Vigorous Exercise in Patients with Hypertrophic Cardiomyopathy.

ABSTRACT: Hypertrophic cardiomyopathy is a genetic heart condition occurring in up to 1 in 200 patients in the United States, many of whom are young and otherwise healthy. This condition puts those affected at increased risk for adverse cardiac outcomes, including sudden cardiac arrest and death, with particular concern for this to occur during exercise and other forms of exertion. Recent studies aimed at evaluating the risk of exercise in hypertrophic cardiomyopathy patients have suggested that moderate and even vigorous exercise may be safe for certain patients. Clinical guidelines are changing to reflect this recent information and to encourage a shared decision-making approach, which can allow more hypertrophic cardiomyopathy patients to participate in health-promoting exercise activities.

Giant Ring Mitochondria in a Patient With Heart Failure and Cerebral White Matter Disease Resulting From an MT-TL1 Mitochondrial Gene Mutation.

BACKGROUND: The presence of giant ring mitochondria on endomyocardial biopsy is rarely reported and does not have a well-defined differential diagnosis. METHODS: We report the case of a 54-year-old man with heart failure and preserved ejection fraction and left ventricular hypertrophy, initially thought to have an infiltrative cardiomyopathy. RESULTS: The patient was found to have extensive vacuolization caused by giant ring mitochondria on endomyocardial biopsy. Mitochondrial genetic testing revealed an A3243G mutation in the MT-TL1 gene, which is a mitochondrial encoded transfer RNA-leucine molecule. CONCLUSIONS: Mitochondrial disease should be considered in patients presenting with unexplained cardiomyopathy and skeletal muscle, cerebral, or metabolic abnormalities. In this case, the presence of unexpected extensive cardiomyocyte vacuolization and giant, ring-shaped mitochondria on endomyocardial biopsy prompted mitochondrial genetic testing, which ultimately resulted in the correct diagnosis and treatment.

Assessing athletes beyond routine screening: Incorporating essential factors to optimize cardiovascular health and performance.

The American Heart Association (AHA) has devised Life's Essential 8, a set of eight evidence-based health behaviors that play a crucial role in optimizing cardiovascular health and overall well-being. In addition to Life's Essential 8, enhanced screening for Cardiovascular-Kidney-Metabolic (CKM) Syndrome risk factors into routine athlete screening also provides a more comprehensive approach for ensuring athlete safety and long-term health. Incorporating Life's Essential 8 and CKM Syndrome metrics into athlete health evaluations will improve the sports performance of athletes and help optimize their long-term health.

Mavacamten in Right Ventricular Outflow Tract Obstruction.

Right ventricular outflow tract (RVOT) obstruction is a rare complication of ventricular hypertrophy in patients with hypertrophic cardiomyopathy (HCM). This study presents an unusual case of a patient with HCM with severe RVOT obstruction that was relieved successfully through the use of mavacamten.

Eighteen-Month Real-World Experience Using Mavacamten for Treatment of Obstructive Hypertrophic Cardiomyopathy in a Racially Diverse Population.

BACKGROUND: Patients with obstructive hypertrophic cardiomyopathy have increased symptomatic burden. Mavacamten was recently approved for treatment of obstructive hypertrophic cardiomyopathy based on 2 randomized controlled trials. However, its use under real-world conditions and in diverse populations is under-studied. METHODS AND RESULTS: This was a prospective observational cohort study of patients seen at the Johns Hopkins HCM center and prescribed mavacamten for obstructive hypertrophic cardiomyopathy between July 7, 2022 and January 6, 2024. Patients were followed longitudinally, with serial echocardiography and clinical evaluation as mandated by the risk evaluation and mitigation strategy program. Sixty-six patients received mavacamten (mean age 59 years, 47% male, 29% non-White [Black, Hispanic/Latino, Asian, Native Hawaiian or Pacific Islander], 47% obese). Before treatment, all patients had New York Heart Association class II (51.5%) or III (48.5%) heart failure symptoms. Initial maximum peak left ventricular outflow tract gradient was 107±46 mm Hg. Median treatment duration was 9 months. For patients on mavacamten after ≥6 months (n=43), symptoms improved by ≥1 New York Heart Association class in 72% of patients, and peak left ventricular outflow tract gradient decreased by 80±46 mm Hg, eliminating hemodynamically significant left ventricular outflow tract obstruction in 79.1% of patients. Mavacamten was temporarily discontinued in 3 patients due to left ventricular ejection fraction decrease <50%. There were no medication-related adverse events. Effectiveness and safety were similar between White and non-White patients, but symptomatic relief was attenuated in patients with body-mass index ≥35 kg/m2. CONCLUSIONS: Mavacamten was effective and safe when used under real-world conditions in a racially diverse population of symptomatic patients with obstructive hypertrophic cardiomyopathy. Patients with comorbid obesity were less likely to experience symptomatic improvement while on mavacamten.

