Observations on the Blood Pressure Paradox in Heart Failure (2017)

This article refers to ‘Prognostic value of long-term blood pressure changes in patients with chronic heart failure’ by F.A. Schmid et al., published in this issue on pages 837–842. In this issue of European Heart Failure Journal, Schmid et al.1 report the influence of long-term blood pressure (BP) changes on clinical outcomes in close to 1000 patients with heart failure (HF). The authors performed a retrospective analysis of patients with HF with either preserved or reduced ejection fraction (HFpEF and HFrEF, respectively) and demonstrated that patients with stable systolic blood pressure (SBP) over a year had the best survival. Systolic blood pressure changes with an increase or decrease of greater than ±10 mmHg/year were associated with a worse composite outcome (mortality or heart transplantation) and, importantly, the subgroup with the lowest SBP levels (<90 mmHg) had the worst survival. On the basis of these and related data, the authors conclude that a SBP <90 mmHg and increased long-term BP variability is associated with poor survival in HF. We will examine the relationship between BP, its variability and HF, focusing on the so-called ‘hypertension (HTN) paradox’ and ‘decapitated BP’ and its prognosis in patients with established HF, amplifying and corroborating the findings of Schmid et al.1 with those from other investigations. The morbidity and mortality associated with HTN relates, among other issues, to the development of hypertensive heart disease and ultimately of HF. Hypertensive heart disease is a assemblage of abnormalities that includes left ventricular (LV) hypertrophy, systolic and diastolic dysfunction, and their clinical manifestations, such as arrhythmias, coronary ischaemia and symptomatic HF.2, 3 Epidemiological data from the Framingham cohort have shown that a history of HTN can be documented in 91% of all newly diagnosed HF patients during up to 20 years of follow-up.1. In addition, among patients with HTN, myocardial infarction, diabetes mellitus (DM), LV hypertrophy, and valvular heart disease also predicted an increased risk of HF in both sexes.4 Not surprisingly, therefore, the prevention of HTN and other HF risk factors, such as obesity and DM in middle-aged subjects, portends HF-free survival.5 Thus, the absence of HTN, obesity, and DM by ages 45 years and 55 years is associated with up to 86% lower risk for incident HF in men and women across the remaining life span.5 Once HF is established and, especially, in patients with advanced HF, SBP is usually low, even in those who presented initially with HTN. This phenomenon has been called ‘decapitated hypertension’, that is, patients who have had HTN at the outset, progressively develop normal and even low BP as HF worsens and becomes more severe. A higher SBP in patients with HF is associated with a paradoxically protective effect on survival. Several studies, including the one published in this issue, have shown that in most HF populations, high and, not as one would expect, low SBP is associated with improved outcomes.1, 6-9 Similarly, a meta-analysis of 10 studies of patients with HF (n = 8088) by Raphael et al.10 demonstrated that a higher SBP was a favourable prognostic marker in HF; per BP increase of 10 mmHg there was a decrease in mortality of 13.0% that was not related to HF therapy. In addition, a retrospective study from the Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS)11 demonstrated that the lower the pretreatment SBP of patients in the cohort, the higher the risk of a major clinical event. For each 10 mmHg decrease in the pretreatment SBP, there was an 18% increase in the risk of death, an 11% increase in the combined risk of death or hospitalization for HF, and a 9% increase in the combined risk of death or hospitalization for any reason.11 However, it is not only BP per se that (paradoxically) determines the prognosis in HF but also variability in BP. Recently, the prognostic influence of BP and its variability was analysed in 288 patients with HFrEF who underwent ambulatory BP monitoring.12 It was found that daytime SBP ≤110 mmHg, daytime BP variability, and severe New York Heart Association (NYHA) class were independent predictors of cardiovascular disease (CVD) events and survival. Patients with a systolic daytime BP variability below a cut-off value of 19 mmHg had the worst prognosis. This study demonstrated that BP and its variability are simple tools in predicting CVD events in patients with HFrEF.12 The study by Schmid et al.1 not only support the