Altered Metabolic Profile With Sodium-Restricted Dietary Approaches to Stop Hypertension Diet in Hypertensive Heart Failure With Preserved Ejection Fraction

Abstract

Background: Heart failure with preserved ejection fraction (HFpEF) is increasingly recognized as a distinct entity with unique pathophysiology. In the Dietary Approaches to Stop Hypertension in Diastolic Heart Failure (DASH-DHF) study, the sodium-restricted Dietary Approaches to Stop Hypertension diet (DASH/SRD) was associated with improved blood pressure and cardiovascular function in 13 hypertensive patients with HFpEF. With the use of targeted metabolomics, we explored metabolite changes and their relationship with energy-dependent measures of cardiac function in DASH-DHF.

Methods and results: With the use of chromatography and mass spectrometry, 152 metabolites including amino acids, free fatty acids, phospholipids, diglycerides, triglycerides, cholesterol esters, and acyl carnitines were measured. Comparison of baseline and post-DASH/SRD samples revealed increases in short-chain acetyl, butryl, and propionyl carnitines (P values .02, .03, .03, respectively). Increases in propionyl carnitine correlated with ventricular-arterial coupling ratio (Ees:Ea; r = 0.78; P = .005) and ventricular contractility (maximum rate of change of pressure-normalized stress [dσ*/dtmax]; r = 0.66; P = .03). Changes in L-carnitine also correlated with Ees:Ea (r = 0.62; P = .04) and dσ*/dtmax (r = 0.60; P = .05) and inversely with ventricular stiffness (r = -0.63; P = .03).

Conclusions: Metabolite profile changes of patients with HFpEF during dietary modification with the use of DASH/SRD suggest improved energy substrate utilization. Additional studies are needed to clarify connections between diet, metabolic changes, and myocardial function in HFpEF.

Keywords: DASH diet; Heart failure with preserved ejection fraction; low-sodium diet; metabolomics.

Published by Elsevier Inc.

Figures

Figure 1. Metabolites pre- and post-DASH/SRD intervention

Heat map of log transformed and auto scaled to standard deviation of each metabolite concentration demonstrating individual subject levels before DASH/SRD diet in the red section and after the diet in the green section. Panel A: Branched chain amino acids, acyl carnitines, short chain fatty acids and long chain fatty acids. Panel B: Phospholipid, diglycerides, triglycerides and cholesterol esters

Figure 2. Short-chain carnitines and relationship of C3 carnitine with cardiac function

Abbreviations: C2, acetyl carnitine; C3, propionyl carnitine; C4, butryl carnitine; Ees:Ea ratio, ventricular-arterial coupling ratio; ds*/dtmax, maximum rate of change of pressure-normalized stress; k, ventricular stiffness constant * denotes p

Figure 3. Metabolic changes during DASH/SRD and potential relation to cardiac energetics

Abbreviations: BCAA: branched-chain amino acids; CAT: carnitine acyl transferase; CPT: Carnitine palmitoyltransferase; PDH: Pyruvate dehydrogenase; TCA: tricarboxylic acid cycle Schematic diagram of effects of DASH/SRD diet on metabolic profile including decreased triglycerides and cholesterol esters and increased diglycerides is shown in Figure 3. Increased circulating acyl carnitines, free fatty acids and branched chain amino acids (BCAA) enter the cell for further oxidation. The fatty acids enter the mitochondria after conversion in to acyl carnitines, excess acyl carnitines escape in to the circulation. Beta oxidation produces acetyl Co A from even chain acyl residues and propionyl CoA from odd chain residues which then enter the Tricarboxylic cycle (TCA). As more carnitine is made available, acetyl CoA to acetyl carnitine conversion by carnitine acetyl transferase (CAT) favors stimulation of pyruvate dehydrogenase (PDH) and entry in to the TCA cycle. BCAA also is oxidized to acetyl and propionyl residues that enter the TCA cycle as well. Thus DASH/SRD diet appears to promote energy utilization through entry of acyl carnitines.