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Pulmonary hypertension (PH) is a rare and severe condition characterized by increased pressure in the pulmonary circulation, often resulting in right ventricular failure and death. The autonomic nervous system (ANS) plays a crucial role in the cardiovascular and pulmonary controls. Dysfunction of ANS has been implicated in the pathogenesis of cardiopulmonary diseases. Conversely, dysfunctions in ANS can arise from these diseases, impacting cardiac and pulmonary autonomic functions and contributing to disease progression. The complex interaction between ANS dysfunction and PH plays a crucial role in the disease progression, making it essential to explore interventions that modulate ANS, such as physical exercise, to improve the treatment and prognosis of patients with PH. This review addresses autonomic dysfunctions found in PH and their implications for the cardiopulmonary system. Furthermore, we discuss how physical exercise, a significant modulator of ANS, may contribute to the prognosis of PH. Drawing from evidence of aerobic and resistance exercise training in patients and experimental models of PH, potential cardiovascular benefits of exercise are presented. Finally, we highlight emerging therapeutic targets and perspectives to better cope with the complex condition. A comprehensive understanding of the interaction between ANS and PH, coupled with targeted physical exercise interventions, may pave the way for innovative therapeutic strategies and significantly improve the treatment and prognosis of vulnerable patients. [ABSTRACT FROM AUTHOR]

This research letter discusses the role of junctophilin-2 (JPH2) in regulating mitochondrial metabolism and its potential impact on right ventricular dysfunction (RVD). RVD is a risk factor for death in various cardiovascular diseases, but effective therapies are lacking. JPH2 is an essential protein involved in calcium handling and maintaining the structure of cardiomyocytes. It may also play a role in mitochondrial function. The study found that JPH2 interacts with a mitochondrial protein called MFN2 and that impaired mitochondrial metabolism contributes to RVD. The findings suggest that targeting JPH2 could potentially improve outcomes in cardiac conditions associated with RVD. [Extracted from the article]

With continued medical and surgical advancements, most children and adolescents with congenital heart disease are expected to survive to adulthood. Chronic heart failure is increasingly being recognized as a major contributor to ongoing morbidity and mortality in this population as it ages, and treatment strategies to prevent and treat heart failure in the pediatric population are needed. In addition to primary myocardial dysfunction, anatomical and pathophysiological abnormalities specific to various congenital heart disease lesions contribute to the development of heart failure and affect potential strategies commonly used to treat adult patients with heart failure. This scientific statement highlights the significant knowledge gaps in understanding the epidemiology, pathophysiology, staging, and outcomes of chronic heart failure in children and adolescents with congenital heart disease not amenable to catheter-based or surgical interventions. Efforts to harmonize the definitions, staging, follow-up, and approach to heart failure in children with congenital heart disease are critical to enable the conduct of rigorous scientific studies to advance our understanding of the actual burden of heart failure in this population and to allow the development of evidence-based heart failure therapies that can improve outcomes for this high-risk cohort. [ABSTRACT FROM AUTHOR]

BACKGROUND: Artificial intelligence–enhanced ECG analysis shows promise to detect ventricular dysfunction and remodeling in adult populations. However, its application to pediatric populations remains underexplored. METHODS: A convolutional neural network was trained on paired ECG–echocardiograms (≤2 days apart) from patients ≤18 years of age without major congenital heart disease to detect human expert–classified greater than mild left ventricular (LV) dysfunction, hypertrophy, and dilation (individually and as a composite outcome). Model performance was evaluated on single ECG–echocardiogram pairs per patient at Boston Children’s Hospital and externally at Mount Sinai Hospital using area under the receiver operating characteristic curve (AUROC) and area under the precision-recall curve (AUPRC). RESULTS: The training cohort comprised 92377 ECG–echocardiogram pairs (46261 patients; median age, 8.2 years). Test groups included internal testing (12631 patients; median age, 8.8 years; 4.6% composite outcomes), emergency department (2830 patients; median age, 7.7 years; 10.0% composite outcomes), and external validation (5088 patients; median age, 4.3 years; 6.1% composite outcomes) cohorts. Model performance was similar on internal test and emergency department cohorts, with model predictions of LV hypertrophy outperforming the pediatric cardiologist expert benchmark. Adding age and sex to the model added no benefit to model performance. When using quantitative outcome cutoffs, model performance was similar between internal testing (composite outcome: AUROC, 0.88, AUPRC, 0.43; LV dysfunction: AUROC, 0.92, AUPRC, 0.23; LV hypertrophy: AUROC, 0.88, AUPRC, 0.28; LV dilation: AUROC, 0.91, AUPRC, 0.47) and external validation (composite outcome: AUROC, 0.86, AUPRC, 0.39; LV dysfunction: AUROC, 0.94, AUPRC, 0.32; LV hypertrophy: AUROC, 0.84, AUPRC, 0.25; LV dilation: AUROC, 0.87, AUPRC, 0.33), with composite outcome negative predictive values of 99.0% and 99.2%, respectively. Saliency mapping highlighted ECG components that influenced model predictions (precordial QRS complexes for all outcomes; T waves for LV dysfunction). High-risk ECG features include lateral T-wave inversion (LV dysfunction), deep S waves in V1 and V2 and tall R waves in V6 (LV hypertrophy), and tall R waves in V4 through V6 (LV dilation). CONCLUSIONS: This externally validated algorithm shows promise to inexpensively screen for LV dysfunction and remodeling in children, which may facilitate improved access to care by democratizing the expertise of pediatric cardiologists. [ABSTRACT FROM AUTHOR]

Atrial cardiomyopathy is a condition that causes electrical and contractile dysfunction of the atria, often along with structural and functional changes. Atrial cardiomyopathy most commonly occurs in conjunction with ventricular dysfunction, in which case it is difficult to discern the atrial features that are secondary to ventricular dysfunction from those that arise as a result of primary atrial abnormalities. Isolated atrial cardiomyopathy (atrial-selective cardiomyopathy [ASCM], with minimal or no ventricular function disturbance) is relatively uncommon and has most frequently been reported in association with deleterious rare genetic variants. The genes involved can affect proteins responsible for various biological functions, not necessarily limited to the heart but also involving extracardiac tissues. Atrial enlargement and atrial fibrillation are common complications of ASCM and are often the predominant clinical features. Despite progress in identifying disease-causing rare variants, an overarching understanding and approach to the molecular pathogenesis, phenotypic spectrum, and treatment of genetic ASCM is still lacking. In this review, we aim to analyze the literature relevant to genetic ASCM to understand the key features of this rather rare condition, as well as to identify distinct characteristics of ASCM and its arrhythmic complications that are related to specific genotypes. We outline the insights that have been gained using basic research models of genetic ASCM in vitro and in vivo and correlate these with patient outcomes. Finally, we provide suggestions for the future investigation of patients with genetic ASCM and improvements to basic scientific models and systems. Overall, a better understanding of the genetic underpinnings of ASCM will not only provide a better understanding of this condition but also promises to clarify our appreciation of the more commonly occurring forms of atrial cardiomyopathy associated with ventricular dysfunction. [ABSTRACT FROM AUTHOR]

