Author + information
- Eylem Levelt, MBBS, DPhil∗ (, )
- Gerry P. McCann, MD,
- Jurgen E. Schneider, PhD and
- Sven Plein, MD, PhD
- ↵∗Address for correspondence:
British Heart Foundation, Cardiovascular Research Centre, University of Leicester, Glenfield Hospital, Groby Road, Leicester LE3 9QP, United Kingdom
We read with great interest the outcomes of the VIVIDD (Vildagliptin in Ventricular Dysfunction Diabetes) trial presented in the article entitled “Effects of Vildagliptin on Ventricular Function in Patients with Type 2 Diabetes Mellitus and Heart Failure” (1). The study found that treatment with vildagliptin in this population was associated with increased left ventricular (LV) volumes, but the treatment was not associated with a decrease in the LV ejection fraction, increase in B-type natriuretic peptide, or worsening of heart failure (HF) status. The authors comment that the increase in ventricular volumes remains an unexplained action of vildagliptin on LV remodeling that most likely reflects the play of chance.
We would like to point out that several potential mechanisms of LV remodeling and function in type 2 diabetes (T2D) have recently emerged, providing further insights into the pathophysiology of cardiac remodeling. The recent literature supports the concept that accumulation of myocardial lipids in diabetes is the cause of concentric remodeling (2). Elevated circulating levels of fatty acids (FA) in combination with increased capacity for myocardial FA uptake seem to cause cardiac steatosis in patients with T2D. As the FA supply exceeds the oxidative capacity of the heart, lipid metabolism is diverted from oxidative processes to nonoxidative processes, with the production of lipotoxic intermediates such as ceramide and diacyl-glycerol. These lipotoxic intermediates have been shown to play a role in cardiac remodeling by activating distinct signaling pathways affecting adenosine triphosphate production, myocellular contractility, and apoptosis. In addition, it has been demonstrated that cardiac steatosis potentiates the effects of angiotensin II on the myocardium (3).
The link between lipotoxicity and concentric LV remodeling has been demonstrated not only in patients with T2D, but also in patients with nonischemic HF (4), and in patients with generalized lipodystrophy who exhibit severe concentric LV hypertrophy and significant cardiac steatosis (5). In individuals with T2DM and HF, intramyocardial lipid overload was shown to be associated with a distinct gene expression profile that is similar to an animal model of lipotoxicity and cardiac dysfunction (6). Successful reduction of myocardial steatosis with the glucagon-like peptide-1 receptor agonist exendin-4 (7), has been shown to reverse concentric LV remodeling.
Taken together, these studies suggest a mechanistic link between cardiac steatosis, lipotoxicity, and concentric LV remodeling in diseases of upregulated FA metabolism, such as diabetes. Given that dipeptidyl peptidase-IV inhibitors suppress the degradation of glucagon-like peptide-1 receptor, we suggest that, in a fashion similar to exentin, vildagliptin may reverse cardiolipotoxicity in T2D, and thereby reverse concentricity in relative terms in patients with HF, without causing a worsening of HF. The elimination of lipotoxicity might reverse these distinct signaling pathways, and affect sarcomere alignment, leading to the changes in cardiac geometry and improvement of cardiac function demonstrated in this study. However, this hypothesis needs to be tested in clinical studies using imaging methods such as cardiovascular magnetic resonance imaging that can more accurately measure ventricular volumes and myocardial mass to assess the effects of concentric and eccentric hypertrophy.
Please note: The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- 2018 American College of Cardiology Foundation
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