Anti-hypertrophic and anti-oxidant effect of beta3-adrenergic stimulation in myocytes requires differential neuronal NOS phosphorylation.

RATIONALE: Stimulation of ß3-adrenoreceptors (ß3-AR) blunts contractility and improves chronic left ventricular function in hypertrophied and failing hearts in a neuronal nitric oxide synthase (nNOS) dependent manner. nNOS can be regulated by post-translational modification of stimulatory phosphorylation residue Ser1412 and inhibitory residue Ser847. However, the role of phosphorylation of these residues in cardiomyocytes and ß3-AR protective signaling has yet to be explored. OBJECTIVE: We tested the hypothesis that ß3-AR regulation of myocyte stress requires changes in nNOS activation mediated by differential nNOS phosphorylation. METHODS AND RESULTS: Endothelin (ET-1) or norepinephrine induced hypertrophy in rat neonatal ventricular cardiomyocytes (NRVMs) was accompanied by increased ß3-AR gene expression. Co-administration of the ß3-AR agonist BRL-37433 (BRL) reduced cell size and reactive oxygen species (ROS) generation, while augmenting NOS activity. BRL-dependent augmentation of NOS activity and ROS suppression due to NE were blocked by inhibiting nNOS (L-VNIO). BRL augmented nNOS phosphorylation at Ser1412 and dephosphorylation at Ser847. Cells expressing constitutively dephosphorylated Ser1412A or phosphorylated Ser847D nNOS mutants displayed reduced nNOS activity and a lack of BRL modulation. BRL also failed to depress ROS from NE in cells with nNOS-Ser847D. Inhibiting Akt decreased BRL-induced nNOS-Ser1412 phosphorylation and NOS activation, whereas Gi/o blockade blocked BRL-regulation of both post-translational modifications, preventing enhancement of NOS activity and ROS reduction. BRL resulted in near complete dephosphorylation of Ser847 and a moderate rise in Ser1412 phosphorylation in mouse myocardium exposed to chronic pressure-overload. CONCLUSION: ß3-AR regulates myocardial NOS activity and ROS via activation of nNOS involving reciprocal changes in phosphorylation at two regulatory sites. These data identify a novel and potent anti-oxidant and anti-hypertrophic pathway due to nNOS post-translational modification that is coupled to ß3-AR receptor stimulation.

Exercise protects against myocardial ischemia-reperfusion injury via stimulation of ß(3)-adrenergic receptors and increased nitric oxide signaling: role of nitrite and nitrosothiols.

RATIONALE: Exercise training confers sustainable protection against ischemia-reperfusion injury in animal models and has been associated with improved survival following a heart attack in humans. It is still unclear how exercise protects the heart, but it is apparent that endothelial nitric oxide synthase (eNOS) and nitric oxide (NO) play a role. OBJECTIVE: To determine the role of ß(3)-adrenergic receptors (ß(3)-ARs), eNOS activation, and NO metabolites (nitrite and nitrosothiols) in the sustained cardioprotective effects of exercise. METHODS AND RESULTS: Here we show that voluntary exercise reduces myocardial injury in mice following a 4-week training period and that these protective effects can be sustained for at least 1 week following the cessation of the training. The sustained cardioprotective effects of exercise are mediated by alterations in the phosphorylation status of eNOS (increase in serine 1177 and decrease in threonine 495), leading to an increase in NO generation and storage of NO metabolites (nitrite and nitrosothiols) in the heart. Further evidence revealed that the alterations in eNOS phosphorylation status and NO generation were mediated by ß(3)-AR stimulation and that in response to exercise a deficiency of ß(3)-ARs leads to an exacerbation of myocardial infarction following ischemia-reperfusion injury. CONCLUSIONS: Our findings clearly demonstrate that exercise protects the heart against myocardial ischemia-reperfusion injury by stimulation of ß(3)-ARs and increased cardiac storage of nitric oxide metabolites (ie, nitrite and nitrosothiols).

