Interleukin-16 Promotes Cardiac Fibrosis and Myocardial Stiffening in Heart Failure with Preserved Ejection Fraction

Abstract

BackgroundChronic heart failure (CHF) with preserved left ventricular (LV) ejection fraction (HFpEF) is observed in half of all patients with CHF and carries the same poor prognosis as CHF with reduced LV ejection fraction (HFrEF). In contrast to HFrEF, there is no established therapy for HFpEF. Chronic inflammation contributes to cardiac fibrosis, a crucial factor in HFpEF; however, inflammatory mechanisms and mediators involved in the development of HFpEF remain unclear. Therefore, we sought to identify novel inflammatory mediators involved in this process.Methods and ResultsAn analysis by multiplex-bead array assay revealed that serum interleukin-16 (IL-16) levels were specifically elevated in patients with HFpEF compared with HFrEF and controls. This was confirmed by enzyme-linked immunosorbent assay in HFpEF patients and controls, and serum IL-16 levels showed a significant association with indices of LV diastolic dysfunction. Serum IL-16 levels were also elevated in a rat model of HFpEF and positively correlated with LV end-diastolic pressure, lung weight and LV myocardial stiffness constant. The cardiac expression of IL-16 was upregulated in the HFpEF rat model. Enhanced cardiac expression of IL-16 in transgenic mice induced cardiac fibrosis and LV myocardial stiffening accompanied by increased macrophage infiltration. Treatment with anti-IL-16 neutralizing antibody ameliorated cardiac fibrosis in the mouse model of angiotensin II-induced hypertension.ConclusionOur data indicate that IL-16 is a mediator of LV myocardial fibrosis and stiffening in HFpEF, and that the blockade of IL-16 could be a possible therapeutic option for HFpEF.

Association Between Use of Statins and Mortality in Patients With Heart Failure and Ejection Fraction of ≥50%

“…This results in cardiomyocyte hypertrophy and interstitial fibrosis, leading to increased stiffness of the myocardium, as well as increased resting tension, which is indeed seen in patients with HFPEF. 22,32,33 There was no interaction between statin use and IHD or diabetes mellitus. This is consistent with the theory that HFPEF may represent a systemic proinflammatory state independent of these risk factors, 22 that is, in our patients, statins may have reduced this inflammation rather than having an effect on atherosclerosis or macrovascular disease per se.…”

Tolvaptan Reduces the Risk of Worsening Renal Function in Patients With Acute Decompensated Heart Failure and Preserved Left Ventricular Ejection Fraction ― Prospective Randomized Controlled Study ―

“…24 Body weight and daily total urine output were measured every day. Vital signs such as blood pressure and heart rate were measured, and sampling of blood was performed at baseline and 6, 12, 24, and 48 h after randomization.…”

Inflammation in HFpEF: Key or circumstantial?

“…Thus, IL-16 was found to be elevated in a rat model of HFpEF and positively correlated with LV end-diastolic pressure, lung weight and LV myocardial stiffness constant. Treatment with anti-IL-16 neutralizing antibody ameliorated cardiac fibrosis [17]. Similarly, IL-18 overexpression in rats fed by fructose to induce metabolic syndrome had comparable effects [18] and IL-17 receptor-A blockade inhibited the development of fibrosis and diastolic dysfunction in spontaneous hypertensive rats [19].…”