Renal Denervation in Patients with Heart Failure with Preserved Ejection Fraction: End of the Beginning? (2016)

This article refers to ‘Renal denervation in heart failure with preserved ejection fraction (RDT-PEF): a randomized controlled trial’, by H.C. Patel et al., published in this issue on pages XXX–XXX. Heart failure (HF) represents a significant and growing health burden affecting nearly 25 million people worldwide.1 Up to 50% of all patients with clinical signs of HF present with heart failure with presevered ejection fraction (HFpEF), which is defined as a clinical HF state accompanied by objective evidence of diastolic dysfunction. The pathophysiology of HFpEF is still incompletely understood but may involve, among others, impaired LV filling, increased LV stiffness, abnormal ventricular–arterial coupling, chronotropic incompetence, hypertension, CAD, and microvascular dysfunction.2 Sympathetic nervous system (SNS) activation with a subsequent increase in the activity of the renin–angiotensin system plays a crucial role and is related to cardiovascular outcomes in chronic systolic HF.3 Current evidence also suggests a relationship between increased SNS activity and HFpEF, measured by MIBG (metaiodobenzylguanidine) scintigraphy, muscle sympathetic nerve activity (MSNA), plasma norepinephrine (NE) levels, and heart rate variability.4 However, available evidence appears insufficient to identify whether features of HFpEF potentiate SNS activity or whether increased SNS causes HFpEF.4 Irrespective of the exact underlying mechanisms, modulation of autonomic tone represents an increasingly interesting treatment target.3, 5 Several experimental studies have nicely shown that surgical sympathectomy of the kidneys after myocardial infarction can down-regulate angiotensin AT1 receptor-mediated maladaptive responses, improve sodium excretion, increase cardiac output, and enhance renal blood flow.3, 6 In light of limited treatment options and the fact that various interventions in HFpEF patients were neutral at best, alternative treatment strategies are urgently needed. Catheter-based renal denervation (RDN) has evolved as an interventional treatment option under investigation for patients with hypertension.7 It has been shown to lower blood pressure (BP) significantly in certain patients with uncontrolled hypertension, but with quite some variability in treatment effects.8 There is evidence indicating that RDN can decrease MSNA9 as well as cardiac sympathetic activity,10 measured by MIBG scintigraphy, thereby demonstrating a direct effect on the myocardium, most probably by altering renal afferent SNS and thereby central SNS. In patients with severe uncontrolled hypertension and in part fulfilling the criteria of HFpEF, RDN has been associated with a reduction of LV mass measured by echocardiography and an improvement of diastolic function as evaluated by tissue Doppler measurements.11 These findings were recently confirmed by a magnetic resonance imaging (MRI) study,12 where MRI evaluations were blinded to procedural and patient's characteristics, in which myocardial hypertrophy reduction and left atrium remodelling occurred in a partly BP-independent manner. Given the strong pathophysiological concept and the sound pre-clinical and early clinical data, scientific assessment of the potential role of RDN in patients with HFpEF appears reasonable. In this issue of the journal, Patel et al.13 present the results of their single-centre, prospective, randomized, controlled, open-label Renal Denervation in Heart Failure with Preserved Ejection Fraction (RDT-PEF) trial. The primary trial success criterion was defined a priori as an improvement in at least three of the six endpoints [the Minnesota Living with Heart Failure Questionnaire; peak treadmill exercise oxygen uptake (VO2 peak); BNP; E/e' (ratio of early mitral outflow velocity to average of medial and lateral mitral annular tissue velocity); left atrial volume; and LV mass index (from cardiac MRI)] at 12 months of follow-up. The trial aimed at randomizing 36 patients (2:1) to receive RDN using the Symplicity single-electrode catheter or medical treatment only. The trial adds to our current knowledge on the importance of proper study design in the field of interventional autonomic modulation studies. Investigators should be encouraged rigorously to investigate and delineate the potential of catheter-based RDN in HF, not just diastolic but also systolic, as studies directly examining the use of RDN to treat HF are still sparse. The non-randomized, single-arm REACH-Pilot study Ref 23 showed in a limited number of patients (n = 7) a trend towards an improvement in the 6-min walking distance at 6-month follow-up, and a trend towards a reduction in diuretic therapy with no adverse effects documented, but the study design and methodology limit interpretation of the findings. Future, randomized, (sham)-controlled studies are needed, and some are ongoing, to clarify the potential of RDN in the management of HF patients.3 The future will hopefully tell us whether the RDT-PEF study will be regarded as the beginning of the end or the end of the beginning for catheter-based RDN in HF. Whatever the case may be, modulation of the autonomic tone remains an interesting target for device-based therapies in HF. Conflict of interest: F.M. is supported by the Deutsche Hochdruckliga und Deutsche Gesellschaft für Kardiologie. M.B. is supported by the Deutsche Forschungsgemeinschaft (KFO 196). The institution received research grants from Medtronic and St. Jude Medical. F.M. and M.B. received speaker honoraria from Medtronic and St. Jude Medical. S.E. reports no potential conflicts of interest.