Relationship of loop diuretic use with exercise intolerance in heart failure with preserved ejection fraction

Loop diuretics (DIUs) are routinely prescribed to relieve and prevent recurrent fluid congestion in patients with heart failure (HF).1,2 Accumulating evidence suggests that long-term use of loop DIU increases cardiovascular mortality in a dose-dependent manner.3–5 The detrimental impact of sustained loop DIU therapy can be exacerbated in normo- or hypovolemic patients presenting with impaired ventricular diastolic filling, predominantly observed in the condition of HF and preserved ejection fraction (HFpEF).6 In these patients, diuresis may further curtail the pressure gradient propelling venous return to the heart, resulting in reduced ventricular filling, preload, and stroke volume,7,8 which thereby limits cardiac output reserve and plausibly contributes to the primary chronic symptom of HFpEF, i.e. exercise intolerance. Therefore, the aim of this study was to assess the relationship between loop DIU use and exercise intolerance determined by peak oxygen consumption (VO2peak), a hallmark of exercise capacity, in stable HFpEF patients. Forty HFpEF patients were identified via a retrospective chart review of the HF outpatient clinic of the University Hospital of Zurich from January 2016 to August 2017. Inclusion criteria comprised: signs and symptoms of HF,1 preserved left ventricular ejection fraction (LVEF >50%), elevated levels of N-terminal pro b-type natriuretic peptide (NT-proBNP >125 pg⋅mL−1), relevant structural and/or functional cardiac alterations, evaluation of VO2peak with incremental cycle ergometry until volitional exhaustion eliciting a heart rate >95% of age-predicted maximal heart rate and/or respiratory exchange ratio >1, as well as stable clinical status, echocardiographic parameters and medication ≥4 weeks before VO2peak assessment. The degree of left ventricular diastolic dysfunction (LVDD) was assessed with a four-point ordinal scale (1 indicates normal; 2 indicates impaired relaxation; 3 indicates pseudonormal; 4 indicates restrictive) according to established guidelines.1,9,10 The study was approved by the local ethics committee and all patients provided written informed consent. Statistical analysis was performed using IBM SPSS v. 20 (Chicago, IL, USA) software package. Data were tested for normal distribution with Kolmogorov–Smirnov test and for homogeneity of variances with Levene’s test. Heart failure and preserved ejection fraction patients treated and non-treated with loop DIU were compared using independent sample t-test, Mann–Whitney U-test and Fisher’s exact test for parametric, non-parametric, and dichotomous data, respectively. Bivariate regression analyses between study variables and exercise capacity [VO2peak, peak power output (Wpeak)] were tested with Pearson’s correlation coefficient. Non-parametric variables were logarithmically transformed to approximate normality before regression analyses. A two-tailed P-value <0.05 was considered significant. Data are reported as mean ± standard deviation. A two-tailed P-value <0.05 was considered significant. The clinical characteristics of HFpEF patients are presented in Table 1. Heart failure and preserved ejection fraction patients treated (n = 23) and non-treated (n = 17) with loop DIU were remarkably similar regarding age, sex, weight, height, body mass index, LVEF, blood pressure, heart rate, aetiology, and comorbidities. Likewise, there was no difference in the dose of prevailing medications (other than loop DIU) such as angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers and beta-blockers. Main clinical characteristics of heart failure with preserved ejection fraction patients treated and non-treated with loop diuretic Significant differences between groups (P < 0.05) are presented in bold. ACEI, angiotensin-converting enzyme inhibitor; AF, atrial fibrillation; ARB, angiotensin II receptor blocker; BB, beta-blocker; BMI, body mass index; BSA, body surface área; CAD, coronary artery disease; CCB, calcium channel blocker; DBP, diastolic blood pressure; DIU, diuretic; DM, diabetes mellitus; HCM, hypertrophic cardiomyopathy; HFpEF, heart failure with preserved ejection fraction; HR, heart