A Mechanistic Study to Assess The Role of Chronotropic Incompetence in Heart Failure With Normal Ejection Fraction (HFNEF)

BACKGROUND AND RATIONALE About 50% of patients with heart failure have a normal ejection fraction (HFNEF). Although traditionally considered a more benign disorder than the related heart failure with reduced ejection fraction (HFREF), the mortality figures for patients with HFNEF and HFREF are now known to be comparable. Surprisingly, despite HFNEF's importance as a major health concern, the pathophysiological basis of HFNEF's remains poorly understood with some commentators even suggesting that HFNEF's pathophysiology is a variant of HFREF. Further confounding the understanding of HFNEF, existing studies included heterogenous patients of stratified ethnicities and ages who were assessed at rest. Such patients may not exhibit the same physiology as the typically elderly female HFNEF patients who experience symptoms during exertion.

Elucidating the mechanisms underlying HFNEF is pressing as there is a paucity of evidence to even begin to guide therapy. In the absence of supportive trial evidence, clinical practice has been predicated on assumptions made regarding the physiology of diastolic (dys)function. For example, rate limitation is often advocated in HFNEF based on the 19th century observations by Lewis Katz that at higher heart rates, shortening of diastolic filling period impairs cardiac filling and results in lower stroke volumes.

Such empirical practices are beset by HFNEF's complexity. A consistent feature of HFNEF is reduced chronotropic reserve. In one study HFNEF patients were assessed invasively using pressure-volume loops during basal conditions and handgrip exercise with atrial pacing at 120bpm. It was concluded that at higher heart rates, there was a significant blunting of frequency-dependent ventricular relaxation and that rate-related diastolic chamber stiffness compromised stroke volume explaining exertional limitation. Other investigators have disputed the aberrancy of diastolic filling limitation, questioning the potential benefits of heart rate limitation using beta-blockers and raising the potential for pacing as a treatment for HNEF. We confirmed the impaired chronotropic reserve in HFNEF. We also demonstrated dynamic slowing of LV relaxation during exercise that was associated with and potentially attributable to impaired cardiac energetics (albeit at rest)9. However, to determine the pertinence of heart rate to inadequate exertional reserve in HFNEF, heart rate needs to be manipulated in the complex neurohormonal, autonomic and haemodynamic context of exercise. The fundamental limitation of existing studies, including those utilizing pacing and handgrip, is that exercise physiology was not recapitulated.

Cardiac MR is the most accurate and versatile method for phenotyping the heart in research studies, and can assess cardiac volumes and mass with unparalleled accuracy and reproducibility. 31P MRS is the only technique that allows non-invasive measurement of cardiac high-energy phosphate metabolism in vivo. Our department has developed a 31P-MRS protocol which allows for measuring high energy phosphate molecules at rest and during exercise Cardiopulmonary exercise testing with peak oxygen consumption measurement has been shown to be a reliable mechanistic readout of integrated cardiac function in heart failure with preserved ejection fraction9,. It is also safe and reliable in elderly patients with heart failure.

In summary, chronotropic incompetence could either be a compensatory phenomenon serving to limit cardiac energetic depletion on exercise and also increasing diastolic filling in the context of an abbreviated diastolic filling time due to dynamic slowing of active relaxation. Alternatively it might contribute to exercise limitation by limiting cardiac output augmentation on exercise (since cardiac output is the product of heart rate and stroke volume). In order to investigate this LV filling and cardiac output pathophysiology in HFNEF, we will employ Ivabradine, that reduces heart rate but has no direct effect on contractile/lusitropic function or on vascular tone.