BACKGROUND: Left ventricular dysfunction in potential donors meeting brain death criteria often results in nonuse of donor hearts for transplantation, yet little is known about its incidence or pathophysiology. Resolving these unknowns was a primary aim of the DHS (Donor Heart Study), a multisite prospective cohort study. METHODS: The DHS enrolled potential donors by neurologic determination of death (n=4333) at 8 organ procurement organizations across the United States between February 2015 and May 2020. Data included medications administered, serial diagnostic tests, and transthoracic echocardiograms (TTEs) performed: (1) within 48 hours after brain death was formally diagnosed; and (2) 24±6 hours later if left ventricular (LV) dysfunction was initially present. LV dysfunction was defined as an LV ejection fraction <50% and was considered reversible if LV ejection fraction was >50% on the second TTE. TTEs were also examined for presence of LV regional wall motion abnormalities and their reversibility. We assessed associations between LV dysfunction, donor heart acceptance for transplantation, and recipient 1-year survival. RESULTS: An initial TTE was interpreted for 3794 of the 4333 potential donors by neurologic determination of death. A total of 493 (13%) of these TTEs showed LV dysfunction. Among those donors with an initial TTE, LV dysfunction was associated with younger age, underweight, and higher NT-proBNP (N-terminal pro-B-type natriuretic peptide) and troponin levels. A second TTE was performed within 24±6 hours for a subset of donors (n=224) with initial LV dysfunction; within this subset, 130 (58%) demonstrated reversibility. Sixty percent of donor hearts with normal LV function were accepted for transplant compared with 56% of hearts with reversible LV dysfunction and 24% of hearts with nonreversible LV dysfunction. Donor LV dysfunction, whether reversible or not, was not associated with recipient 1-year survival. CONCLUSIONS: LV dysfunction associated with brain death occurs in many potential heart donors and is sometimes reversible. These findings can inform decisions made during donor evaluation and help guide donor heart acceptance for transplantation. [ABSTRACT FROM AUTHOR]

Chronic right ventricular (RV) pacing is an often-unrecognized cause of cardiomyopathy, despite research that has revealed that chronic RV pacing can cause significant cardiomyopathy and heart failure, leading causes of hospitalization in the United States. Studies have found that chronic RV apical pacing results in ventricular dyssynchrony, reduced cardiac function, and heart failure. This article describes the deleterious effects of permanent cardiac pacemakers and their association with cardiomyopathy and heart failure. More research is needed to investigate other forms of pacing and treatment to prevent ventricular dyssynchrony and myocardial remodeling. [ABSTRACT FROM AUTHOR]

BACKGROUND: Left ventricular (LV) systolic dysfunction is associated with a >8-fold increased risk of heart failure and a 2-fold risk of premature death. The use of ECG signals in screening for LV systolic dysfunction is limited by their availability to clinicians. We developed a novel deep learning-based approach that can use ECG images for the screening of LV systolic dysfunction. METHODS: Using 12-lead ECGs plotted in multiple different formats, and corresponding echocardiographic data recorded within 15 days from the Yale New Haven Hospital between 2015 and 2021, we developed a convolutional neural network algorithm to detect an LV ejection fraction <40%. The model was validated within clinical settings at Yale New Haven Hospital and externally on ECG images from Cedars Sinai Medical Center in Los Angeles, CA; Lake Regional Hospital in Osage Beach, MO; Memorial Hermann Southeast Hospital in Houston, TX; and Methodist Cardiology Clinic of San Antonio, TX. In addition, it was validated in the prospective Brazilian Longitudinal Study of Adult Health. Gradient-weighted class activation mapping was used to localize class-discriminating signals on ECG images. RESULTS: Overall, 385 601 ECGs with paired echocardiograms were used for model development. The model demonstrated high discrimination across various ECG image formats and calibrations in internal validation (area under receiving operation characteristics [AUROCs], 0.91; area under precision-recall curve [AUPRC], 0.55); and external sets of ECG images from Cedars Sinai (AUROC, 0.90 and AUPRC, 0.53), outpatient Yale New Haven Hospital clinics (AUROC, 0.94 and AUPRC, 0.77), Lake Regional Hospital (AUROC, 0.90 and AUPRC, 0.88), Memorial Hermann Southeast Hospital (AUROC, 0.91 and AUPRC 0.88), Methodist Cardiology Clinic (AUROC, 0.90 and AUPRC, 0.74), and Brazilian Longitudinal Study of Adult Health cohort (AUROC, 0.95 and AUPRC, 0.45). An ECG suggestive of LV systolic dysfunction portended >27-fold higher odds of LV systolic dysfunction on transthoracic echocardiogram (odds ratio, 27.5 [95% CI, 22.3-33.9] in the held-out set). Class-discriminative patterns localized to the anterior and anteroseptal leads (V2 and V3), corresponding to the left ventricle regardless of the ECG layout. A positive ECG screen in individuals with an LV ejection fraction =40% at the time of initial assessment was associated with a 3.9-fold increased risk of developing incident LV systolic dysfunction in the future (hazard ratio, 3.9 [95% CI, 3.3-4.7]; median follow-up, 3.2 years). CONCLUSIONS: We developed and externally validated a deep learning model that identifies LV systolic dysfunction from ECG images. This approach represents an automated and accessible screening strategy for LV systolic dysfunction, particularly in low-resource settings. [ABSTRACT FROM AUTHOR]

BACKGROUND: The development of left ventricular systolic dysfunction (LVSD) in hypertrophic cardiomyopathy (HCM) is rare but serious and associated with poor outcomes in adults. Little is known about the prevalence, predictors, and prognosis of LVSD in patients diagnosed with HCM as children. METHODS: Data from patients with HCM in the international, multicenter SHaRe (Sarcomeric Human Cardiomyopathy Registry) were analyzed. LVSD was defined as left ventricular ejection fraction <50% on echocardiographic reports. Prognosis was assessed by a composite of death, cardiac transplantation, and left ventricular assist device implantation. Predictors of developing incident LVSD and subsequent prognosis with LVSD were assessed using Cox proportional hazards models. RESULTS: We studied 1010 patients diagnosed with HCM during childhood (<18 years of age) and compared them with 6741 patients with HCM diagnosed as adults. In the pediatric HCM cohort, median age at HCM diagnosis was 12.7 years (interquartile range, 8.0–15.3), and 393 (36%) patients were female. At initial SHaRe site evaluation, 56 (5.5%) patients with childhood-diagnosed HCM had prevalent LVSD, and 92 (9.1%) developed incident LVSD during a median follow-up of 5.5 years. Overall LVSD prevalence was 14.7% compared with 8.7% in patients with adult-diagnosed HCM. Median age at incident LVSD was 32.6 years (interquartile range, 21.3–41.6) for the pediatric cohort and 57.2 years (interquartile range, 47.3–66.5) for the adult cohort. Predictors of developing incident LVSD in childhood-diagnosed HCM included age <12 years at HCM diagnosis (hazard ratio [HR], 1.72 [CI, 1.13–2.62), male sex (HR, 3.1 [CI, 1.88–5.2), carrying a pathogenic sarcomere variant (HR, 2.19 [CI, 1.08–4.4]), previous septal reduction therapy (HR, 2.34 [CI, 1.42–3.9]), and lower initial left ventricular ejection fraction (HR, 1.53 [CI, 1.38–1.69] per 5% decrease). Forty percent of patients with LVSD and HCM diagnosed during childhood met the composite outcome, with higher rates in female participants (HR, 2.60 [CI, 1.41–4.78]) and patients with a left ventricular ejection fraction <35% (HR, 3.76 [2.16–6.52]). CONCLUSIONS: Patients with childhood-diagnosed HCM have a significantly higher lifetime risk of developing LVSD, and LVSD emerges earlier than for patients with adult-diagnosed HCM. Regardless of age at diagnosis with HCM or LVSD, the prognosis with LVSD is poor, warranting careful surveillance for LVSD, especially as children with HCM transition to adult care. [ABSTRACT FROM AUTHOR]

BACKGROUND: Coronary artery bypass grafting (CABG) is the recommended mode of revascularization in patients with ischemic left ventricular dysfunction (iLVSD) and multivessel disease. However, contemporary percutaneous coronary intervention (PCI) outcomes have improved with the integration of novel technologies and refinement of revascularization strategies, and PCI is often used in clinical practice in this population. There is a lack of evidence from randomized trials comparing contemporary state-of-the-art PCI versus CABG for the treatment of iLVSD and multivessel disease. This was the impetus for the STICH3C trial (Canadian CABG or PCI in Patients With Ischemic Cardiomyopathy), described here. METHODS: The STICH3C trial is a prospective, unblinded, international, multicenter trial with an expected sample size of 754 participants from -45 centers. Patients with multivessel/left main coronary artery disease and iLVSD with left ventricular ejection fraction =40% considered by the local Heart Team appropriate for and amenable to revascularization by both modes of revascularization will be randomized in a 1:1 ratio to state-of-the-art PCI or CABG. RESULTS: The primary end point is the composite of death from any cause, stroke, spontaneous myocardial infarction, urgent repeat revascularization, or heart failure readmission, summarized as a time-to-event outcome. The key hierarchical end point is time to death and frequency of hospitalizations for heart failure. The key safety outcome is a composite of major adverse events. Disease-specific quality-of-life and health economics measures will be compared between groups. Participants will be followed for a median of 5 years, with a minimum follow-up of 4 years. CONCLUSIONS: STICH3C will directly inform patients, clinicians, and international practice guidelines about the efficacy and safety of CABG versus PCI in patients with iLVSD. The results will provide novel and broad evidence, including clinical events, health status, and economic assessments, to guide care for patients with iLVSD and severe coronary artery disease. [ABSTRACT FROM AUTHOR]