findings that patients with HF and low SBP have a poor prognosis but also adds to our knowledge that changes in BP during follow-up are associated with CVD events. Heart failure patients with stable BP over a year had the best survival, BP changes with an increase or decrease of more than ±10 mmHg/year were associated with a worse composite outcome (mortality or heart transplantation) and the subgroup with the lowest SBP levels (<90 mmHg) had the worst survival. The majority of the studies previously summarized included patients with HFrEF, and in those patients, low SBP is associated with worse survival and CVD events. However, two recent studies have not shown a relationship between SBP and CVD mortality in HF. Huynh et al.13 reported on patients with a mean ejection fraction of 43% and an average SBP of 158 mmHg, and Koike et al.14 included 23% of patients with HTN as the aetiology of HF, with a mean SBP of 140 mmHg but no systolic function measurement; in these types of patients, HTN is a common cause of HFpEF. Whether or not SBP portends a difference in the prognosis in HFpEF than it does in HFrEF is not known. Notably, in the study of Schmid et al.,1 the majority of patients had HFrEF. A close relationship between SBP and CVD morbidity and mortality is anticipated from cardiac physiology. Arterial BP is determined by the cardiac output and the systemic vascular resistance. In patients with CVD but normal LV systolic function, BP is mostly determined by peripheral vasoconstriction. In patients with HFrEF, a low BP reflects not only a lower LV systolic contractility but also a lower cardiac output. Indeed, BP is low because the heart is unable to contract normally (decapitated hypertension). Therefore, a higher BP is associated with a decreased mortality because, in patients with HF, BP may be an indirect measure of LV function. Four decades ago this concept was put forth by Oakley15 when she wrote ‘The development of LV failure because of HTN determines a decrease of the previously raised BP to normal levels and, since the failure usually persists, the BP remains normal. If the patient recovers from HF, then the BP rises and the diagnosis is likely to be HTN’. This concept of decapitated hypertension was recently studied in patients with HF undergoing cardiac resynchronization therapy (CRT). A meta-analysis demonstrated that the utilization of CRT was associated with an increase in SBP by about 4 mmHg, no change in diastolic BP and an increase in pulse pressure compared with baseline or medical therapy. Whether this increase in BP is associated with improved survival is not yet known.16 However, in a recent study by Tanaka et al.,17 an increase in SBP following CRT was associated with a decrease in the combined endpoint of hospitalization owing to HF and mortality. Treating BP in HF patients means very much navigating between Scylla and Charybdis. Clearly, the studies reviewed herein have shown a close (paradoxical) relationship between BP and CVD events (i.e. the higher BP the better the outcome). However, measurement of SBP should not be considered as a substitute for measurements of LVEF and other markers more closely associated with cardiac output. Its value lies in its simplicity; SBP can be routinely measured at all outpatient visits and changes in SBP can be recorded to monitor disease progression, as the study by Schmid et al.1 shows. Notably, however, most if not all efficacious HF treatments will lower BP. In doing so the LV is unburdened, systolic function will improve and so will outcome. Thus, we are facing the paradoxical situation that a high BP remains a marker for a good prognosis in HF, but lowering BP remains a therapeutic necessity to improve or maintain LV function. This study, and others, have shown that there is a close relationship between SBP changes and CVD morbidity and mortality in patients with HF. This is called the BP paradox in HF and is contrary to the majority of CVD, where a high BP is an adverse prognostic sign. Quantitative awareness of this relationship between SBP and mortality may be of use in assessment or follow-up of patients with HF. In addition, it also lends indirect credence to the concept of monitoring SBP as a simple haemodynamic marker during non-invasive haemodynamic optimization of therapy, including CRT. Now that we have clearly identified a BP paradox in HF, we may learn from Niels Bohr, Nobel Laureate in physics, who commented to observers when an experiment took an unexpected turn, ‘How wonderful that we have met this paradox. Now we have some hope of making progress’.18