Renal Dysfunction in Heart Failure with a Preserved Ejection Fraction: Cause or Consequence?

It has long been recognized that heart failure and renal dysfunction are a detrimental combination, and multiple studies have shown that chronic kidney disease (CKD) in heart failure patients is associated with an increased risk of mortality.1, 2 Although this is true for both heart failure patients with a reduced (HFrEF) and a preserved ejection fraction (HFpEF), this association has lately been suggested to be more pronounced in HFpEF patients. In a population-based study, poor renal function was significantly related to new-onset HFpEF, but was not a predictor for the onset of HFrEF.3 In a meta-analysis including >1 000 000 patients with established heart failure, the association between CKD and mortality was stronger in patients with HFpEF compared with patients with HFrEF.1 Similarly, in a propensity-matched study, CKD-associated mortality was higher in HFpEF patients than in HFrEF patients.4 Therefore, the association between renal function and heart failure seems to be of particular interest in patients with HFpEF. Despite several (recent) attempts to gain more insight into the pathogenesis of HFpEF using biomarkers,5-7 studies specifically investigating the underlying pathophysiology and characteristics of HFpEF patients with CKD are scarce. Therefore, the study by Unger et al. in this issue of the journal is of great importance, as it sheds more light on the association between abnormalities in cardiac function and CKD in HFpEF patients.8 The authors prospectively studied 299 HFpEF patients of which 145 patients (48%) had CKD at baseline, defined as an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2. Both established and novel echocardiographic measurements were used, including LV and right ventricular (RV) strain and left atrial strain parameters (booster, conduit, and reservoir strains). HFpEF patients with CKD had significantly higher LV mass, more impaired diastolic relaxation, and worse left atrial strain, LV longitudinal strain, and RV free wall strain. These findings remained significant after adjustment for multiple variables. Additionally, reduced eGFR was associated with an increased risk of impaired cardiac function parameters, and greater risk of poor outcome. On the basis of these findings, the authors conclude that in HFpEF patients, CKD is independently associated with increased cardiac remodelling, significantly worse cardiac mechanics, and outcome. This study provides several important insights into the interaction between HFpEF and renal dysfunction. First, it demonstrates that within a HFpEF population, patients with CKD have significantly more impaired diastolic dysfunction than those without CKD. Secondly, this study shows that systolic LV and RV function, as reflected by LV longitudinal strain and RV free wall strain, is worse in HFpEF patients with concomitant CKD. Interestingly, it was recently shown that HFpEF patients demonstrated significantly lower LV longitudinal strain and LV circumferential strain compared with both normal controls and hypertensive heart disease patients.9 So, patients with HFpEF have signs of impaired LV systolic function, and the current study adds that patients with HFpEF and CKD have even worse RV and LV systolic function. Thirdly, this study confirms the increased risk of poor outcome in patients with HFpEF and CKD. The major finding of this study is the association between CKD and impaired cardiac (systolic and diastolic) function in patients with HFpEF. This association can be explained by three possible scenarios: (i) CKD causing cardiac remodelling/dysfunction; (ii) cardiac remodelling/dysfunction causing worsening renal function; or (iii) a common mechanism causing both cardiac and renal failure. The first scenario is supported by several studies suggesting that CKD may affect cardiac dysfunction. We will provide a few selected examples. In a large cohort of CKD patients without known heart failure, the prevalence of LV hypertrophy increased from 32% to 75% over worsening stages of CKD.10 In CKD patients on dialysis, LV mass has, furthermore, been shown to increase with dialysis duration.11 In addition, a study comparing strain parameters in stage 2 and 3 CKD patients without cardiovascular disease with those in healthy controls found significantly reduced mean global strain and strain rate in CKD patients.12 Similarly, a study in haemodialysis patients without heart failure demonstrated abnormal strain parameters compared with controls.13 Proposed mechanisms by which renal dysfunction causes cardiac dysfunction are uraemic toxins, altered levels of renal endocrine factors, and dialysis.14 Uraemic toxins increase oxidative stress, and have been shown to cause vascular smooth muscle cell dysfunction.15 Dialysis is thought to cause regional myocardial stunning due to microvascular dysfunction, and hence to influence myocardial function negatively.16 Detrimental effects of HFpEF on renal function might explain the second scenario. Increased filling pressures typical for HFpEF both cause a decreased cardiac output (especially in situations of high demand) and increase central venous pressure. Together with an impaired ventricular–vascular coupling, this can lead to reduced renal blood flow, ultimately causing renal dysfunction.14 Finally, common pathways may have caused the development of both HFpEF and CKD at the same time. Common denominators underlying both are activation of the renin–angiotensin–aldosterone system and endothelial dysfunction. Multiple studies have shown an association between endothelial dysfunction and HFpEF, and a novel paradigm suggesting endothelial dysfunction as a prominent determinant of HFpEF was recently proposed.17 Similarly, there is evidence suggesting a relationship between endothelial dysfunction and renal failure.18 Unfortunately, due to the cross-sectional study design, the study by Unger et al. is unable to distinguish the causality of the association between HFpEF and CKD. Unravelling the observed association between CKD and cardiac structure and function in HFpEF is of importance and may lead to identification of (novel) targets for treatment for this high-risk patient group.19 In the case of the first scenario, therapies should be targeted at preventing the development of CKD. In the second scenario, therapies should be aimed at preventing or treating HFpEF. Finally, if common pathways are identified in the development of HFpEF and CKD, treatment will have to be aimed at targeting these. To achieve this, we will need to gain more knowledge regarding the interaction between HFpEF and CKD, as available therapies in both patient groups are limited,20 and are complicated by detrimental interactions, such as loop diuretics and aldosterone antagonists. The findings of Unger et al. are therefore of great value as they provide novel, important information regarding cardiac dysfunction in HFpEF patients with CKD. Conflict of interest: none declared.