BACKGROUND: Tricuspid regurgitation (TR) is common in chronic heart failure (HF) and is associated with negative prognosis. However, evidence on prognostic implications of TR in acute HF is lacking. We sought to investigate the association between TR and mortality and the interaction with pulmonary hypertension (PH) in patients admitted for acute HF. METHODS: We enrolled 1176 consecutive patients with a primary diagnosis of acute HF and with available noninvasive estimation of TR and pulmonary arterial systolic pressure. RESULTS: Moderate-severe TR was present in 352 patients (29.9%) and was associated with older age and more comorbidities. The prevalence of PH (ie, pulmonary arterial systolic pressure >40 mm Hg), right ventricular dysfunction, and mitral regurgitation was higher in moderate-severe TR. At 1 year, 184 (15.6%) patients died. Moderate-severe TR was associated with higher 1-year mortality risk after adjustment for other echocardiographic parameters (pulmonary arterial systolic pressure, left ventricle ejection fraction, right ventricular dysfunction, mitral regurgitation, left and right atrial indexed volumes; hazard ratio, 1.718; P =0.009), and the association with outcome was maintained when clinical variables (eg, natriuretic peptides, serum creatinine and urea, systolic blood pressure, atrial fibrillation) were added to the multivariable model (hazard ratio, 1.761; P =0.024). The association between moderate-severe TR and outcome was consistent in patients with versus without PH, with versus without right ventricular dysfunction, and with versus without left ventricle ejection fraction <50%. Patients with coexistent moderate-severe TR and PH had 3-fold higher 1-year mortality risk compared with patients with no TR or PH (hazard ratio, 3.024; P <0.001). CONCLUSIONS: In patients hospitalized for acute HF, the severity of TR is associated with 1-year survival, regardless of the presence of PH. The coexistence of moderate-severe TR and estimated PH was associated with a further increase in mortality risk. Our data must be interpreted in the context of potential underestimation of pulmonary arterial systolic pressure in patients with severe TR. [ABSTRACT FROM AUTHOR]

Background: Cardiac-specific myosin light chain kinase (cMLCK), encoded by MYLK3 , regulates cardiac contractility through phosphorylation of ventricular myosin regulatory light chain. However, the pathophysiological and therapeutic implications of cMLCK in human heart failure remain unclear. We aimed to investigate whether cMLCK dysregulation causes cardiac dysfunction and whether the restoration of cMLCK could be a novel myotropic therapy for systolic heart failure. Methods: We generated the knock-in mice (Mylk3 +/fs and Mylk 3fs/fs) with a familial dilated cardiomyopathy–associated MYLK3 frameshift mutation (MYLK3 +/fs) that had been identified previously by us (c.1951-1G>T; p.P639Vfs*15) and the human induced pluripotent stem cell–derived cardiomyocytes from the carrier of the mutation. We also developed a new small-molecule activator of cMLCK (LEUO-1154). Results: Both mice (Mylk3 +/fs and Mylk 3fs/fs) showed reduced cMLCK expression due to nonsense-mediated messenger RNA decay, reduced MLC2v (ventricular myosin regulatory light chain) phosphorylation in the myocardium, and systolic dysfunction in a cMLCK dose–dependent manner. Consistent with this result, myocardium from the mutant mice showed an increased ratio of cardiac superrelaxation/disordered relaxation states that may contribute to impaired cardiac contractility. The phenotypes observed in the knock-in mice were rescued by cMLCK replenishment through the AAV9_ MYLK3 vector. Human induced pluripotent stem cell–derived cardiomyocytes with MYLK3+/fs mutation reduced cMLCK expression by 50% and contractile dysfunction, accompanied by an increased superrelaxation/disordered relaxation ratio. CRISPR-mediated gene correction, or cMLCK replenishment by AAV9_ MYLK3 vector, successfully recovered cMLCK expression, the superrelaxation/disordered relaxation ratio, and contractile dysfunction. LEUO-1154 increased human cMLCK activity ≈2-fold in the V max for ventricular myosin regulatory light chain phosphorylation without affecting the K m. LEUO-1154 treatment of human induced pluripotent stem cell–derived cardiomyocytes with MYLK3+/fs mutation restored the ventricular myosin regulatory light chain phosphorylation level and superrelaxation/disordered relaxation ratio and improved cardiac contractility without affecting calcium transients, indicating that the cMLCK activator acts as a myotrope. Finally, human myocardium from advanced heart failure with a wide variety of causes had a significantly lower MYLK3 / PPP1R12B messenger RNA expression ratio than control hearts, suggesting an altered balance between myosin regulatory light chain kinase and phosphatase in the failing myocardium, irrespective of the causes. Conclusions: cMLCK dysregulation contributes to the development of cardiac systolic dysfunction in humans. Our strategy to restore cMLCK activity could form the basis of a novel myotropic therapy for advanced systolic heart failure. [ABSTRACT FROM AUTHOR]

Pulmonary hypertension, defined as an elevation in blood pressure in the pulmonary arteries, is associated with an increased risk of death. The prevalence of pulmonary hypertension is increasing, with an aging population, a rising prevalence of heart and lung disease, and improved pulmonary hypertension survival with targeted therapies. Patients with pulmonary hypertension frequently require noncardiac surgery, although pulmonary hypertension is associated with excess perioperative morbidity and death. This scientific statement provides guidance on the evaluation and management of pulmonary hypertension in patients undergoing noncardiac surgery. We advocate for a multistep process focused on (1) classification of pulmonary hypertension group to define the underlying pathology; (2) preoperative risk assessment that will guide surgical decision-making; (3) pulmonary hypertension optimization before surgery to reduce perioperative risk; (4) intraoperative management of pulmonary hypertension to avoid right ventricular dysfunction and to maintain cardiac output; and (5) postoperative management of pulmonary hypertension to ensure recovery from surgery. Last, this scientific statement highlights the paucity of evidence to support perioperative pulmonary hypertension management and identifies areas of uncertainty and opportunities for future investigation. [ABSTRACT FROM AUTHOR]

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiac disease characterized by fibrofatty replacement of myocardial tissue and is an important cause of ventricular dysrhythmias, ventricular dysfunction, and sudden cardiac death. The clinical course and genetics of this condition are highly variable, and definitive diagnosis can be challenging, despite published diagnostic criteria. Recognizing symptoms and risk factors for ventricular dysrhythmias is key to managing affected patients and family members. High-intensity and endurance exercise is widely known to increase disease expression and progression; however, a safe exercise regimen remains uncertain, and a personalized approach to management should be considered. This article reviews the incidence, pathophysiology, diagnostic criteria, and treatment considerations for ARVC. [ABSTRACT FROM AUTHOR]

Hypertrophic cardiomyopathy (HCM) is a genetic autosomal dominant disorder of the heart muscle that is characterized by left ventricular hypertrophy and sudden cardiac death. It is the most common inherited cardiac disease. HCM is defined by sarcomeric mutations that result in fibrosis of the heart, affecting contraction. In most cases, clinical presentations can range from asymptomatic to systolic and diastolic ventricular dysfunction, arrhythmias, and sudden cardiac death. Some histopathologic features typical of the disease are changes in myocyte disarray and myocardial fibrosis. Mutations in the β-myosin heavy chain and myosin-binding protein C have been identified as the cause of the disease. The goals of pharmacological therapy as well as nonpharmacological therapy are to alleviate the symptoms and to prevent sudden cardiac death. Anatomical defects are treated primarily by surgical intervention, whereas other issues such as hypercontractility are treated with pharmacotherapy. In this article, we review the pathophysiology and treatment options for HCM. [ABSTRACT FROM AUTHOR]

