Cardiac Magnetic Resonance Assessment of Interstitial Myocardial Fibrosis and Cardiomyocyte Hypertrophy in Hypertensive Mice Treated With Spironolactone

Background: Nearly 50% of patients with heart failure (HF) have preserved LV ejection fraction, with interstitial fibrosis and cardiomyocyte hypertrophy as early manifestations of pressure overload. However, methods to assess both tissue characteristics dynamically and noninvasively with therapy are lacking. We measured the effects of mineralocorticoid receptor blockade on tissue phenotypes in LV pressure overload using cardiac magnetic resonance (CMR). Methods and Results: Mice were randomized to l‐nitro‐ω‐methyl ester (l‐NAME, 3 mg/mL in water; n=22), or l‐NAME with spironolactone (50 mg/kg/day in subcutaneous pellets; n=21). Myocardial extracellular volume (ECV; marker of diffuse interstitial fibrosis) and the intracellular lifetime of water (τic; marker of cardiomyocyte hypertrophy) were determined by CMR T1 imaging at baseline and after 7 weeks of therapy alongside histological assessments. Administration of l‐NAME induced hypertensive heart disease in mice, with increases in mean arterial pressure, LV mass, ECV, and τic compared with placebo‐treated controls, while LV ejection fraction was preserved (>50%). In comparison, animals receiving both spironolactone and l‐NAME (“l‐NAME+S”) showed less concentric remodeling, and a lower myocardial ECV and τic, indicating decreased interstitial fibrosis and cardiomyocyte hypertrophy (ECV: 0.43±0.09 for l‐NAME versus 0.25±0.03 for l‐NAME+S, P<0.001; τic: 0.42±0.11 for l‐NAME groups versus 0.12±0.05 for l‐NAME+S group). Mice treated with a combination of l‐NAME and spironolactone were similar to placebo‐treated controls at 7 weeks. Conclusions: Spironolactone attenuates interstitial fibrosis and cardiomyocyte hypertrophy in hypertensive heart disease. CMR can phenotype myocardial tissue remodeling in pressure‐overload, furthering our understanding of HF progression

Effect of Sleep Apnea and Continuous Positive Airway Pressure on Cardiac Structure and Recurrence of Atrial Fibrillation

Background: Sleep apnea (SA) is associated with an increased risk of atrial fibrillation (AF). We sought to determine the effect of SA on cardiac structure in patients with AF, whether therapy for SA was associated with beneficial cardiac structural remodelling, and whether beneficial cardiac structural remodelling translated into a reduced risk of recurrence of AF after pulmonary venous isolation (PVI). Methods and Results: A consecutive group of 720 patients underwent a cardiac magnetic resonance study before PVI. Patients with SA (n=142, 20%) were more likely to be male, diabetic, and hypertensive and have an increased pulmonary artery pressure, right ventricular volume, atrial dimensions, and left ventricular mass. Treated SA was defined as duration of continuous positive airway pressure therapy of >4 hours per night. Treated SA patients (n=71, 50%) were more likely to have paroxysmal AF, a lower blood pressure, lower ventricular mass, and smaller left atrium. During a follow‐up of 42 months, AF recurred in 245 patients. The cumulative incidence of AF recurrence was 51% in patients with SA, 30% in patients without SA, 68% in patients with untreated SA, and 35% in patients with treated SA. In a multivariable model, the presence of SA (hazard ratio 2.79, CI 1.97 to 3.94, P<0.0001) and untreated SA (hazard ratio 1.61, CI 1.35 to 1.92, P<0.0001) were highly associated with AF recurrence. Conclusions: Patients with SA have an increased blood pressure, pulmonary artery pressure, right ventricular volume, left atrial size, and left ventricular mass. Therapy with continuous positive airway pressure is associated with lower blood pressure, atrial size, and ventricular mass, and a lower risk of AF recurrence after PVI

Myocardial Tissue Remodeling in Adolescent Obesity

Background: Childhood obesity is a significant risk factor for cardiovascular disease in adulthood. Although ventricular remodeling has been reported in obese youth, early tissue‐level markers within the myocardium that precede organ‐level alterations have not been described. Methods and Results: We studied 21 obese adolescents (mean age, 17.7±2.6 years; mean body mass index [BMI], 41.9±9.5 kg/m2, including 11 patients with type 2 diabetes [T2D]) and 12 healthy volunteers (age, 15.1±4.5 years; BMI, 20.1±3.5 kg/m2) using biomarkers of cardiometabolic risk and cardiac magnetic resonance imaging (CMR) to phenotype cardiac structure, function, and interstitial matrix remodeling by standard techniques. Although left ventricular ejection fraction and left atrial volumes were similar in healthy volunteers and obese patients (and within normal body size‐adjusted limits), interstitial matrix expansion by CMR extracellular volume fraction (ECV) was significantly different between healthy volunteers (median, 0.264; interquartile range [IQR], 0.253 to 0.271), obese adolescents without T2D (median, 0.328; IQR, 0.278 to 0.345), and obese adolescents with T2D (median, 0.376; IQR, 0.336 to 0.407; P=0.0001). ECV was associated with BMI for the entire population (r=0.58, P<0.001) and with high‐sensitivity C‐reactive protein (r=0.47, P<0.05), serum triglycerides (r=0.51, P<0.05), and hemoglobin A1c (r=0.76, P<0.0001) in the obese stratum. Conclusions: Obese adolescents (particularly those with T2D) have subclinical alterations in myocardial tissue architecture associated with inflammation and insulin resistance. These alterations precede significant left ventricular hypertrophy or decreased cardiac function

Myocarditis Associated with Immune Checkpoint Inhibitors: An Expert Consensus on Data Gaps and a Call to Action.

Immune checkpoint inhibitors (ICIs) have transformed the treatment landscape for cancer. Due to the mechanism of action of ICIs, inflammatory reactions against normal tissue were an anticipated side effect of these agents; these immune-related adverse events have been documented and are typically low grade and manageable. Myocarditis has emerged as an uncommon but potentially life-threatening adverse reaction in patients treated with ICIs. Assessment and characterization of ICI-associated myocarditis is challenging because of its low incidence and protean manifestations. Nevertheless, the seriousness of ICI-associated myocarditis justifies a coordinated effort to increase awareness of this syndrome, identify patients who may be at risk, and enable early diagnosis and appropriate treatment. The Checkpoint Inhibitor Safety Working Group, a multidisciplinary committee of academic, industry, and regulatory partners, convened at a workshop hosted by Project Data Sphere, LLC, on December 15, 2017. This meeting aimed to evaluate the current information on ICI-associated myocarditis, determine methods to collect and share data on this adverse reaction, and establish task forces to close the identified knowledge gaps. In this report, we summarize the workshop findings and proposed steps to address the impact of ICI-associated myocarditis in patients with cancer