The variable natural history of idiopathic dilated cardiomyopathy.

BACKGROUND: Determining the prognosis of patients with heart failure is essential for patient management and clinical trial conduct. The relative value of traditional prognostic criteria remains unclear and the assessment of long-term prognosis for individual patients is problematic. OBJECTIVES: To determine the ability of clinical, hemodynamic and echocardiographic parameters to predict the long-term prognosis of patients with idiopathic dilated cardiomyopathy. METHODS: We investigated the ability of clinical, hemodynamic and echocardiographic parameters to predict the long-term prognosis of individual patients in a large, representative, contemporary cohort of idiopathic dilated cardiomyopathy (IDCM) patients referred to Johns Hopkins from 1997 to 2004 for evaluation of cardiomyopathy. In all patients a baseline history was taken, and physical examination, laboratory studies, echocardiogram, right heart catheterization and endomyocardial biopsy were performed. RESULTS: In 171 IDCM patients followed for a median 3.5 years, there were 50 long-term event-free survivors (LTS) (median survival 6.4 years) and 34 patients died or underwent ventricular assist device placement or transplantation within 5 years (NLTS; non-long-term survivors) (median time to event 1.83 years. Established risk factors (gender, race, presence of diabetes, serum creatinine, sodium) and the use of accepted heart failure medications (angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta blockers) were similar between the two groups. Although LTS had younger age, higher ejection fraction (EF) and lower New York Heart Association (NYHA) class at presentation, the positive predictive value of an EF < 25% was 64% (95% CI 41%-79%) and that of NYHA class > 2 was 53% (95% CI 36-69%). A logistic model incorporating these three variables incorrectly classified 29% of patients. CONCLUSIONS: IDCM exhibits a highly variable natural history and standard clinical predictors have limited ability to classify IDCM patients into broad prognostic categories. These findings suggest that there are important host-environmental factors still unappreciated in the biology of IDCM.

Swimming-Induced Pulmonary Edema: An Underrecognized Cause of Triathlon-Associated Medical Emergencies.

Swimming-induced pulmonary edema is a leading cause of triathlon-associated emergencies and death. Cold water immersion, female sex, age>50, and wetsuit compression are associated risk factors. Pathophysiology is due to increased central blood pooling, leading to increased pulmonary capillary wedge pressure. Treatment is focused on prevention; however, recurrence is common. (Level of Difficulty: Intermediate.).

Caloric restriction in leptin deficiency does not correct myocardial steatosis: failure to normalize PPAR{alpha}/PGC1{alpha} and thermogenic glycerolipid/fatty acid cycling.

OBJECTIVE: Evidence supports an antilipotoxic role for leptin in preventing inappropriate peripheral tissue lipid deposition. Obese, leptin-deficient mice develop left ventricular (LV) hypertrophy and myocardial steatosis with increased apoptosis and decreased longevity. Here we investigated the cardiac effects of caloric restriction versus leptin repletion in obese leptin-deficient (ob/ob) mice. METHODS: Echocardiography was performed on 7 mo old C57BL/6 wild-type mice (WT) and ob/ob mice fed ad libitum, leptin-repleted (LR-ob/ob), or calorie-restricted (CR-ob/ob) for 4 wk. Ventricular tissue was examined by electron microscopy (EM), triglyceride (TAG) content, oil red O staining, mitochondrial coupling assay, and microarray expression profiling. RESULTS: LR and CR-ob/ob mice showed decreased body and heart weight, and LV wall thickness compared with ad libitum ob/ob mice. LV fractional shortening was decreased in ad libitum ob/ob mice, but restored to WT in LR and CR groups. However, myocardial lipid content by EM and TAG analysis revealed persistent cardiac steatosis in the CR-ob/ob group. Although CR restored mitochondrial coupling to WT levels, PPARα was suppressed and genes associated with oxidative stress and cell death were upregulated in CR-ob/ob animals. In contrast, LR eliminated cardiac steatosis, normalized mitochondrial coupling, and restored PGC1α and PPARα expression, while inducing core genes involved in glycerolipid/free fatty acid (GL/FFA) cycling, a thermogenic pathway that can reduce intracellular lipids. CONCLUSIONS: Thus, CR in the absence of leptin fails to normalize cardiac steatosis. GL/FFA cycling may be, at least in part, leptin-dependent and a key pathway that protects the heart from lipid accumulation.

