Diastolic Heart Failure (HFPEF)

More than 14 million Europeans suffer from heart failure (HF). Despite significant improvements in the treatment of this disease, morbidity and mortality remain unacceptably high. At least 50 % of the total HF population is considered to have HF with Preserved Left Ventricular (LV) Ejection Fraction (EF) (HFPEF, "diastolic heart failure"). HFPEF is currently defined as the presence of symptoms of HF, a non-dilated LV with an EF above 50%, and abnormalities of relaxation or compliance of the LV.Besides advanced age and female gender, prevalent modifiable risk factors for HFPEF also include hypertension, diabetes, obesity, and inactive lifestyle.2

Photo: NTNU/Geir Mogen
Cardinal features of HFPEF are severely impaired exercise capacity, which is objectively determined as peak oxygen uptake (peakVO2), and increased diastolic filling pressure, determined by ultrasound as the ratio between mitral peak velocity of early filling (E) to early diastolic mitral annular velocity (é) (E/é ratio). The majority of HFPEF patients have such low peakVO2 values and high E/é ratio that they are at increased risk for functional dependence and they have reduced quality of life.3


The pathophysiology of exercise intolerance in HFPEF is complex and can be divided into: 1) central hemodynamic and 2) peripheral components.

  1. The central hemodynamic disturbance is of cardiac origin and results from remodeling processes that include myocyte and non-myocyte components, including accumulation of extracellular matrix (fibrosis), increased collagen content and cross-linking, left ventricular hypertrophy and concentric remodeling and stiffening of cardiomyocytes. In consequence, diastolic dysfunction ensues with impaired LV relaxation, reduced LV compliance, failure of the Frank-Starling mechanism at rest and a rapid increase in left ventricular filling pressures (measured as E/é ratio) even at low levels of physical activity. Furthermore, inadequate contractile reserve, leading to an insufficient increase in EF during exercise, and lower stroke volume, as well as chronotropic incompetence together contributes to lower peak cardiac output in HFPEF.
     
  2. The peripheral disturbance is characterized by impaired vasodilator reserve, which becomes explicit during exercise, as well as increased arterial stiffness and impaired skeletal muscle energy metabolism, both important determinants of exercise capacity. Blunting of the arterial-venous oxygen difference at peak exercise indirectly suggests peripheral vascular dysfunction, microvascular dysfunction and/or abnormal skeletal muscle oxygen utilization in HFPEF patients. Indeed, microvascular endothelial dysfunction, both at rest and following exercise, has been demonstrated in HFPEF patients.4 In addition, preliminary data obtained with phosphate magnetic resonance spectroscopy of the quadriceps muscle in HFPEF patients are compatible with impaired skeletal muscle oxidative metabolism.5 Therefore analysis of vascular function and energetic deprivation of skeletal myocytes has to be an integral part of our strategy to study the effects of exercise training in patients with HFPEF.

Ageing of populations partly explains why HFPEF is the only cardiovascular disease with increasing prevalence and incidence, affecting 10-20% of the elderly and contributing substantially to hospitalizations of elderly heart failure patients. Although the prognosis of HFPEF patients is slightly better than for those with HF with Reduced EF (HFREF), the 3-year fatality rate approaches 25 %6. As a result, the economic, social and personal burden of HFPEF is enormous. Therefore, this disease constitutes one of the most pressing unmet clinical needs in Europe.

1 Paulus WJ, et al. How to diagnose diastolic heart failure: a consensus statement on the diagnosis of heart failure with normal left ventricular ejection fraction by the Heart Failure and Echocardiography Associations of the European Society of Cardiology. Eur Heart J 2007 Oct; 28(20):2539-50
2 Owan TE, et al. Trends in prevalence and outcome of heart failulre with preserved ejection fraction. N Engl J Med 2006, 355: 251-259.
3 Haykowsky M, Brubaker P, Kitzman D. Role of physical training in heart failure with preserved ejection fraction. Curr Heart Fail Rep. 2012 Jun;9(2):101-6.
4 Borlaug BA et al. Global cardiovascular reserve dysfunction in heart failure with preserved ejection fraction. J Am Coll Cardiol. 2010 Sep 7;56(11):845-54.
5 Stoylen A, et al. Controlled study of myocardial recovery after interval training in heart failure: SMARTEX-HF--rationale and design.  Eur J Prev Cardiol. 2012 Aug;19(4):813-21.
6 Pocock Sj, et al. Prediciting survival in heart failure: a risk score based on 39372 patients from 30 studies, Eur Heart J 2013 May; 34(19):1404-13.