosciences and received honoraria from Springer Nature and American Board of Internal Medicine, all unrelated to the present topic. The other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Dilated cardiomyopathy (DCM) can lead to advanced disease, defined herein as necessitating a durable left ventricular assist device or a heart transplant (LVAD/HT). DCM is known to have a genetic basis, but the association of rare variant genetics with advanced DCM has not been studied., Methods: We analyzed clinical and genetic sequence data from patients enrolled between 2016 and 2021 in the US multisite DCM Precision Medicine Study, which was a geographically diverse, multiracial, multiethnic cohort. Clinical evaluation included standardized patient interview and medical record query forms. DCM severity was classified into 3 groups: patients with advanced disease with LVAD/HT; patients with an implantable cardioverter defibrillator (ICD) only; or patients with no ICD or LVAD/HT. Rare variants in 36 DCM genes were classified as pathogenic or likely pathogenic or variants of uncertain significance. Confounding factors we considered included demographic characteristics, lifestyle factors, access to care, DCM duration, and comorbidities. Crude and adjusted associations between DCM severity and rare variant genetic findings were assessed using multinomial models with generalized logit link., Results: Patients' mean (SD) age was 51.9 (13.6) years; 42% were of African ancestry, 56% were of European ancestry, and 44% were female. Of 1198 patients, 347 had LVAD/HT, 511 had an ICD, and 340 had no LVAD/HT or ICD. The percentage of patients with pathogenic or likely pathogenic variants was 26.2%, 15.9%, and 15.0% for those with LVAD/HT, ICD only, or neither, respectively. After controlling for sociodemographic characteristics and comorbidities, patients with DCM with LVAD/HT were more likely than those without LVAD/HT or ICD to have DCM-related pathogenic or likely pathogenic rare variants (odds ratio, 2.3 [95% CI, 1.5-3.6]). The association did not differ by ancestry. Rare variant genetic findings were similar between patients with DCM with an ICD and those without LVAD/HT or ICD., Conclusions: Advanced DCM was associated with higher odds of rare variants in DCM genes adjudicated as pathogenic or likely pathogenic, compared with individuals with less severe DCM. This finding may help assess the risk of outcomes in management of patients with DCM and their at-risk family members., Registration: URL: https://www., Clinicaltrials: gov; Unique identifier: NCT03037632., Competing Interests: Disclosures None.

Purpose of Review: Heart failure with preserved ejection fraction (HFpEF) is a complex and heterogeneous condition of multiple causes, characterized by a clinical syndrome resulting from elevated left ventricular filling pressures, with an apparently unimpaired left ventricular systolic function. Although HFpEF has been long recognized as a distinct entity with significant morbidity for patients, its diagnosis remains challenging to this day. In recent years, few diagnostic algorithms have been postulated to aid in the identification of this condition. Invasive hemodynamic and metabolic evaluation is often warranted for the conclusive diagnosis and risk stratification of HFpEF, in patients presenting with undifferentiated DOE., Recent Findings: Rest and provoked hemodynamics remain the golden-standard diagnostic tool to unequivocally confirm the diagnosis of both established and incipient HFpEF, respectively. Cycle exercise hemodynamics is the paramount provocative maneuver to unveil this condition. Rapid saline loading does not offer a significant benefit over that of cycle exercise. Vasoactive agents can also uncover and confirm incipient HFpEF disease. The role of metabolic evaluation in patients presenting with idiopathic dyspnea on exertion (DOE) is of unparalleled value for those who have expertise in cardiopulmonary exercise test (CPET) interpretation; however, the average clinician who focuses solely on oxygen consumption will find it underwhelming. Invasive CPET stands alone as the ultimate diagnostic tool to discriminate between pulmonary, cardiovascular, and skeletal muscle disorders, and their respective contribution to DOE and exercise intolerance., Summary: Several hemodynamic and metabolic parameters have demonstrated not only strong diagnostic value, but also predictive power in HFpEF. Additionally, these diagnostic methods have given rise to several therapeutic interventions that are now part of our clinical armamentarium. Regrettably, due to the heterogeneity and multicausality of HFpEF, none of the targeted interventions have been so far successful in decreasing the mortality burden of this prevalent condition.