Restoring leptin signaling reduces hyperlipidemia and improves vascular stiffness induced by chronic intermittent hypoxia.

Chronic intermittent hypoxia (IH) during sleep can result from obstructive sleep apnea (OSA), a disorder that is particularly prevalent in obesity. OSA is associated with high levels of circulating leptin, cardiovascular dysfunction, and dyslipidemia. Relationships between leptin and cardiovascular function in OSA and chronic IH are poorly understood. We exposed lean wild-type (WT) and obese leptin-deficient ob/ob mice to IH for 4 wk, with and without leptin infusion, and measured cardiovascular indices including aortic vascular stiffness, endothelial function, cardiac myocyte morphology, and contractile properties. At baseline, ob/ob mice had decreased vascular compliance and endothelial function vs. WT mice. We found that 4 wk of IH decreased vascular compliance and endothelial relaxation responses to acetylcholine in both WT and leptin-deficient ob/ob animals. Recombinant leptin infusion in both strains restored IH-induced vascular abnormalities toward normoxic WT levels. Cardiac myocyte morphology and function were unaltered by IH. Serum cholesterol and triglyceride levels were significantly decreased by leptin treatment in IH mice, as was hepatic stearoyl-Coenzyme A desaturase 1 expression. Taken together, these data suggest that restoring normal leptin signaling can reduce vascular stiffness, increase endothelial relaxation, and correct dyslipidemia associated with IH.

Prevention Starts in the Womb: Opportunities for Addressing Cardiovascular Risk Factors During Pregnancy and Beyond.

Early identification and mitigation of sex-specific cardiovascular disease risk factors is a potential trajectory-changing strategy to improve lifelong cardiovascular health in women. These sex-specific risk factors include adverse pregnancy outcomes, polycystic ovarian syndrome, and premature menopause. We start by discussing the impact and management of risk factors for adverse pregnancy outcomes as an upstream intervention for cardiovascular disease risk reduction and then address the long-term effect and mitigation of sex-specific risk factors for cardiovascular disease.

Beta 3-adrenoreceptor regulation of nitric oxide in the cardiovascular system.

The presence of a third beta-adrenergic receptor (beta 3-AR) in the cardiovascular system has challenged the classical paradigm of sympathetic regulation by beta1- and beta2-adrenergic receptors. While beta 3-AR's role in the cardiovascular system remains controversial, increasing evidence suggests that it serves as a "brake" in sympathetic overstimulation - it is activated at high catecholamine concentrations, producing a negative inotropic effect that antagonizes beta1- and beta2-AR activity. The anti-adrenergic effects induced by beta 3-AR were initially linked to nitric oxide (NO) release via endothelial NO synthase (eNOS), although more recently it has been shown under some conditions to increase NO production in the cardiovascular system via the other two NOS isoforms, namely inducible NOS (iNOS) and neuronal NOS (nNOS). We summarize recent findings regarding beta 3-AR effects on the cardiovascular system and explore its prospective as a therapeutic target, particularly focusing on its emerging role as an important mediator of NO signaling in the pathogenesis of cardiovascular disorders.

PDE5A suppression of acute beta-adrenergic activation requires modulation of myocyte beta-3 signaling coupled to PKG-mediated troponin I phosphorylation.