Seven patients (16%) had nonspecific ST-segments or T-wave abnormalities, 9 patients (20%) had LV hypertrophy, and 2 patients (5%) had a prolonged QTc interval. Two patients (5%) had nonspecific ST-segment or T-wave abnormalities, 7 patients (16%) had LV hypertrophy, and 1 patient had an intraventricular conduction abnormality. Keywords: disease progression; progeria; ventricular dysfunction; left EN disease progression progeria ventricular dysfunction left 1782 1784 3 06/02/23 20230606 NES 230606 Hutchinson-Gilford Progeria syndrome (HGPS) is an ultrarare systemic disorder that causes accelerated aging and premature death, often due to cardiovascular disease.[1],[2] Because of its rarity, the characterization of cardiac abnormalities has been limited to cross-sectional assessment of small cohorts, and data on the progression of these abnormalities are lacking.[3] As a follow-up to our previous cross-sectional report, we evaluated longitudinal changes in cardiac abnormalities in patients with HGPS. [Extracted from the article]

BACKGROUND: It remains unknown to what extent intrinsic atrial cardiomyopathy or left ventricular diastolic dysfunction drive atrial remodeling and functional failure in heart failure with preserved ejection fraction (HFpEF). Computational 3-dimensional (3D) models fitted to cardiovascular magnetic resonance allow state-of-the-art anatomic and functional assessment, and we hypothesized to identify a phenotype linked to HFpEF. METHODS: Patients with exertional dyspnea and diastolic dysfunction on echocardiography (E/e', >8) were prospectively recruited and classified as HFpEF or noncardiac dyspnea based on right heart catheterization. All patients underwent rest and exercise-stress right heart catheterization and cardiovascular magnetic resonance. Computational 3D anatomic left atrial (LA) models were generated based on short-axis cine sequences. A fully automated pipeline was developed to segment cardiovascular magnetic resonance images and build 3D statistical models of LA shape and find the 3D patterns discriminant between HFpEF and noncardiac dyspnea. In addition, atrial morphology and function were quantified by conventional volumetric analyses and deformation imaging. A clinical follow-up was conducted after 24 months for the evaluation of cardiovascular hospitalization. RESULTS: Beyond atrial size, the 3D LA models revealed roof dilation as the main feature found in masked HFpEF (diagnosed during exercise-stress only) preceding a pattern shift to overall atrial size in overt HFpEF (diagnosed at rest). Characteristics of the 3D model were integrated into the LA HFpEF shape score, a biomarker to characterize the gradual remodeling between noncardiac dyspnea and HFpEF. The LA HFpEF shape score was able to discriminate HFpEF (n=34) to noncardiac dyspnea (n=34; area under the curve, 0.81) and was associated with a risk for atrial fibrillation occurrence (hazard ratio, 1.02 [95% CI, 1.01-1.04]; P=0.003), as well as cardiovascular hospitalization (hazard ratio, 1.02 [95% CI, 1.00-1.04]; P=0.043). CONCLUSIONS: LA roof dilation is an early remodeling pattern in masked HFpEF advancing to overall LA enlargement in overt HFpEF. These distinct features predict the occurrence of atrial fibrillation and cardiovascular hospitalization. [ABSTRACT FROM AUTHOR]

Background: There is a paucity of data regarding the phenotype of dilated cardiomyopathy (DCM) gene variants in the general population. We aimed to determine the frequency and penetrance of DCM-associated putative pathogenic gene variants in a general adult population, with a focus on the expression of clinical and subclinical phenotype, including structural, functional, and arrhythmic disease features.Methods: UK Biobank participants who had undergone whole exome sequencing, ECG, and cardiovascular magnetic resonance imaging were selected for study. Three variant-calling strategies (1 primary and 2 secondary) were used to identify participants with putative pathogenic variants in 44 DCM genes. The observed phenotype was graded DCM (clinical or cardiovascular magnetic resonance diagnosis); early DCM features, including arrhythmia or conduction disease, isolated ventricular dilation, and hypokinetic nondilated cardiomyopathy; or phenotype-negative.Results: Among 18 665 individuals included in the study, 1463 (7.8%) possessed ≥1 putative pathogenic variant in 44 DCM genes by the main variant calling strategy. A clinical diagnosis of DCM was present in 0.34% and early DCM features in 5.7% of individuals with putative pathogenic variants. ECG and cardiovascular magnetic resonance analysis revealed evidence of subclinical DCM in an additional 1.6% and early DCM features in an additional 15.9% of individuals with putative pathogenic variants. Arrhythmias or conduction disease (15.2%) were the most common early DCM features, followed by hypokinetic nondilated cardiomyopathy (4%). The combined clinical/subclinical penetrance was ≤30% with all 3 variant filtering strategies. Clinical DCM was slightly more prevalent among participants with putative pathogenic variants in definitive/strong evidence genes as compared with those with variants in moderate/limited evidence genes.Conclusions: In the UK Biobank, ≈1 of 6 of adults with putative pathogenic variants in DCM genes exhibited early DCM features potentially associated with DCM genotype, most commonly manifesting with arrhythmias in the absence of substantial ventricular dilation or dysfunction. [ABSTRACT FROM AUTHOR]

Background: Timely diagnosis of structural heart disease improves patient outcomes, yet many remain underdiagnosed. While population screening with echocardiography is impractical, ECG-based prediction models can help target high-risk patients. We developed a novel ECG-based machine learning approach to predict multiple structural heart conditions, hypothesizing that a composite model would yield higher prevalence and positive predictive values to facilitate meaningful recommendations for echocardiography.Methods: Using 2 232 130 ECGs linked to electronic health records and echocardiography reports from 484 765 adults between 1984 to 2021, we trained machine learning models to predict the presence or absence of any of 7 echocardiography-confirmed diseases within 1 year. This composite label included the following: moderate or severe valvular disease (aortic/mitral stenosis or regurgitation, tricuspid regurgitation), reduced ejection fraction <50%, or interventricular septal thickness >15 mm. We tested various combinations of input features (demographics, laboratory values, structured ECG data, ECG traces) and evaluated model performance using 5-fold cross-validation, multisite validation trained on 1 site and tested on 10 independent sites, and simulated retrospective deployment trained on pre-2010 data and deployed in 2010.Results: Our composite rECHOmmend model used age, sex, and ECG traces and had a 0.91 area under the receiver operating characteristic curve and a 42% positive predictive value at 90% sensitivity, with a composite label prevalence of 17.9%. Individual disease models had area under the receiver operating characteristic curves from 0.86 to 0.93 and lower positive predictive values from 1% to 31%. Area under the receiver operating characteristic curves for models using different input features ranged from 0.80 to 0.93, increasing with additional features. Multisite validation showed similar results to cross-validation, with an aggregate area under the receiver operating characteristic curve of 0.91 across our independent test set of 10 clinical sites after training on a separate site. Our simulated retrospective deployment showed that for ECGs acquired in patients without preexisting structural heart disease in the year 2010, 11% were classified as high risk and 41% (4.5% of total patients) developed true echocardiography-confirmed disease within 1 year.Conclusions: An ECG-based machine learning model using a composite end point can identify a high-risk population for having undiagnosed, clinically significant structural heart disease while outperforming single-disease models and improving practical utility with higher positive predictive values. This approach can facilitate targeted screening with echocardiography to improve underdiagnosis of structural heart disease. [ABSTRACT FROM AUTHOR]