Background Left ventricular non-compaction remains a poorly described entity, which has led to challenges of overdiagnosis. We aimed to evaluate if the presence of a thin compacted myocardial layer portends poorer outcomes in individuals meeting cardiac magnetic resonance criteria for left ventricular non-compaction . Methods and Results This was an observational, retrospective cohort study involving individuals selected from the Cleveland Clinic Foundation cardiac magnetic resonance database (N=26 531). Between 2000 and 2018, 328 individuals ≥12 years, with left ventricular non-compaction or excessive trabeculations based on the cardiac magnetic resonance Petersen criteria were included. The cohort comprised 42% women, mean age 43 years. We assessed the predictive ability of myocardial thinning for the primary composite end point of major adverse cardiac events (composite of all-cause mortality, heart failure hospitalization, left ventricular assist device implantation/heart transplant, ventricular tachycardia, or ischemic stroke). At mean follow-up of 3.1 years, major adverse cardiac events occurred in 102 (31%) patients. After adjusting for comorbidities, the risk of major adverse cardiac events was nearly doubled in the presence of significant compacted myocardial thinning (hazard ratio [HR], 1.88 [95% CI, 1.18‒3.00]; P =0.016), tripled in the presence of elevated plasma B-type natriuretic peptide (HR, 3.29 [95% CI, 1.52‒7.11]; P =0.006), and increased by 5% for every 10-unit increase in left ventricular end-systolic volume (HR, 1.01 [95% CI, 1.00‒1.01]; P =0.041). Conclusions The risk of adverse clinical events is increased in the presence of significant compacted myocardial thinning, an elevated B-type natriuretic peptide or increased left ventricular dimensions. The combination of these markers may enhance risk assessment to minimize left ventricular non-compaction overdiagnosis whilst facilitating appropriate diagnoses in those with true disease.

Background: Prior study has demonstrated that transitioning patients in acutely decompensated heart failure with a low cardiac output directly from intravenous (i.v.) vasoactive (ie, vasodilators or inotropes) drugs to sacubitril-valsartan (S/V) can be done safely with tolerance to the 1-month follow-up. Here, we further characterize the hemodynamic impact of S/V after patients have been optimized on vasoactive therapy., Methods and Results: In a single-center, retrospective analysis, 25 patients with cardiac index of less than 2.2 L/min/m 2 were admitted to the cardiac intensive care unit and newly initiated on angiotensin receptor-neprilysin inhibitor therapy with the guidance of invasive hemodynamic monitoring. Hemodynamic data were gathered and compared upon cardiac intensive care unit admission, after optimization with i.v. vasoactive therapy, and after S/V initiation and weaning off i.v., Therapy: All patients who tolerated S/V (n = 20) were weaned off vasoactive medications before transfer out of cardiac intensive care unit. Patients maintained their significant improvement in cardiac index and reduction in SVR/PVR on transition from i.v. inotropic and vasodilator therapy to oral S/V. There was an increase in pulmonary artery pulsatility index with S/V therapy compared with the i.v. vasoactive phase of care., Conclusions: Patients in the cardiac intensive care unit can be successfully bridged from vasoactive i.v. therapy to oral S/V with sustained improvement in cardiac index garnered from vasoactive agents. We also observed improvement in the pulmonary artery pulsatility index and maintenance of left and right ventricular unloading with S/V. These encouraging findings merit further prospective study., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background We sought to determine whether mitochondrial DNA (mtDNA) content can be used as markers for 12 key phenotypes among cardiovascular disease patients, and whether these markers are valid across patients with diverse ancestries. Methods and Results DNA was collected from the peripheral blood of 996 cardiovascular disease patients at the Cleveland Clinic. The mtDNA copy number and DNA-level variation were assessed from whole-genome sequence. Patients were also ascertained retrospectively for histories of 10 clinical events, as well as for maximum stenosis and extent of disease at baseline. Self-reported race and maternal ancestry inferred from mtDNA sequence were recorded. MtDNA copy number and overall mtDNA rare variant load were significantly lower in patients with histories of various adverse clinical events, and mtDNA copy number was inversely correlated with extent of disease. Strong associations were also found between absence of rare variants in the genes MT -ATP6 and MT-COII and patient histories of hyperlipidemia and myocardial infarction, respectively. Importantly, associations were not ancestry dependent. Conclusions This study provides evidence that mtDNA copy number in circulation is associated with a variety of cardiovascular disease patient phenotypes. Results also suggest a protective role for some rare inherited mtDNA variants. Overall, the study supports the potential of mtDNA content and abundance as biomarkers in heart disease, in a manner that is valid across diverse ancestries.

