Dietary carbohydrates restriction inhibits the development of cardiac hypertrophy and heart failure

Abstract

Aims A diet with modified components, such as a ketogenic low-carbohydrate (LC) diet, potentially extends longevity and healthspan. However, how a LC diet impacts on cardiac pathology during hemodynamic stress remains elusive. This study evaluated the effects of a LC diet high in either fat (Fat-LC) or protein (Pro-LC) in a mouse model of chronic hypertensive cardiac remodeling. Methods and Results Wild-type mice were subjected to transverse aortic constriction, followed by feeding with the Fat-LC, the Pro-LC, or a high-carbohydrate control diet. After 4 weeks, echocardiographic, hemodynamic, histological and biochemical analyses were performed. LC diet consumption after pressure overload inhibited the development of pathological hypertrophy and systolic dysfunction compared to the control diet. An anti-hypertrophic serine/threonine kinase, GSK-3β, was re-activated by both LC diets; however, the Fat-LC, but not the Pro-LC, diet exerted cardioprotection in GSK-3β cardiac-specific knockout mice. β-hydroxybutyrate, a major ketone body in mammals, was increased in the hearts of mice fed the Fat-LC, but not the Pro-LC, diet. In cardiomyocytes, ketone body supplementation inhibited phenylephrine-induced hypertrophy, in part by suppressing mTOR signaling. Conclusions Strict carbohydrate restriction suppresses pathological cardiac growth and heart failure after pressure overload through distinct anti-hypertrophic mechanisms elicited by supplemented macronutrients. Translational Perspective Hemodynamic stress, such as hypertension, induces pathological cardiac hypertrophy, leading to heart failure. There is growing evidence that modulating components of diet affects cardiac function in humans, although the causality and underlying mechanisms are poorly understood. Our study demonstrates that strict restriction of dietary carbohydrates supplemented with either fat or proteins during acute hemodynamic stress attenuates the development and progression of cardiac hypertrophy and heart failure by activating distinct anti-hypertrophic and cardioprotective signaling mechanisms. The study suggests that it would be useful to investigate the therapeutic benefit of carbohydrate restriction in patients with hypertension and cardiac hypertrophy in clinical studies.

Deranged Myocardial Fatty Acid Metabolism in Heart Failure

“…It is well-known that mammalian target of rapamycin (mTOR) signaling is involved in the pathogenesis of cardiac hypertrophy and diabetic nephropathy. Ketone bodies have a protective effect on cardiac hypertrophy and diabetic nephropathy by inhibiting mTOR signaling [118,119]. In addition, ketone body inhibits class I histone deacetylases (HDACs) and activate Notch signaling in intestinal epithelial cells, thereby promoting stem cell self-renewal [120].…”

β-Hydroxybutyrate, a Ketone Body, Potentiates the Antioxidant Defense via Thioredoxin 1 Upregulation in Cardiomyocytes

“…This is significantly higher in diabetic patients at baseline or in response to fasting in non-diabetic patients. We have previously shown that 1 mM βHB affects signaling in cardiomyocytes [10]. Therefore, we chose dosages of βHB ranging from 0.1 to 10 mM.…”

“…Since mTOR is regulated by multiple mechanisms, βHB may affect the overall activity of mTOR through multiple mechanisms, both positively and negatively. For example, βHB inhibits mTOR activation and cardiomyocyte hypertrophy induced by phenylephrine, an agonist of the α1-adrenergic receptor [10]. Phenylephrine-induced mTOR activation is mediated by Erk, and phenylephrine-induced Erk activation is sensitive to antioxidant treatment [21,22].…”

“…Although excessive production of ketone bodies leads to life-threatening ketoacidosis in diabetic patients under glucose lowering treatment, increasing lines of evidence suggests that modest levels of ketone bodies, including β-hydroxybutyrate (βHB), play adaptive or salutary roles in the heart [9]. A ketogenic diet protects the heart against stress, such as ischemia and pressure overload [10,11]. Sodium glucose cotransporter 2 (SGLT2) treatment in diabetic patients increases circulating levels of βHB, which may play an important role in mediating some of the protective effects of SGLT2 inhibitors [12].…”

Ketogenic Diet and Health

“…However, emerging evidence suggests the possibility that ketone metabolic modulation might become a viable treatment paradigm for HF [137,139]. Recent studies indicate that enhanced myocardial ketone use is adaptive in HF, and limited data demonstrate beneficial effects of exogenous ketone therapy in studies of animal models [140] and humans with HF [138,[140][141][142][143][144][145][146]. As noted in a recent review from Selvaraj and colleagues, "Although a number of important questions remain regarding the use of therapeutic ketosis and mechanism of action in HF, current evidence suggests potential benefit, in particular, in HF with reduced ejection fraction, with theoretical rationale for its use in HF with preserved ejection fraction.…”