Myocarditis remains a clinical challenge in pediatrics. Originally, it was recognized at autopsy before the application of endomyocardial biopsy, which led to a histopathology-based diagnosis such as in the Dallas criteria. Given the invasive and low-sensitivity nature of endomyocardial biopsy, its diagnostic focus shifted to a reliance on clinical suspicion. With the advances of cardiac magnetic resonance, an examination of the whole heart in vivo has gained acceptance in the pursuit of a diagnosis of myocarditis. The presentation may vary from minimal symptoms to heart failure, life-threatening arrhythmias, or cardiogenic shock. Outcomes span full resolution to chronic heart failure and the need for heart transplantation with inadequate clues to predict the disease trajectory. The American Heart Association commissioned this writing group to explore the current knowledge and management within the field of pediatric myocarditis. This statement highlights advances in our understanding of the immunopathogenesis, new and shifting dominant pathogeneses, modern laboratory testing, and use of mechanical circulatory support, with a special emphasis on innovations in cardiac magnetic resonance imaging. Despite these strides forward, we struggle without a universally accepted definition of myocarditis, which impedes progress in disease-targeted therapy. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Cardiac magnetic resonance (CMR) derived biventricular global function index (BVGFI) is a new CMR parameter that integrates biventricular volumes, mass, and function using clinically available CMR parameters. The associations of BVGFI with clinical outcomes in repaired tetralogy of Fallot are unknown. METHODS: Patients with repaired tetralogy of Fallot who had a CMR before the occurrence of a composite outcome of death, resuscitated sudden death, or sustained ventricular tachycardia were studied. BVGFI was calculated as the average of right and left GFI. GFI was defined as (ventricular stroke volume×100)/(ventricular mean cavity volume + total ventricular myocardial volume). Ventricular mean cavity volume was defined as ([end-diastolic + end-systolic volume]/2). Cox multivariable regression analysis and classification and regression tree methodology were used. RESULTS: Of the 736 eligible subjects (mean age at CMR 25.4±14.5 years), with a median follow-up of 28 months, 55 subjects (7.4%) reached the composite outcome (46 deaths and 9 sustained ventricular tachycardia). Independent associations with the composite outcome were as follows: BVGFI <37 (hazard ratio, 2.52; P=0.004), right ventricular end-systolic volume index >85 mL/m2 (hazard ratio, 3.25; P<0.001), atrial tachycardia (hazard ratio, 2.03; P=0.021), and age at repair >2.5 years (hazard ratio, 3.37; P<0.001). Classification and regression tree analysis identified BVGFI as the most discriminatory CMR parameter associated with a high risk for adverse outcomes. CONCLUSIONS: BVGFI, a novel CMR-derived imaging biomarker combining biventricular volumes, mass, and function, may improve risk stratification for adverse clinical outcomes in patients with repaired tetralogy of Fallot. [ABSTRACT FROM AUTHOR]

Background: Patients with left ventricular (LV) systolic dysfunction after myocardial infarction are at a high risk of developing heart failure. The addition of neprilysin inhibition to renin angiotensin system inhibition may result in greater attenuation of adverse LV remodeling as a result of increased levels of substrates for neprilysin with vasodilatory, antihypertrophic, antifibrotic, and sympatholytic effects.Methods: We performed a prospective, multicenter, randomized, double-blind, active-comparator trial comparing sacubitril/valsartan 97/103 mg twice daily with valsartan 160 mg twice daily in patients ≥3 months after myocardial infarction with a LV ejection fraction ≤40% who were taking a renin angiotensin system inhibitor (equivalent dose of ramipril ≥2.5 mg twice daily) and a β-blocker unless contraindicated or intolerant. Patients in New York Heart Association class ≥II or with signs and symptoms of heart failure were excluded. The primary outcome was change from baseline to 52 weeks in LV end-systolic volume index measured using cardiac magnetic resonance imaging. Secondary outcomes included other magnetic resonance imaging measurements of LV remodeling, change in NT-proBNP (N-terminal pro-B-type natriuretic peptide) and high-sensitivity cardiac troponin I, and a patient global assessment of change questionnaire.Results: From July 2018 to June 2019, we randomized 93 patients with the following characteristics: mean age, 60.7±10.4 years; median time from myocardial infarction, 3.6 years (interquartile range, 1.2-7.2); mean LV ejection fraction, 36.8%±7.1%; and median NT-proBNP, 230 pg/mL (interquartile range, 124-404). Sacubitril/valsartan, compared with valsartan, did not significantly reduce LV end-systolic volume index; adjusted between-group difference, -1.9 mL/m2 (95% CI, -4.9 to 1.0); P=0.19. There were no significant between-group differences in NT-proBNP, high-sensitivity cardiac troponin I, LV end-diastolic volume index, left atrial volume index, LV ejection fraction, LV mass index, or patient global assessment of change.Conclusions: In patients with asymptomatic LV systolic dysfunction late after myocardial infarction, treatment with sacubitril/valsartan did not have a significant reverse remodeling effect compared with valsartan. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03552575. [ABSTRACT FROM AUTHOR]

Atrial fibrillation and heart failure with reduced ejection fraction are increasing in prevalence worldwide. Atrial fibrillation can precipitate and can be a consequence of heart failure with reduced ejection fraction and cardiomyopathy. Atrial fibrillation and heart failure, when present together, are associated with worse outcomes. Together, these 2 conditions increase the risk of stroke, requiring oral anticoagulation in many or left atrial appendage closure in some. Medical management for rate and rhythm control of atrial fibrillation in heart failure remain hampered by variable success, intolerance, and adverse effects. In multiple randomized clinical trials in recent years, catheter ablation for atrial fibrillation in patients with heart failure and reduced ejection fraction has shown superiority in improving survival, quality of life, and ventricular function and reducing heart failure hospitalizations compared with antiarrhythmic drugs and rate control therapies. This has resulted in a paradigm shift in management toward nonpharmacological rhythm control of atrial fibrillation in heart failure with reduced ejection fraction. The primary objective of this American Heart Association scientific statement is to review the available evidence on the epidemiology and pathophysiology of atrial fibrillation in relation to heart failure and to provide guidance on the latest advances in pharmacological and nonpharmacological management of atrial fibrillation in patients with heart failure and reduced ejection fraction. The writing committee's consensus on the implications for clinical practice, gaps in knowledge, and directions for future research are highlighted. [ABSTRACT FROM AUTHOR]

Background: Patients with isolated left ventricular failure may have positive outcomes after being implanted with a left ventricular assist device. Unfortunately, almost half of patients with heart failure and reduced ejection fraction also have evidence of right ventricular dysfunction. For a subset of this populationwith severe biventricular failure, or those who develop right ventricular dysfunction after left ventricular assist device implantation, patients may necessitate biventricular assist devices or the total artificial heart. Objectives: This overview of mechanical circulatory support devices will enhance nurses' ability to differentiate criteria for implantation, current practice, and outcomes with a focus on durable ventricular assist devices and the total artificial heart. Methods: A review of the literature involved searching CINAHL and PubMed databases using keywords biventricular assist devices, total artificial heart, and durablemechanical circulatory support. Results were narrowed to articles based on adults, 18 years or older. Seventy-eight relevant articles were identified, and 8 articles compared the durable biventricular assist devices. Results: Similar patient outcomes were found when comparing the use of left ventricular assist devices as biventricular support versus the total artificial heart. Discussion: The decision to implant the appropriate durable mechanical circulatory support for a patient in biventricular failure is complex and dependent on patient factors. [ABSTRACT FROM AUTHOR]