Although most prevalent in elderly, myocardial infarction (MI) also affects younger adults. We sought to investigate baseline characteristics in young patients (<55 years) with MI using the National Inpatient Sample (NIS) database between 2004 and 2015. Multivariable logistic regression models were used to assess factors associated with acute myocardial infarction (AMI) in young patients. After multivariable analyses adjusted for age, sex, race, family history of atherosclerosis, body mass index (BMI), diabetes, hypertension, hyperlipidemia, chronic kidney disease, and current cigarette smoking; novel risk factors such as human immunodeficiency virus (HIV), systemic lupus erythematosus (SLE), and obstructive sleep apnea (OSA) were associated with a higher risk of developing an AMI in the young (adjusted OR for HIV 4.06; 95 CI 3.48-4.71, p < 0.001), (adjusted OR for SLE 2.12; 95 CI 1.89-2.39, p 0.04), and (adjusted OR for OSA 1.16; 95 CI 1.12-1.20, p < 0.001), respectively. Rheumatoid arthritis was associated with a lower risk of AMI (adjusted OR 0.83; 95 CI 0.76-0.89, p < 0.001). After multivariable analyses, cigarette smoking (adjusted OR 1.98; 95 CI 1.95-2.02, p < 0.001), obesity (adjusted OR 1.37; 95 CI 1.33-1.41, p = 0.003), hyperlipidemia (adjusted OR 1.07; 95 CI 1.04-1.08, p < 0.001) and a family history of CAD (adjusted OR 1.35; 95 CI 1.3-1.4, p < 0.001) were also associated with a higher risk of developing an AMI in the young. In conclusion, young patients with AMI have both traditional risk factors and non-traditional risk factors. In addition to traditional risk factors, close attention should be paid to emerging risk factors such as SLE, HIV and OSA., Competing Interests: The authors report no relationships that could be construed as a conflict of interest., (© 2020 The Author(s).)

Background: Studies examining the role of factor V Leiden among patients at higher risk of atherothrombotic events, such as those with established coronary heart disease (CHD), are lacking. Given that coagulation is involved in the thrombus formation stage on atherosclerotic plaque rupture, we hypothesized that factor V Leiden may be a stronger risk factor for atherothrombotic events in patients with established CHD., Methods: We performed an individual-level meta-analysis including 25 prospective studies (18 cohorts, 3 case-cohorts, 4 randomized trials) from the GENIUS-CHD (Genetics of Subsequent Coronary Heart Disease) consortium involving patients with established CHD at baseline. Participating studies genotyped factor V Leiden status and shared risk estimates for the outcomes of interest using a centrally developed statistical code with harmonized definitions across studies. Cox proportional hazards regression models were used to obtain age- and sex-adjusted estimates. The obtained estimates were pooled using fixed-effect meta-analysis. The primary outcome was composite of myocardial infarction and CHD death. Secondary outcomes included any stroke, ischemic stroke, coronary revascularization, cardiovascular mortality, and all-cause mortality., Results: The studies included 69 681 individuals of whom 3190 (4.6%) were either heterozygous or homozygous (n=47) carriers of factor V Leiden. Median follow-up per study ranged from 1.0 to 10.6 years. A total of 20 studies with 61 147 participants and 6849 events contributed to analyses of the primary outcome. Factor V Leiden was not associated with the combined outcome of myocardial infarction and CHD death (hazard ratio, 1.03 [95% CI, 0.92-1.16]; I 2 =28%; P -heterogeneity=0.12). Subgroup analysis according to baseline characteristics or strata of traditional cardiovascular risk factors did not show relevant differences. Similarly, risk estimates for the secondary outcomes including stroke, coronary revascularization, cardiovascular mortality, and all-cause mortality were also close to identity., Conclusions: Factor V Leiden was not associated with increased risk of subsequent atherothrombotic events and mortality in high-risk participants with established and treated CHD. Routine assessment of factor V Leiden status is unlikely to improve atherothrombotic events risk stratification in this population.

Familial hypercholesterolemia is an autosomal dominant disorder that affects the metabolism of low-density lipo-protein cholesterol (LDL-C) through mutations in the gene for LDL receptor ( LDLR ), and less commonly in those for apolipoprotein B ( APOB ), proprotein convertase subtili-sin-kexin type 9 ( PCSK9 ), and others. Patients with these mutations have elevated plasma levels of LDL-C and, as a result, an increased risk of atherosclerotic cardiovascular disease beginning in childhood, leading to significant risk of illness and death., (Copyright © 2020 The Cleveland Clinic Foundation. All Rights Reserved.)

