Response to Letter Regarding Article, “Diastolic Stiffness of the Failing Diabetic Heart: Importance of Fibrosis, Advanced Glycation End Products, and Myocyte Resting Tension”
The authors appreciated the thoughtful comment of Connelly et al on their study,1 which indeed did not imply that fibrosis was no determinant of diastolic left ventricular (LV) dysfunction in patients with heart failure and normal LV ejection fraction (HFNEF). A previous study from our group identified both collagen volume fraction (CVF) and cardiomyocyte resting tension to be determinants of diastolic LV stiffness in HFNEF.2 A subsequent comparative analysis of patients with HFNEF and heart failure with reduced LV ejection fraction (HFREF), however, revealed a trend for lower collagen volume fraction (CVF) in patients with HFNEF than in those with HFREF (12.2±1.4 versus 14.4±1.5%; NS).3 The present study confirmed this trend and revealed significantly lower CVF in patients with HFNEF than in those with HFREF (11.7±0.8 versus 17.3±1.1%; P<0.001). The prominent myocardial fibrosis observed in diabetic HFREF patients accounted for this difference. Lower myocardial CVF in HFNEF than in HFREF was a surprising outcome of both studies but could explain the reduced efficacy of antifibrotic treatment strategies in HFNEF, as is evident from the outcomes of the Candesartan in Heart Failure-Assessment of Reduction of Mortality and Morbidity (CHARM) Preserve and Perindopril in Elderly People With Chronic Heart Failure (PEP-CHF) studies. The findings of the recent Valsartan in Diastolic Dysfunction (VALIDD) trial,4 which observed no additional benefit for diastolic LV dysfunction of angiotensin-II receptor blockade over regular blood pressure lowering, are also in accordance with myocardial fibrosis having fewer functional implications in patients with HFNEF than originally presumed.
Because myocardial CVF is higher than normal in those with HFNEF, antifibrotic treatment is meaningful in these patients. Our recent studies,1–3 however, also propose cardiomyocyte hypertrophy and phosphorylation of cytoskeletal proteins as important future targets of a specific treatment strategy for HFNEF.
Van Heerebeek L, Hamdani N, Handoko L, Falcao-Pires I, Musters RJ, Kupreishvili K, Ijsselmuiden AJJ, Schalkwijk CG, Bronzwaer JGF, Diamant M, Borbely A, van der Velden J, Stienen GJM, Laarman GJ, Niessen HWM, Paulus WJ. Diastolic stiffness of the failing diabetic heart: importance of fibrosis, advanced glycation endproducts, and myocyte resting tension. Circulation. 2008; 117: 52–60.
Borbély A, van der Velden J, Papp Z, Bronzwaer JGF, Edes I, Stienen GJ, Paulus WJ. Cardiomyocyte Stiffness in Diastolic Heart Failure. Circulation. 2005; 111: 774–781.
Van Heerebeek L, Borbely A, Niessen HW, Bronzwaer JGF, van der Velden J, Stienen GJ, Linke WA, Laarman GJ, Paulus WJ. Myocardial structure and function differ in systolic and diastolic heart failure. Circulation. 2006; 113: 1966–1973.
Solomon SD, Janardhanan R, Verma A, Bourgoun M, Daley WL, Purkayastha D, Lacourciere Y, Hippler SE, Fields H, Naqvi TZ, Mulvagh SL, Arnold JMO, Thomas JD, Zile MR, Aurigemma GP and the Valsartan in diastolic dysfunction (VALIDD) investigators. Effect of angiotensin receptor blockade and antihypertensive drugs on diastolic function in patients with hypertension and diastolic dysfunction: a randomised trial. Lancet. 2007; 369: 2079–2087.