BACKGROUND: Left atrial assessment is complex, particularly in heart failure with reduced ejection fraction due to interactions with functional mitral regurgitation (FMR). Pilot data suggest that left atrial volumetric/mechanical coupling index (LACI) may be useful, but large outcome data are lacking. METHODS: We enrolled a comprehensively characterized cohort of patients in sinus rhythm with heart failure with reduced ejection fraction diagnosis at Mayo Clinic from 2007 to 2011. Routinely measured left atrial volume index and tissuedoppler- imaging a' allowed LACI calculation as (left atrial volume index)/(tissuedoppler- imaging a'). Survival was the outcome measured. RESULTS: The cohort's 4196 patients (69 [58-77] years, ejection fraction 40 [31-45]%) had mild FMR in 1505 and moderate-severe FMR in 1068. LACI was overall 5.06 (3.50-8.10) and increased with each FMR grade (3.86 [2.94-5.29] without FMR, 5.38 [3.80-8.02] with mild, 5.45 [1.49-8.07] with moderate/ severe FMR; P<0.0001). At diagnosis, higher LACI was independently determined by more severe FMR and by higher left ventricular mass index, lower ejection fraction, higher E/e', and lower glomerular filtration rate (all P<0.0001). During follow-up 1588 (38%) patients died. In spline modeling, excess mortality appeared around LACI=6 and steeply increased thereafter (5-year survival 72±1% with LACI<6 and 49±2% with LACI ≥6, P<0.0001). Multivariable comprehensive adjustment showed LACI strong association with excess mortality (adjusted hazard ratio, 1.41 [1.23-1.61], P<0.0001 for LACI ≥6). Independent link to mortality persistent across FMR grades (adjusted hazard ratio, 1.45 [1.13-1.86], P=0.004 without FMR, 1.42 [1.16-1.77], P=0.0008 with mild FMR, and 1.38 [1.01-1.66], P=0.04 with moderate/severe FMR) without interaction (P=0.3). LACI independent impact on outcome was incremental to that of left atrial volume index, tissue-doppler-imaging a', or any other characteristic including the Meta- Analysis Global Group in Chronic-score (least significant P=0.02). CONCLUSIONS: In this large cohort, left atrial volumetric/mechanical coupling measured by LACI in routine practice integrates the influence of several morphological/hemodynamic determinants but displays progressive deterioration with increasing FMR severity in heart failure with reduced ejection fraction. About outcome, higher LACI is strongly, independently, and incrementally associated with excess mortality, irrespective of FMR grade and in all subsets. Hence, LACI is a novel and critical measure in heart failure with reduced ejection fraction, quantifiable in routine practice, which should be integrated in prognostication and decision-making. [ABSTRACT FROM AUTHOR]

Background: The term "end stage" has been used to describe hypertrophic cardiomyopathy (HCM) with left ventricular systolic dysfunction (LVSD), defined as occurring when left ventricular ejection fraction is <50%. The prognosis of HCM-LVSD has reportedly been poor, but because of its relative rarity, the natural history remains incompletely characterized.Methods: Data from 11 high-volume HCM specialty centers making up the international SHaRe Registry (Sarcomeric Human Cardiomyopathy Registry) were used to describe the natural history of patients with HCM-LVSD. Cox proportional hazards models were used to identify predictors of prognosis and incident development.Results: From a cohort of 6793 patients with HCM, 553 (8%) met the criteria for HCM-LVSD. Overall, 75% of patients with HCM-LVSD experienced clinically relevant events, and 35% met the composite outcome (all-cause death [n=128], cardiac transplantation [n=55], or left ventricular assist device implantation [n=9]). After recognition of HCM-LVSD, the median time to composite outcome was 8.4 years. However, there was substantial individual variation in natural history. Significant predictors of the composite outcome included the presence of multiple pathogenic/likely pathogenic sarcomeric variants (hazard ratio [HR], 5.6 [95% CI, 2.3-13.5]), atrial fibrillation (HR, 2.6 [95% CI, 1.7-3.5]), and left ventricular ejection fraction <35% (HR, 2.0 [95% CI, 1.3-2.8]). The incidence of new HCM-LVSD was ≈7.5% over 15 years. Significant predictors of developing incident HCM-LVSD included greater left ventricular cavity size (HR, 1.1 [95% CI, 1.0-1.3] and wall thickness (HR, 1.3 [95% CI, 1.1-1.4]), left ventricular ejection fraction of 50% to 60% (HR, 1.8 [95% CI, 1.2, 2.8]-2.8 [95% CI, 1.8-4.2]) at baseline evaluation, the presence of late gadolinium enhancement on cardiac magnetic resonance imaging (HR, 2.3 [95% CI, 1.0-4.9]), and the presence of a pathogenic/likely pathogenic sarcomeric variant, particularly in thin filament genes (HR, 1.5 [95% CI, 1.0-2.1] and 2.5 [95% CI, 1.2-5.1], respectively).Conclusions: HCM-LVSD affects ≈8% of patients with HCM. Although the natural history of HCM-LVSD was variable, 75% of patients experienced adverse events, including 35% experiencing a death equivalent an estimated median time of 8.4 years after developing systolic dysfunction. In addition to clinical features, genetic substrate appears to play a role in both prognosis (multiple sarcomeric variants) and the risk for incident development of HCM-LVSD (thin filament variants). [ABSTRACT FROM AUTHOR]

5 This analysis of STICH extends the findings of ISCHEMIA to patients with severe left ventricular dysfunction and defines another patient population in whom ischemia fails to identify patients who derive a mortality benefit from revascularization. When ischemia was analyzed as a dichotomous (175 of 255 [69%] with ischemia died versus 90 of 147 [61%] without ischemia; aHR, 1.21 [95% CI, 0.93-1.58]; P=0.15) or continuous (aHR, 1.89 [95% CI, 0.66-5.40]; P=0.24) variable, neither the presence (Figure [B]) nor the extent of ischemia was associated with higher mortality. Recently, the ISCHEMIA study (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches) that randomized patients with moderate to severe ischemia to invasive or conservative treatment disproved this belief. [Extracted from the article]

Background: Imaging evaluation of arrhythmogenic right ventricular cardiomyopathy (ARVC) remains challenging. Myocardial strain assessment by echocardiography is an increasingly utilized technique for detecting subclinical left ventricular (LV) and right ventricular (RV) dysfunction. We aimed to evaluate the diagnostic and prognostic utility of LV and RV strain in ARVC., Methods: Patients with suspected ARVC (n = 109) from a multicenter registry were clinically phenotyped using the 2010 ARVC Revised Task Force Criteria and underwent baseline strain echocardiography. Diagnostic performance of LV and RV strain was evaluated using the area under the receiver operating characteristic curve analysis against the 2010 ARVC Revised Task Force Criteria, and the prognostic value was assessed using the Kaplan-Meier analysis., Results: Mean age was 45.3±14.7 years, and 48% of patients were female. Estimation of RV strain was feasible in 99/109 (91%), and LV strain was feasible in 85/109 (78%) patients. ARVC prevalence by 2010 ARVC Revised Task Force Criteria is 91/109 (83%) and 83/99 (84%) in those with RV strain measurements. RV global longitudinal strain and RV free wall strain had diagnostic area under the receiver operating characteristic curve of 0.76 and 0.77, respectively (both P <0.001; difference NS). Abnormal RV global longitudinal strain phenotype (RV global longitudinal strain > -17.9%) and RV free wall strain phenotype (RV free wall strain > -21.2%) were identified in 41/69 (59%) and 56/69 (81%) of subjects, respectively, who were not identified by conventional echocardiographic criteria but still met the overall 2010 ARVC Revised Task Force Criteria for ARVC. LV global longitudinal strain did not add diagnostic value but was prognostic for composite end points of death, heart transplantation, or ventricular arrhythmia (log-rank P =0.04)., Conclusions: In a prospective, multicenter registry of ARVC, RV strain assessment added diagnostic value to current echocardiographic criteria by identifying patients who are missed by current echocardiographic criteria yet still fulfill the diagnosis of ARVC. LV strain, by contrast, did not add incremental diagnostic value but was prognostic for identification of high-risk patients., Competing Interests: Disclosures Dr Namasivayam received support from the Nvidia Corporation Academic Hardware Grant for work unrelated to this article. The other authors report no conflicts.