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 pVO 2 (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/VCO 2 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 pVO 2 (r = -0.424, P = 0.00227) and positive correlations between ADMA and VE/VCO 2 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 (VO 2 /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., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: In a recent individual patient data meta-analysis, high-sensitivity troponin T (hs-TnT) emerged as robust predictor of prognosis in stable chronic heart failure (HF). In the same population, we compared the relative predictive performances of hs-TnT, N-terminal fraction of pro-B-type natriuretic peptide (NT-proBNP), hs-C-reactive protein (hs-CRP), and estimated glomerular filtration rate (eGFR) for prognosis., Methods and Results: 9289 patients (66 ± 12 years, 77% men, 85% LVEF <40%, 60% ischemic HF) were evaluated over a 2.4-year median follow-up. Median eGFR was 58 mL/min/1.73 m 2 (interquartile interval 46-70; n = 9220), hs-TnT 16 ng/L (8-20; n = 9289), NT-proBNP 1067 ng/L (433-2470; n = 8845), and hs-CRP 3.3 mg/L (1.4-7.8; n = 7083). In a model including all 3 biomarkers, only hs-TnT and NT-proBNP were independent predictors of all-cause and cardiovascular mortality and cardiovascular hospitalization. hs-TnT was a stronger predictor than NT-proBNP: for example, the risk for all-cause death increased by 54% per doubling of hs-TnT vs. 24% per doubling of NT-proBNP. eGFR showed independent prognostic value from both hs-TnT and NT-proBNP. The best hs-TnT and NT-proBNP cut-offs for the prediction of all-cause death increased progressively with declining renal function (eGFR ≥ 90: hs-TnT 13 ng/L and NT-proBNP 825 ng/L; eGFR < 30: hs-TnT 40 ng/L and NT-proBNP 4608 ng/L). Patient categorization according to these cut-offs effectively stratified patient prognosis across all eGFR classes., Conclusions: hs-TnT conveys independent prognostic information from NT-proBNP, while hs-CRP does not. Concomitant assessment of eGFR may further refine risk stratification. Patient classification according to hs-TnT and NT-proBNP cut-offs specific for the eGFR classes holds prognostic significance., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Objective: To compare the activity of high-density lipoprotein (HDL)-associated paraoxonase 1 (PON1) in patients with psoriasis (PsO) and patients with psoriatic arthritis (PsA), and to evaluate the association of PON1 activity with the extent of disease activity and severity of the cardiovascular disease (CVD) burden in these patients., Methods: Serum levels of paraoxonase and arylesterase activity (both measures of PON1 function in humans) were measured in patients with PsA (n = 198, 51.0% male) and patients with PsO (n = 145, 50.3% male) who were enrolled in a longitudinal psoriatic disease biorepository. Data on PsA disease activity (using the Disease Activity Score in 28 joints [DAS28], Clinical Disease Activity Index, and painful/swollen joint counts), preexistent CVD and CVD risk factors (including diabetes, dyslipidemia, hypertension, and smoking), Framingham Risk Scores for CVD, quality of life measures, and laboratory test findings (erythrocyte sedimentation rate, C-reactive protein level, and lipid profiles) were recorded., Results: Serum arylesterase activities were significantly lower in patients with PsO and patients with PsA (mean ± SD 111.1 ± 25.5 μmoles/minute/ml and 124.4 ± 33.4 μmoles/minute/ml, respectively) compared to healthy controls (144.3 ± 33.4 μmoles/minute/ml) (each P < 0.001 versus healthy controls). Serum arylesterase activity decreased in parallel with increasing levels of disease activity (DAS28 scores, P = 0.012), older age (P = 0.013), higher body mass index (P = 0.042), greater incidence of metabolic syndrome (P = 0.004) and hypertension (P = 0.014), and worsening Framingham Risk Scores (P = 0.001). However, no correlation was seen between serum arylesterase activity and the extent of disease activity or CVD burden in patients with PsO. Serum paraoxonase activity trended lower both in patients with PsO and in patients with PsA (each P = 0.073 versus healthy controls). However, no association was seen between serum paraoxonase activity and the extent of disease activity or CVD burden in either of the patient cohorts., Conclusion: PON1 activity is decreased in psoriatic diseases. In the PsA cohort, decreases in arylesterase activity correlated with increasing severity of joint disease and CVD burden. Arylesterase activity, as compared to paraoxonase activity, appeared to serve as a more sensitive predictor of preexisting CV risk factors in the PsA cohort. However, this correlation was not observed in the PsO population., (© 2018, American College of Rheumatology.)

