Effects of Catecholamine Stress on Diastolic Function and Myocardial Energetics in Obesity

Abstract

Background-Obesity is characterized by impaired cardiac energetics, which may play a role in the development of diastolic dysfunction and inappropriate shortness of breath. We assessed whether, in obesity, derangement of energetics and diastolic function is further altered during acute cardiac stress. Methods and Results-Normal-weight (body mass index, 22Ϯ2 kg/m 2 ; nϭ9 -17) and obese (body mass index, 39Ϯ7 kg/m 2 ; nϭ17-46) subjects underwent assessment of diastolic left ventricular function (cine magnetic resonance imaging volume-time curve analysis) and cardiac energetics (phosphocreatine/ATP ratio; 31 P-magnetic resonance spectroscopy) at rest and during dobutamine stress (heart rate increase, 65Ϯ22% and 69Ϯ14%, respectively; Pϭ0.61). At rest, obesity was associated with a 22% lower peak filling rate (PϽ0.001) and a 15% lower phosphocreatine/ATP ratio (1.73Ϯ0.40 versus 2.03Ϯ0.28; Pϭ0.048). Peak filling rate correlated with fat mass, left ventricular mass, leptin, waist-to-hip ratio, and phosphocreatine/ATP ratio. On multivariable analysis, phosphocreatine/ATP was the only independent predictor of peak filling rate (␤ϭ0.50; Pϭ0.03). During stress, a further reduction in phosphocreatine/ATP occurred in obese (from 1.73Ϯ0.40 to 1.53Ϯ0.50; Pϭ0.03) but not in normal-weight (from 1.98Ϯ0.24 to 2.04Ϯ0.34; Pϭ0.50) subject. For similar levels of inotropic stress, there were smaller increases in peak filling rate in obesity (38% versus 70%; Pϭ0.01). Conclusions-In

Impact of Comorbidities on Myocardial Remodeling and Dysfunction In Heart Failure with Preserved Ejection Fraction

“…Furthermore, obesity, DMII and IR can have direct adverse effects on myocardial structure and function independently of common confounders as hypertension or coronary artery disease, which has been referred to as "obesity" [116], "diabetic" [117] or "insulin-resistant" [118] cardiomyopathy. Adverse myocardial structural and functional changes induced by obesity, DMII and IR include myocardial hypertrophy and fibrosis [119][120][121], reduced myocardial energetic reserve [122][123][124], impaired myocardial relaxation [115,125] and increased diastolic LV [72] and cardiomyocyte stiffness [126]. Metabolic risk factors are strongly associated with myocardial and systemic inflammation, oxidative stress and endothelial dysfunction [116][117][118], which importantly contribute to myocardial dysfunction and remodeling and result in downregulation of NO-cGMP-PKG signaling [127,128].…”

“…Impaired myocardial relaxation results from obesity-induced myocardial mitochondrial dysfunction, lipotoxicity, uncoupled oxidative phosphorylation and disturbed cardiomyocyte calcium handling [135]. Compared to normal weight subjects, obese individuals had impaired myocardial energetics (phosphocreatine/ATP ratio) and diastolic filling rate at rest, which further deteriorated after inotropic stress [123]. Myocardial blood flow, as measured by PET, was significantly reduced in obese postmenopausal women, which was negatively correlated with waist/hip ratio [136].…”

Myocardial substrate metabolism in obesity

“…23,29 It has been shown that in animal models of obesity 35 and in humans with no other co-morbidity, abnormally low PCr/ATP ratios occur at rest, potentially due to, in addition to changes in substrate utilization, a loss of the total creatine pool in proportion to the loss of PCr, as occurs in many other forms of hypertrophy. 1,[78][79][80][81] Furthermore, this has been linked to altered cardiac diastolic function and is exacerbated during catecholamine stress. 80 …”

“…1,[78][79][80][81] Furthermore, this has been linked to altered cardiac diastolic function and is exacerbated during catecholamine stress. 80 …”

“…7 Cardiac metabolism and ATP production is altered in obesity and has emerged as a candidate mechanism to explain the increase in heart failure in this population. 8 Indeed, it has recently been shown that obesity, in the absence of co-morbidities, is linked to impaired myocardial high-energy phosphate metabolism 9 and diastolic dysfunction, [10][11][12] both markers of increased cardiovascular risk, 13 providing a mechanistic link between altered myocardial energy production and mortality.…”