Phosphodiesterase type 5A (PDE5A) inhibitors acutely suppress beta-adrenergic receptor (beta-AR) stimulation in left ventricular myocytes and hearts. This modulation requires cyclic GMP synthesis via nitric oxide synthase (NOS)-NO stimulation, but upstream and downstream mechanisms remain un-defined. To determine this, adult cardiac myocytes from genetically engineered mice and controls were studied by video microscopy to assess sarcomere shortening (SS) and fura2-AM fluorescence to measure calcium transients (CaT). Enhanced SS from isoproterenol (ISO, 10 nM) was suppressed >or=50% by the PDE5A inhibitor sildenafil (SIL, 1 microM), without altering CaT. This regulation was unaltered despite co-inhibition of either the cGMP-stimulated cAMP-esterase PDE2 (Bay 60-7550), or cGMP-inhibited cAMP-esterase PDE3 (cilostamide). Thus, the SIL response could not be ascribed to cGMP interaction with alternative PDEs. However, genetic deletion (or pharmacologic blockade) of beta3-ARs, which couple to NOS signaling, fully prevented SIL modulation of ISO-stimulated SS. Importantly, both PDE5A protein expression and activity were similar in beta3-AR knockout (beta3-AR(-/-)) myocytes as in controls. Downstream, cGMP stimulates protein kinase G (PKG), and we found contractile modulation by SIL required PKG activation and enhanced TnI phosphorylation at S23, S24. Myocytes expressing the slow skeletal TnI isoform which lacks these sites displayed no modulation of ISO responses by SIL. Non-equilibrium isoelectric focusing gel electrophoresis showed SIL increased TnI phosphorylation above that from concomitant ISO in control but not beta3-AR(-/-) myocytes. These data support a cascade involving beta3-AR stimulation, and subsequent PKG-dependent TnI S23, S24 phosphorylation as primary factors underlying the capacity of acute PDE5A inhibition to blunt myocardial beta-adrenergic stimulation.

ß2-adrenergic receptor-coupled phosphoinositide 3-kinase constrains cAMP-dependent increases in cardiac inotropy through phosphodiesterase 4 activation.

BACKGROUND: Emerging evidence suggests that phosphoinositide 3-kinase (PI3K) may modulate cardiac inotropy; however, the underlying mechanism remains elusive. We hypothesized that ß(2)-adrenergic receptor (AR)-coupled PI3K constrains increases in cardiac inotropy through cyclic adenosine monophosphate (cAMP)-dependent phosphodiesterase (PDE) activation. METHODS: We tested the effects of PI3K and PDE4 inhibition on myocardial contractility by using isolated murine cardiac myocytes to study physiologic functions (sarcomere shortening [SS] and intracellular Ca(+) transients), as well as cAMP and PDE activity. RESULTS: PI3K inhibition with the reversible inhibitor LY294002 (LY) resulted in a significant increase in SS and Ca(2+) handling, indicating enhanced contractility. This response depended on G(iα) protein activity, because incubation with pertussis toxin (an irreversible G(iα) inhibitor) abolished the LY-induced hypercontractility. In addition, PI3K inhibition had no greater effect on SS than both a PDE3,4 inhibitor (milrinone) and LY combined. Furthermore, LY decreased PDE4 activity in a concentration-dependent manner (58.0% of PDE4 activity at LY concentrations of 10 µM). Notably, PI3K(γ) coimmunoprecipitated with PDE4D. The ß(2)-AR inverse agonist, ICI 118,551 (ICI), abolished induced increases in contractility. CONCLUSIONS: PI3K modulates myocardial contractility by a cAMP-dependent mechanism through the regulation of the catalytic activity of PDE4. Furthermore, basal agonist-independent activity of the ß(2)-AR and its resultant cAMP production and enhancement of the catalytic activity of PDE4 through PI3K represents an example of integrative cellular signaling, which controls cAMP dynamics and thereby contractility in the cardiac myocyte. These results help to explain the mechanism by which milrinone is able to increase myocardial contractility in the absence of direct ß-adrenergic stimulation and why it can further augment contractility in the presence of maximal ß-adrenergic stimulation.

Adverse ventricular remodeling and exacerbated NOS uncoupling from pressure-overload in mice lacking the beta3-adrenoreceptor.