Purpose of Review: Evidence that artificial intelligence (AI) is useful for predicting risk factors for hypertension and its management is emerging. However, we are far from harnessing the innovative AI tools to predict these risk factors for hypertension and applying them to personalized management. This review summarizes recent advances in the computer science and medical field, illustrating the innovative AI approach for potential prediction of early stages of hypertension. Additionally, we review ongoing research and future implications of AI in hypertension management and clinical trials, with an eye towards personalized medicine., Recent Findings: Although recent studies demonstrate that AI in hypertension research is feasible and possibly useful, AI-informed care has yet to transform blood pressure (BP) control. This is due, in part, to lack of data on AI's consistency, accuracy, and reliability in the BP sphere. However, many factors contribute to poorly controlled BP, including biological, environmental, and lifestyle issues. AI allows insight into extrapolating data analytics to inform prescribers and patients about specific factors that may impact their BP control. To date, AI has been mainly used to investigate risk factors for hypertension, but has not yet been utilized for hypertension management due to the limitations of study design and of physician's engagement in computer science literature. The future of AI with more robust architecture using multi-omics approaches and wearable technology will likely be an important tool allowing to incorporate biological, lifestyle, and environmental factors into decision-making of appropriate drug use for BP control.

Background: Rheumatoid arthritis (RA) patients are at high risk of developing cardiovascular disease (CVD). In RA, chronic inflammation may lead to endothelial dysfunction, an early indicator of CVD, owing to diminished nitric oxide (NO) production. Because L-arginine is the sole precursor of NO, we hypothesized that levels of L-arginine metabolic products reflecting NO metabolism are altered in patients with RA., Methods: Plasma samples from patients with RA (n = 119) and age- and sex-matched control subjects (n = 238) were used for this study. Using LC-MS/MS, we measured plasma levels of free L-arginine, L-ornithine, L-citrulline, L-N G -monomethyl arginine (MMA), asymmetric dimethylarginine (ADMA), and symmetric dimethylarginine (SDMA). We compared global arginine bioavailability ratio (GABR) (i.e., ratio of L-arginine to L-ornithine + L-citrulline) and arginine methylation index (ArgMI) (i.e., ADMA + SDMA/MMA) in patients with RA vs. control subjects. Plasma arginase activity was measured using a sensitive arginase assay kit. The relationship of L-arginine metabolites and arginase activity to CVD risk factors was evaluated using Pearson's chi-square test., Results: Compared with healthy control subjects, the RA cohort showed significantly lower levels of plasma L-arginine (46.11 ± 17.29 vs. 74.2 ± 22.53 μmol/L, p < 0.001) and GABR (0.36 ± 0.16 vs. 0.73 ± 0.24, p < 0.001), elevated levels of ADMA (0.76 ± 0.12 vs. 0.62 ± 0.12 μmol/L, p < 0.001), SDMA (0.54 ± 0.14 vs. 0.47 ± 0.13 μmol/L, p < 0.001), and ArgMI (6.51 ± 1.86 vs. 5.54 ± 1.51, p < 0.001). We found an approximately fourfold increase in arginase activity (33.8 ± 1.1 vs. 8.4 ± 0.8 U/L, p < 0.001), as well as elevated levels of arginase-mediated L-arginine catalytic product L-ornithine (108.64 ± 30.26 vs. 69.3 ± 20.71 μmol/L, p < 0.001), whereas a nitric oxide synthase (NOS) catalytic product, the L-citrulline level, was diminished in RA (30.32 ± 9.93 vs. 36.17 ± 11.64 μmol/L, p < 0.001). Patients with RA with existing CVD had higher arginase activity than patients with RA without CVD (p = 0.048)., Conclusions: Global L-arginine bioavailability was diminished, whereas plasma arginase activity, ADMA, and SDMA levels were elevated, in patients with RA compared with healthy control subjects. Plasma SDMA was associated with hypertension and hyperlipidemia in patients with RA. This dysregulated L-arginine metabolism may function as a potential indicator of CVD risk in patients with RA.