BACKGROUND: Sunitinib, used widely in metastatic renal cell carcinoma, can result in hypertension, left ventricular dysfunction, and heart failure. However, the relationships between vascular function and cardiac dysfunction with sunitinib are poorly understood. METHODS AND RESULTS: In a multicenter prospective study of 84 metastatic renal cell carcinoma patients, echocardiography, arterial tonometry, and BNP (B-type natriuretic peptide) measures were performed at baseline and at 3.5, 15, and 33 weeks after sunitinib initiation, correlating with sunitinib cycles 1, 3, and 6. Mean change in vascular function parameters and 95% confidence intervals were calculated. Linear regression models were used to estimate associations between vascular function and left ventricular ejection fraction, longitudinal strain, diastolic function (E/e'), and BNP. After 3.5 weeks of sunitinib, mean systolic blood pressure increased by 9.5 mm Hg (95% confidence interval, 2.0-17.1; P=0.02) and diastolic blood pressure by 7.2 mm Hg (95% confidence interval, 4.3-10.0; P<0.001) across all participants. Sunitinib resulted in increases in large artery stiffness (carotid--femoral pulse wave velocity) and resistive load (total peripheral resistance and arterial elastance; all P<0.05) and changes in pulsatile load (total arterial compliance and wave reflection). There were no statistically significant associations between vascular function and systolic dysfunction (left ventricular ejection fraction and longitudinal strain). However, baseline total peripheral resistance, arterial elastance, and aortic impedance were associated with worsening diastolic function and filling pressures over time. CONCLUSIONS: In patients with metastatic renal cell carcinoma, sunitinib resulted in early, significant increases in blood pressure, arterial stiffness, and resistive and pulsatile load within 3.5 weeks of treatment. Baseline vascular function parameters were associated with worsening diastolic but not systolic function. [ABSTRACT FROM AUTHOR]

Background: Most patients with chronic heart failure have detectable troponin concentrations when evaluated by high-sensitivity assays. The prognostic relevance of this finding has not been clearly established so far. We aimed to assess high-sensitivity troponin assay for risk stratification in chronic heart failure through a meta-analysis approach.Methods: Medline, EMBASE, Cochrane Library, and Scopus were searched in April 2017 by 2 independent authors. The terms were "troponin" AND "heart failure" OR "cardiac failure" OR "cardiac dysfunction" OR "cardiac insufficiency" OR "left ventricular dysfunction." Inclusion criteria were English language, clinical stability, use of a high-sensitivity troponin assay, follow-up studies, and availability of individual patient data after request to authors. Data retrieved from articles and provided by authors were used in agreement with the PRISMA statement. The end points were all-cause death, cardiovascular death, and hospitalization for cardiovascular cause.Results: Ten studies were included, reporting data on 11 cohorts and 9289 patients (age 66±12 years, 77% men, 60% ischemic heart failure, 85% with left ventricular ejection fraction <40%). High-sensitivity troponin T data were available for all patients, whereas only 209 patients also had high-sensitivity troponin I assayed. When added to a prognostic model including established risk markers (sex, age, ischemic versus nonischemic etiology, left ventricular ejection fraction, estimated glomerular filtration rate, and N-terminal fraction of pro-B-type natriuretic peptide), high-sensitivity troponin T remained independently associated with all-cause mortality (hazard ratio, 1.48; 95% confidence interval, 1.41-1.55), cardiovascular mortality (hazard ratio, 1.40; 95% confidence interval, 1.33-1.48), and cardiovascular hospitalization (hazard ratio, 1.42; 95% confidence interval, 1.36-1.49), over a median 2.4-year follow-up (all P<0.001). High-sensitivity troponin T significantly improved risk prediction when added to a prognostic model including the variables above. It also displayed an independent prognostic value for all outcomes in almost all population subgroups. The area under the curve-derived 18 ng/L cutoff yielded independent prognostic value for the 3 end points in both men and women, patients with either ischemic or nonischemic etiology, and across categories of renal dysfunction.Conclusions: In chronic heart failure, high-sensitivity troponin T is a strong and independent predictor of all-cause and cardiovascular mortality, and of hospitalization for cardiovascular causes, as well. This biomarker then represents an additional tool for prognostic stratification. [ABSTRACT FROM AUTHOR]

Objectives: To compare the effects of two lung-protective ventilation strategies on pulmonary vascular mechanics in early acute respiratory distress syndrome. Design: Experimental study. Setting: University animal research laboratory. Subjects: Twelve pigs (30.8 ± 2.5 kg). Interventions: Acute respiratory distress syndrome was induced by repeated lung lavages and injurious mechanical ventilation. Thereafter, animals were randomized to 4 hours ventilation according to the Acute Respiratory Distress Syndrome Network protocol or to an open lung approach strategy. Pressure and flow sensors placed at the pulmonary artery trunk allowed continuous assessment of pulmonary artery resistance, effective elastance, compliance, and reflected pressure waves. Respiratory mechanics and gas exchange data were collected. Measurements and Main Results: Acute respiratory distress syndrome led to pulmonary vascular mechanics deterioration. Four hours after randomization, pulmonary vascular mechanics was similar in Acute Respiratory Distress Syndrome Network and open lung approach: resistance (578 ± 252 vs 626 ± 153 dyn.s/cm5; p = 0.714), effective elastance, (0.63 ± 0.22 vs 0.58 ± 0.17 mm Hg/mL; p = 0.710), compliance (1.19 ± 0.8 vs 1.50 ± 0.27 mL/mm Hg; p = 0.437), and reflection index (0.36 ± 0.04 vs 0.34 ± 0.09; p = 0.680). Open lung approach as compared to Acute Respiratory Distress Syndrome Network was associated with improved dynamic respiratory compliance (17.3 ± 2.6 vs 10.5 ± 1.3 mL/cm H2O; p < 0.001), driving pressure (9.6 ± 1.3 vs 19.3 ± 2.7 cm H2O; p < 0.001), and venous admixture (0.05 ± 0.01 vs 0.22 ± 0.03, p < 0.001) and lower mean pulmonary artery pressure (26 ± 3 vs 34 ± 7 mm Hg; p = 0.045) despite of using a higher positive end-expiratory pressure (17.4 ± 0.7 vs 9.5 ± 2.4 cm H2O; p < 0.001). Cardiac index, however, was lower in open lung approach (1.42 ± 0.16 vs 2.27 ± 0.48 L/min; p = 0.005). Conclusions: In this experimental model, Acute Respiratory Distress Syndrome Network and open lung approach affected pulmonary vascular mechanics similarly. The use of higher positive end-expiratory pressures in the open lung approach strategy did not worsen pulmonary vascular mechanics, improved lung mechanics, and gas exchange but at the expense of a lower cardiac index. [ABSTRACT FROM AUTHOR]

Right ventricular (RV) failure remains a major cause of global morbidity and mortality for patients with advanced heart failure, pulmonary hypertension, or acute myocardial infarction and after major cardiac surgery. Over the past 2 decades, percutaneously delivered acute mechanical circulatory support pumps specifically designed to support RV failure have been introduced into clinical practice. RV acute mechanical circulatory support now represents an important step in the management of RV failure and provides an opportunity to rapidly stabilize patients with cardiogenic shock involving the RV. As experience with RV devices grows, their role as mechanical therapies for RV failure will depend less on the technical ability to place the device and more on improved algorithms for identifying RV failure, patient monitoring, and weaning protocols for both isolated RV failure and biventricular failure. In this review, we discuss the pathophysiology of acute RV failure and both the mechanism of action and clinical data exploring the utility of existing RV acute mechanical circulatory support devices. [ABSTRACT FROM AUTHOR]