rate; LVEF, left ventricular ejection fraction; MRA, mineralocorticoid receptor antagonist; SBP, systolic blood pressure; y/n, yes/no. Torasemide. Perindopril equivalents. Candesartan equivalents. Carvedilol equivalents. Spironolactone equivalents. Rosuvastatin equivalents. Main clinical characteristics of heart failure with preserved ejection fraction patients treated and non-treated with loop diuretic Significant differences between groups (P < 0.05) are presented in bold. ACEI, angiotensin-converting enzyme inhibitor; AF, atrial fibrillation; ARB, angiotensin II receptor blocker; BB, beta-blocker; BMI, body mass index; BSA, body surface área; CAD, coronary artery disease; CCB, calcium channel blocker; DBP, diastolic blood pressure; DIU, diuretic; DM, diabetes mellitus; HCM, hypertrophic cardiomyopathy; HFpEF, heart failure with preserved ejection fraction; HR, heart rate; LVEF, left ventricular ejection fraction; MRA, mineralocorticoid receptor antagonist; SBP, systolic blood pressure; y/n, yes/no. Torasemide. Perindopril equivalents. Candesartan equivalents. Carvedilol equivalents. Spironolactone equivalents. Rosuvastatin equivalents. Table 2 shows exercise capacity, echocardiographic, haematology, and blood chemistry variables. VO2peak and Wpeak at the incremental exercise test were reduced (−24% and −35%, respectively) in HFpEF patients treated vs. non-treated with loop DIU (15.62 ± 4.97 vs. 19.39 ± 5.03 mL·min−1·kg−1, P = 0.024; 1.36 ± 0.66 vs. 1.84 ± 0.78 W·kg−1, P = 0.040, respectively), despite similar peak exercise effort as reflected by the respiratory exchange ratio. An echocardiographic difference was noted for the degree of LVDD, which was augmented (+59%) in HFpEF patients treated with loop DIU (2.60 ± 0.83 vs. 1.64 ± 0.50, P = 0.002). None of the haematological and blood chemistry variables differed between groups, with the exception of a 7% decrease in NT-proBNP in HFpEF patients treated with loop DIU (1291.2 ± 1261.3 vs. 1379.9 ± 3977.3 pg·mL−1, P = 0.012). In regression analyses (Table 3), loop DIU dose (r = −0.35, P = 0.027), ascending aorta diameter (r = −0.43, P = 0.010), degree of LVDD (r = −0.41, P = 0.037), Quick (r = −0.37, P = 0.042), C-reactive protein (r = −0.60, P < 0.001), and low-density lipoprotein (r = −0.42, P = 0.025) were negatively associated with VO2peak. Exercise capacity, echocardiographic and biochemical characteristics of heart failure with preserved ejection fraction patients treated and non-treated with loop diuretic Significant differences between groups (P < 0.05) are presented in bold. CRP, C-reactive protein; eGFR, estimated glomerular filtration rate; Hb, haemoglobin; Hct, haematocrit; HFpEF, heart failure with preserved ejection fraction; K, potassium; LA, left atrium; LDL, low-density lipoprotein; LV, left ventricle; LVDD, left ventricular diastolic dysfunction; LVEDV, left ventricular end-diastolic volume; LVEDVI, left ventricular end-diastolic volume index; LVMMI, left ventricular myocardial mass index; MCH, mean corpuscular haemoglobin; MCHC, mean corpuscular haemoglobin concentration; MCV, mean corpuscular volume; Na, sodium; NT-proBNP, N-terminal pro b-type natriuretic peptide; RA, right atrium; RDW, red cell distribution width; RERpeak, peak respiratory exchange ratio; RV, right ventricle; TAM, tricuspid annulus motion; TSH, thyroid-stimulating hormone; VEpeak, peak pulmonary ventilation; VO2peak, peak oxygen consumption; Wpeak, peak power output. The degree of LVDD was assessed on a four-point ordinal scale (1 indicates normal; 2 indicates impaired relaxation; 3 indicates pseudonormal; 4 indicates restrictive) according to established guidelines.1,9,10 Exercise capacity, echocardiographic and biochemical characteristics of heart failure with preserved ejection fraction patients treated and non-treated with loop diuretic Significant differences between groups (P < 0.05) are presented in bold. CRP, C-reactive protein; eGFR, estimated glomerular filtration rate; Hb, haemoglobin; Hct, haematocrit; HFpEF, heart failure with preserved ejection fraction; K, potassium; LA, left atrium; LDL, low-density lipoprotein; LV, left ventricle; LVDD, left ventricular diastolic dysfunction; LVEDV, left ventricular end-diastolic volume; LVEDVI, left