Stimulation of the beta-adrenergic system is important in the pathological response to sustained cardiac stress, forming the rationale for the use of beta-blockers in heart failure. The beta3-adrenoreceptor (AR) is thought to couple to the inhibitory G-protein, G(i), with downstream signaling through nitric oxide, although its role in the heart remains controversial. In this study, we tested whether lack of beta3-AR influences the myocardial response to pressure-overload. Baseline echocardiography in mice lacking beta3-AR (beta3(-/-)) compared to wild type (WT) showed mild LV hypertrophy at 8 weeks that worsened as they aged. beta3(-/-) mice had much greater mortality after transverse aortic constriction (TAC) than WT controls. By 3 weeks of TAC, systolic function was worse. After 9 weeks of TAC, beta3(-/-) mice also had greater LV dilation, myocyte hypertrophy and enhanced fibrosis. NOS activity declined in beta3(-/-)TAC hearts after 9 weeks, and total and NOS-dependent superoxide rose, indicating heightened oxidative stress and NOS uncoupling. The level of eNOS phosphorylation in beta3(-/-)TAC hearts was diminished, and nNOS and iNOS expression levels were increased. GTP cyclohydrolase-1 expression was reduced, although total BH4 levels were not depleted. 3 weeks of BH4 treatment rescued beta3(-/-) mice from worsened remodeling after TAC, and lowered NOS-dependent superoxide. Thus, lack of beta3-AR signaling exacerbates cardiac pressure-overload induced remodeling and enhances NOS uncoupling and consequent oxidant stress, all of which can be rescued with exogenous BH4. These data suggest a cardioprotective role for the beta3-AR in modulating oxidative stress and adverse remodeling in the failing heart.

Leptin signaling and obesity: cardiovascular consequences.

Leptin, among the best known hormone markers for obesity, exerts pleiotropic actions on multiple organ systems. In this review, we summarize major leptin signaling pathways, namely Janus-activated kinase/signal transducers and activators of transcription and mitogen-activated protein kinase, including possible mechanisms of leptin resistance in obesity. The effects of leptin on the cardiovascular system are discussed in detail, including its contributions to hypertension, atherosclerosis, depressed myocardial contractile function, fatty acid metabolism, hypertrophic remodeling, and reduction of ischemic/reperfusion injury. The overall goal is to summarize current understanding of how altered leptin signaling in obesity contributes to obesity-related cardiovascular disease.

Readmission Risk Trajectories for Patients With Heart Failure Using a Dynamic Prediction Approach: Retrospective Study.

BACKGROUND: Patients hospitalized with heart failure suffer the highest rates of 30-day readmission among other clinically defined patient populations in the United States. Investigation into the predictability of 30-day readmissions can lead to clinical decision support tools and targeted interventions that can help care providers to improve individual patient care and reduce readmission risk. OBJECTIVE: This study aimed to develop a dynamic readmission risk prediction model that yields daily predictions for patients hospitalized with heart failure toward identifying risk trajectories over time and identifying clinical predictors associated with different patterns in readmission risk trajectories. METHODS: A two-stage predictive modeling approach combining logistic and beta regression was applied to electronic health record data accumulated daily to predict 30-day readmission for 534 hospital encounters of patients with heart failure over 2750 patient days. Unsupervised clustering was performed on predictions to uncover time-dependent trends in readmission risk over the patient's hospital stay. We used data collected between September 1, 2013, and August 31, 2015, from a community hospital in Maryland (United States) for patients with a primary diagnosis of heart failure. Patients who died during the hospital stay or were transferred to other acute care hospitals or hospice care were excluded. RESULTS: Readmission occurred in 107 (107/534, 20.0%) encounters. The out-of-sample area under curve for the 2-stage predictive model was 0.73 (SD 0.08). Dynamic clinical predictors capturing laboratory results and vital signs had the highest predictive value compared with demographic, administrative, medical, and procedural data included. Unsupervised clustering identified four risk trajectory groups: decreasing risk (131/534, 24.5% encounters), high risk (113/534, 21.2%), moderate risk (177/534, 33.1%), and low risk (113/534, 21.2%). The decreasing risk group demonstrated change in average probability of readmission from admission (0.69) to discharge (0.30), whereas the high risk (0.75), moderate risk (0.61), and low risk (0.39) groups maintained consistency over the hospital course. A higher level of hemoglobin, larger decrease in potassium and diastolic blood pressure from admission to discharge, and smaller number of past hospitalizations are associated with decreasing readmission risk (P<.001). CONCLUSIONS: Dynamically predicting readmission and quantifying trends over patients' hospital stay illuminated differing risk trajectory groups. Identifying risk trajectory patterns and distinguishing predictors may shed new light on indicators of readmission and the isolated effects of the index hospitalization.