Objective: To test whether positive end-expiratory pressure consistent with an open lung approach improves pulmonary vascular mechanics compared with higher or lower positive end-expiratory pressures in experimental acute respiratory distress syndrome.Design: Experimental study.Setting: Animal research laboratory.Subjects: Ten pigs, 35 ± 5.2 kg.Interventions: Acute respiratory distress syndrome was induced combining saline lung lavages with injurious mechanical ventilation. The positive end-expiratory pressure level resulting in highest compliance during a decremental positive end-expiratory pressure trial after lung recruitment was determined. Thereafter, three positive end-expiratory pressure levels were applied in a random order: hyperinflation, 6 cm H2O above; open lung approach, 2 cm H2O above; and collapse, 6 cm H2O below the highest compliance level. High fidelity pressure and flow sensors were placed at the main pulmonary artery for measuring pulmonary artery resistance (Z0), effective arterial elastance, compliance, and reflected pressure waves.Measurements and Main Results: After inducing acute respiratory distress syndrome, Z0 and effective arterial elastance increased (from 218 ± 94 to 444 ± 115 dyn.s.cm and from 0.27 ± 0.14 to 0.62 ± 0.22 mm Hg/mL, respectively; p < 0.001), vascular compliance decreased (from 2.76 ± 0.86 to 1.48 ± 0.32 mL/mm Hg; p = 0.003), and reflected waves arrived earlier (0.23 ± 0.07 vs 0.14 ± 0.05, arbitrary unit; p = 0.002) compared with baseline. Comparing the three positive end-expiratory pressure levels, open lung approach resulted in the lowest: 1) Z0 (297 ± 83 vs 378 ± 79 dyn.s.cm, p = 0.033, and vs 450 ± 119 dyn.s.cm, p = 0.002); 2) effective arterial elastance (0.37 ± 0.08 vs 0.50 ± 0.15 mm Hg/mL, p = 0.04, and vs 0.61 ± 0.12 mm Hg/mL, p < 0.001), and 3) reflection coefficient (0.35 ± 0.17 vs 0.48 ± 0.10, p = 0.024, and vs 0.53 ± 0.19, p = 0.005), comparisons with hyperinflation and collapse, respectively.Conclusions: In this experimental setting, positive end-expiratory pressure consistent with the open lung approach resulted in the best pulmonary vascular mechanics compared with higher or lower positive end-expiratory pressure settings. [ABSTRACT FROM AUTHOR]

Background: Sacubitril/valsartan has been approved for the management of heart failure (HF) with reduced ejection fraction in adults. PANORAMA-HF trial (Prospective Trial to Assess the Angiotensin Receptor Blocker Neprilysin Inhibitor LCZ696 Versus Angiotensin-Converting Enzyme Inhibitor for the Medical Treatment of Pediatric HF) investigated its effects on clinical outcomes in pediatric patients with HF. Methods: PANORAMA-HF is a multicenter, Phase II/III study using an adaptive, seamless, 2-part design. The study aimed to evaluate the pharmacokinetics and pharmacodynamics of single doses of sacubitril/valsartan (Part 1), and the efficacy and safety of sacubitril/valsartan versus enalapril administered twice daily for 52 weeks (Part 2) in pediatric patients with HF due to left ventricular systolic dysfunction with biventricular heart physiology. An innovative trial design using a novel global rank assessment of severity was employed. For analysis, eligible patients were stratified into 3 age groups (Group 1, 6 to <18 years; Group 2a, 2 to <6 years; and Group 3a, 1 month to <2 years) and functional classification (New York Heart Association/Ross class I/II and III/IV). Results: We report the key demographic, baseline, and clinical characteristics of 375 pediatric patients randomized to receive the study medication. The mean age for patients in Groups 1, 2a, and 3a was 12.2, 3.2, and 1.3 years, respectively. About 70% of patients had a prior HF hospitalization, 85% had New York Heart Association/Ross class I/II HF, and ≈8% were angiotensin-converting enzyme inhibitor/angiotensin receptor blocker naïve. Conclusions: Compared to other pediatric HF studies, PANORAMA-HF recruited a relatively homogeneous pediatric HF population across 3 age groups, enabling a more robust evaluation of pharmacokinetics/pharmacodynamics and efficacy/safety of sacubitril/valsartan. Most patients had mildly symptomatic HF at baseline. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02678312. [ABSTRACT FROM AUTHOR]

Individuals with Fontan circulation are at risk of late mortality from both cardiac and noncardiac causes. Despite the known risk of mortality, referral indications for advanced heart failure care vary between centers, and many individuals die from Fontan circulation-related complications either after late consideration for advanced heart failure therapies or having never seen a heart failure specialist. There is a critical need for guidelines to direct appropriately timed referral for advanced heart failure consultation. The Advanced Cardiac Therapies Improving Outcomes Network (ACTION) Fontan Committee has developed recommended thresholds for advanced heart failure referral to guide primary cardiologists. These recommendations are divided into 4 categories of clinical Fontan circulatory dysfunction including (1) cardiac/systemic ventricular dysfunction, (2) Fontan pathway dysfunction, (3) lymphatic dysfunction, and (4) extracardiac dysfunction. [ABSTRACT FROM AUTHOR]

Background: Guidelines recommend that patients with low ejection fraction (EF) after myocardial infarction (MI) have their EF reassessed 40 days after MI for implantable cardioverter-defibrillator (ICD) candidacy. This study examines rates of EF reassessment and their association with 1-year ICD implantation in post-MI patients with low EF.Methods: We examined rates of postdischarge EF reassessment and ICD implantation among 10 289 Medicare-insured patients ≥65 years of age with an EF≤35% during the index MI admission from January 2007 through September 2010 in ACTION Registry-GWTG (Acute Coronary Treatment and Intervention Outcomes Network Registry-Get With The Guidelines). Multivariable Cox models tested the association between time-dependent EF reassessment and 1-year ICD implantation, stratified by revascularization status during the index MI admission.Results: Among patients with EF ≤35% during the index MI admission, 66.8% (95% confidence interval [CI], 65.9-67.8) had EF reassessment within the next year. Revascularized patients were more likely to have EF reassessment (76.9% [95% CI, 75.8-78.0)] versus 53.7% [95% CI, 52.2-55.2]; P<0.001) and had shorter times to EF reassessment (median, 67 versus 84 days; P<0.001) than nonrevascularized patients. Among patients with EF reassessment, only 11% received an ICD within 1 year. Reassessment of EF was associated with a higher likelihood of ICD implantation for both revascularized (unadjusted, 12.1% versus 2.4%, P<0.001; adjusted hazard ratio, 10.6, 95% CI, 7.7-14.8) and nonrevascularized (unadjusted, 10.0% versus 1.7%, P<0.001; adjusted hazard ratio, 6.1, 95% CI, 4.1-9.2) patients.Conclusions: In US practice, EF reassessments are commonly performed among patients with MI with an initially reduced EF. Although 1-year EF reassessment is associated with increased likelihood of ICD implantation, 1-year ICD implantation rates remain very low even among patients with EF reassessment, regardless of revascularization status. [ABSTRACT FROM AUTHOR]

Background: Guidelines recommend coronary artery bypass graft surgery (CABG) over percutaneous coronary intervention (PCI) for multivessel disease and severe left ventricular systolic dysfunction. However, CABG has not been compared with PCI in such patients in randomized trials.Methods and Results: Patients with multivessel disease and severe left ventricular systolic dysfunction (ejection fraction ≤35%) who underwent either PCI with everolimus-eluting stent or CABG were selected from the New York State registries. The primary outcome was long-term all-cause death. Secondary outcomes were individual outcomes of myocardial infarction, stroke, and repeat revascularization. Among the 4616 patients who fulfilled our inclusion criteria (1351 everolimus-eluting stent and 3265 CABG), propensity score matching identified 2126 patients with similar propensity scores. In the short term, PCI was associated with a lower risk of stroke (hazard ratio [HR], 0.05; 95% confidence interval [CI], 0.01-0.39; P=0.004) in comparison with CABG. At long-term follow-up (median, 2.9 years), PCI was associated with a similar risk of death (HR, 1.01; 95% CI, 0.81-1.28; P=0.91), a higher risk of myocardial infarction (HR, 2.16; 95% CI, 1.42-3.28; P=0.0003), a lower risk of stroke (HR, 0.57; 95% CI, 0.33-0.97; P=0.04), and a higher risk of repeat revascularization (HR, 2.54; 95% CI, 1.88-3.44; P<0.0001). The test for interaction was significant (P=0.002) for completeness of revascularization, such that, in patients in whom complete revascularization was achieved with PCI, there was no difference in myocardial infarction between PCI and CABG.Conclusions: Among patients with multivessel disease and severe left ventricular systolic dysfunction, PCI with everolimus-eluting stent had comparable long-term survival in comparison with CABG. PCI was associated with higher risk of myocardial infarction (in those with incomplete revascularization) and repeat revascularization, and CABG was associated with higher risk of stroke. [ABSTRACT FROM AUTHOR]

Challenge yourself and interpret this ECG strip! [ABSTRACT FROM AUTHOR]