ventricular end-diastolic volume index; LVMMI, left ventricular myocardial mass index; MCH, mean corpuscular haemoglobin; MCHC, mean corpuscular haemoglobin concentration; MCV, mean corpuscular volume; Na, sodium; NT-proBNP, N-terminal pro b-type natriuretic peptide; RA, right atrium; RDW, red cell distribution width; RERpeak, peak respiratory exchange ratio; RV, right ventricle; TAM, tricuspid annulus motion; TSH, thyroid-stimulating hormone; VEpeak, peak pulmonary ventilation; VO2peak, peak oxygen consumption; Wpeak, peak power output. The degree of LVDD was assessed on a four-point ordinal scale (1 indicates normal; 2 indicates impaired relaxation; 3 indicates pseudonormal; 4 indicates restrictive) according to established guidelines.1,9,10 Bivariate regression analyses between study variables and exercise capacity in heart failure with preserved ejection fraction patients BB, beta-blocker; CRP, C-reactive protein; DIU, diuretic; HFpEF, heart failure with preserved ejection fraction; LDL, low-density lipoprotein; LV, left ventricle; LVDD, left ventricular diastolic dysfunction; LVEDVI, left ventricular end-diastolic volume index; NS, not significant; r, Pearson correlation coefficient; RV, right ventricle; VO2peak, peak oxygen consumption; Wpeak, peak power output. Bivariate regression analyses between study variables and exercise capacity in heart failure with preserved ejection fraction patients BB, beta-blocker; CRP, C-reactive protein; DIU, diuretic; HFpEF, heart failure with preserved ejection fraction; LDL, low-density lipoprotein; LV, left ventricle; LVDD, left ventricular diastolic dysfunction; LVEDVI, left ventricular end-diastolic volume index; NS, not significant; r, Pearson correlation coefficient; RV, right ventricle; VO2peak, peak oxygen consumption; Wpeak, peak power output. This study determined the association between use of loop DIU and exercise intolerance, measured objectively by VO2peak, in stable HFpEF patients. The main results are: (i) VO2peak is markedly reduced in HFpEF patients treated compared with non-treated with loop DIU; (ii) the dose of loop DIU is linearly related to the impairment of VO2peak; (iii) LVDD is augmented in HFpEF patients treated with loop DIU and correlated to VO2peak. Considering that clinical characteristics and common medications for HF did not differ between groups, these findings suggest a potential contribution of loop DIU to the limitation of exercise capacity in HFpEF patients. Prior clinical investigations have demonstrated that short-term preload reduction therapy including loop DIU induces substantial decrements in LV diastolic filling, stroke volume, and cardiac output in HFpEF [but not in HF with reduced ejection fraction (HFrEF)] patients, notably in those presenting with higher left ventricular (LV) stiffness and degree of LVDD.7 In these patients, loop DIU withdrawal enhances LV diastolic filling and orthostatic tolerance as well as reduces renin-angiotensin system activation.8,11 These phenotypic modifications resulting from loop DIU withdrawal are consistent with improved blood volume regulation in HFpEF patients. The present is the first study assessing the relationship of loop DIU with exercise intolerance, the primary chronic symptom of the HFpEF condition.1 The observation that loop DIU is negatively associated with VO2peak in a dose-dependent manner, concurrent with depressed LVDD (correlated to the dose of loop DIU), extends precedent findings of haemodynamic dysregulation attributed to loop DIU.7,8,11 Hence, prolonged loop DIU therapy may chronically diminish LV diastolic filling, preload, stroke volume, and cardiac output reserve, leading to exercise intolerance in HFpEF patients. A limitation to this study, involves the assessment of LV diastolic function with the four-point ordinal scale primarily based on LV filling dynamics. Further studies may pinpoint more specific features of LVDD in association with loop DIU therapy. Taken together, this study highlights the need of further scrutiny of loop DIU medication in the attempt to optimize the treatment of HFpEF.12 D.M. received research salary from the Forschungskredit Grant, Faculty of Medicine, University of Zurich. Conflict of interest: none declared.