Purpose of Review: This review illustrates the dynamic role of palliative care in heart failure management and encapsulates the commonly utilized pharmacologic and non-pharmacologic therapeutic strategies for symptom palliation in heart failure. In addition, we provide our experience regarding patient care issues common to the domain of heart failure and palliative medicine which are commonly encountered by heart failure teams., Recent Findings: Addition of palliative care to conventional heart failure management plan results in improvement in quality of life, anxiety, depression, and spiritual well-being among patients. Palliative care should not be confused with hospice care. Palliative care teams should be involved early in the care of heart failure patients with the aims of improving symptom palliation, discussing goals of care and improving quality of life without compromising utilization of evidence-based heart failure therapies. A consensus on the appropriate timing of involvement and evidence for many symptom palliation therapies is still emerging.

As the population ages and our ability to care for patients with cardiac disease improves, an increasing number of passengers with cardiovascular conditions will be traveling long distances. Many have had cardiac symptoms, recent interventions, devices, or surgery. Air travel is safe for most individuals with stable cardiovascular disease. However, a thorough understanding of the physiologic changes during air travel is essential given the potential impact on cardiovascular health and the risk of complications in passengers with preexisting cardiac conditions. It is important for clinicians to be aware of the current recommendations and precautions that need to be taken before and during air travel for passengers with cardiovascular concerns., (© 2017 Wiley Periodicals, Inc.)

Background: Loop diuretic resistance is a common barrier to effective decongestion in acute heart failure (AHF), and is associated with poor outcome. Specific mechanisms underlying diuretic resistance are currently unknown in contemporary AHF patients. We therefore aimed to determine the relative importance of defects in diuretic delivery vs. renal tubular response in determining diuretic response (DR) in AHF., Methods and Results: Fifty AHF patients treated with intravenous bumetanide underwent a 6-h timed urine collection for sodium and bumetanide clearance. Whole-kidney DR was defined as sodium excreted per doubling of administered loop diuretic and represents the sum of defects in drug delivery and renal tubular response. Tubular DR, defined as sodium excreted per doubling of renally cleared (urinary) loop diuretic, captures resistance specifically in the renal tubule. Median administered bumetanide dose was 3.0 (2.0-4.0) mg with 52 (33-77)% of the drug excreted into the urine. Significant between-patient variability was present as the administered dose only explained 39% of variability in the quantity of bumetanide in urine. Cumulatively, factors related to drug delivery such as renal bumetanide clearance, administered dose, and urea clearance explained 28% of the variance in whole-kidney DR. However, resistance at the level of the renal tubule (tubular DR) explained 71% of the variability in whole-kidney DR., Conclusion: Defects at the level of the renal tubule are substantially more important than reduced diuretic delivery in determining diuretic resistance in patients with AHF., (© 2017 The Authors. European Journal of Heart Failure © 2017 European Society of Cardiology.)

Background: Multiple definitions of reverse ventricular remodeling (RVR) employing various changes in left ventricular end-systolic (LVESV) or diastolic volumes (LVEDVs) or left ventricular ejection fraction (LVEF) have been used in determining cardiac resynchronization therapy (CRT) response, making comparability across studies difficult. We compared different metrics to each other, and in combination, in terms of association with long-term outcomes., Methods: We collected clinical and echocardiographic data on 436 patients undergoing CRT. LVEF was assessed via a combined volumetric and visual assessment. Volumes were manually traced. Using a nested multivariate model of a priori determined predictors of long-term survival free of left ventricular assist device (LVAD) or heart transplant, multiple definitions of RVR were added to the model individually to determine which provided the best model fit., Results: Over a mean follow-up of 5.4 ± 2.3 years, there were 198 endpoints (10 LVADs, 15 heart transplants, and 173 deaths). When added to a nested model controlling for multiple potential confounders, all definitions of RVR were significantly associated with improved survival. Changes in LVEF and LVESV were superior to changes in LVEDV. A combination metric of an LVEF improvement ≥ 5% and LVESV reduction ≥ 10% was the best overall metric for model fit., Conclusions: Changes in LVESV and LVEF are better predictors of long-term outcome following CRT compared to changes in LVEDV. Adding an assessment of LVEF to reduction in LVESV ≥ 10% provided the best overall definition for RVR in predicting CRT outcomes., (© 2017 Wiley Periodicals, Inc.)