Blood pressure control in heart failure: Is everything black and white?

A new term, “heart failure with mid‐range ejection fraction (HFmrEF),” was introduced in 2016 by the European Society of Cardiology guidelines. It referred to the heart failure (HF) patients with mildly reduced ejection fraction of 40%‐49% with the aim to stimulate research in this “gray area”.1

Current data suggest that HFmrEF represents 13%‐21% among patients with HF.2, 3 Several studies have demonstrated that clinical features of HFmrEF are intermediate between heart failure with preserved ejection fraction (HFpEF) and heart failure with reduced ejection fraction (HFrEF). Therefore, suggesting that HFmrEF is a transitional stage from HFpEF to HFrEF, or from HFrEF to HFpEF, or an overlap zone of HFpEF with lower‐end left ventricular ejection fraction (LVEF) and HFrEF with higher‐end LVEF, rather than a distinct entity from HF.4

Previous studies on HFmrEF showed that its etiology is more similar to HrEF than HFpEF. In the Swedish Heart Failure Registry that included 42 987 patients, the percentage of ischemic disease was 60% for HFrEF, 61% for HFmrEF, and 52% for HFpEF.3, 5 Other investigators showed that HFmrEF had an intermediate prevalence of hypertensive heart disease (HHD) in comparison with HFpEF (14.3% vs 24.5%4 and 27.6% vs 11.6%).6

There are several studies that investigated long‐term outcomes in HFmrEF patients.6, 7, 8 In the GWTG‐HF registry, all‐cause readmission rates for patients with HFmrEF were 20.9% at 30 days and 63.2% at 1 year, which were similar to those seen in patients with HFpEF (20.5% and 62.5%) and slightly higher than those seen in patients with HFrEF (19.7% and 59.6%). However, rates of cardiovascular readmission for patients with HFmrEF were higher than those seen in HFpEF and closer to those observed in patients with HFrEF.7, 8 The ESC Heart Failure Long‐Term Registry revealed that all‐cause mortality after 1 year was 8.8% for HFrEF, 7.6% for HFmrEF, and 6.4% in HFpEF (with a significant difference between HFpEF and HFrEF).6

Blood pressure (BP) is a significant prognostic factor in the incidence of HF and the treatment of hypertension is strongly recommended in order to prevent HF complications and decrease mortality in these patients.1 However, data regarding effect of BP on the outcome in HFmrEF patients are still scarce.

In this issue of the Journal, Marketou et al9 assessed the long‐term clinical outcomes of hypertensive patients with HFmrEF and HFpEF, as well as the impact of BP on cardiovascular outcome. This retrospective study included 121 HFpEF and 149 HFmrEF hypertensive patients. Age, gender distribution, heart rate, systolic blood pressure, and smoking status were similar between the observed groups.

After a median 84‐month follow‐up, the authors did not find a significant difference in mortality or morbidity between the HFmrEF and HFpEF patients. That can be explained that this HFmrEF population was homogenous, consisting of hypertensive patients without major comorbidities (eg, coronary artery disease (CAD) or severe valvular disease). In addition, the same results of the absence of significant difference in 5‐year outcomes between patients hospitalized with HFpEF, HFmrEF, and HFpEF were recently published.10 Although in this registry patients with HFmrEF and HFpEF had much more comorbidities including CAD, prior myocardial infarction, atrial fibrillation/flutter, chronic obstructive pulmonary disease or asthma, anemia, depression, and valvular heart disease.

Another interesting find of this study is during the 7‐year follow‐up period, uncontrolled systolic BP (SBP) and diastolic BP (DBP) were important predictors mainly in the HFmrEF patients. Namely, an office SBP > 139 mm Hg was significantly associated with both, overall survival and cardiovascular survival in the HFmrEF group. No significant association was found between SBP and outcome parameters in the HFpEF group. In a similar manner, DBP > 89 mm Hg had a significant negative impact on both overall survival and cardiovascular survival in the HFpEF group. Elevated DBP and increased left ventricular mass index had negative synergistic effects on overall and cardiovascular survival in hypertensive patients with HFmrEF. Moreover, the authors reported significant association between uncontrolled BP and mortality and hospitalization rate in HFmrEF, but not in HFpEF patients. This could be partly explained with the fact that the HFmrEF patients were frequently taking groups of the antihypertensive medications (renin‐angiotensin‐aldosterone inhibitors and β‐blockers) that are related with lower mortality rate in hypertensive population.

Several studies investigated the role of BP control on the outcome in hypertensive patients with HFpEF. Tsujimoto et al11 showed that low, rather than high, SBP at admission in the patients with HFpEF is an independent predictor of short‐ and long‐term mortality in this population. In patients with mild hypertension, SBP between 120 and 130 mm Hg and DBP between 70 and 80 mm Hg were associated with the lowest all‐cause mortality. On the other hand, the authors found an increased risk of myocardial infarction in patients with SBP < 120 mm Hg and DBP < 80 mm Hg.12

One should be cautious in the interpretation of the results of the present investigation. As the authors stated, the main limitation is a relatively small sample size and retrospective nature of the study. Therefore, there are several more points that need to be discussed in order to provide better clarification of obtained findings.

HFmrEF group had less comorbidities, such as atrial fibrillation, diabetes mellitus (DM) and obesity, in comparison with HFpEF group,9 which was not the case with other studies4, 10 Interestingly, the prevalence of NYHA functional class III was significantly higher in HFpEF than in HFmrEF patients (36% vs 7%), which demonstrated that HFpEF individuals were more symptomatic than HFmrEF. This could be probably explained with higher prevalence of diuretics usage in HFmrEF patients. Another important point is the absence BP data after follow‐up period. Therefore, it is unknown if BP was better controlled in one of the observed groups, which could also significantly effect outcome. Furthermore, the ambulatory BP monitoring was not performed and therefore the effect of white coat and masked hypertension in both groups could not be eliminated.

The significant difference in the proscribed therapy between the observed groups, which mostly refers to more frequent prescription of angiotensin‐renin‐aldosterone inhibitors and beta‐blockers in HFpEF patients, could significantly effect the obtained results because these medications improve outcome in HF patients13 and might induce better outcome in HFmrEF patients in the present study. Additionally, the medications were probably changed and adjusted over the 7‐year period, which should also be taken into account in the discussion of the current findings. Considering the fact that study was performed in Greece, the possible influence of lifestyle and Mediterranean diet in this cohort could not be excluded.

One should also notice that even though HFmrEF cohort included older patients with overt hypertensive heart disease and high prevalence of DM with reduced LVEF (45.9% ± 3.2%), this cohort of patients still had only slightly elevated NTproBNP and intermediate E/e' with significantly dilated left atrium. The reason for this could be a difference in therapy between the observed groups.

An important point that needs to be mentioned is the possibility that some patients may have moved between different HF categories during the duration of the study, which the authors of the study did not consider. Accuracy in LVEF measurement and interobserver variability may represent the important technical limitations.14, 15

Chronic HF patients in ambulatory settings represent different phenotypes in terms of demography, etiology, pathophysiology, clinical presentation, and outcomes. Furthermore, these patients have a high burden of cardiovascular and non‐cardiovascular comorbidities, which may interact on different levels. Hypertension is one of the most common comorbidities in patients with HF and most medications that have demonstrated to improve prognosis of these patients concomitantly reduce BP. The relationship between BP and clinical outcomes, as well as the relevance of BP reduction in HF remain to be clarified in larger, prospective and randomized studies in the future.

CONFLICT OF INTEREST

None.