Hypertensive response to exercise, hypertension and heart failure with preserved ejection fraction (HFpEF)—a continuum of disease?

The global prevalence of heart failure (HF) ranges between 1–2% in developed countries and, despite outcome improvement over the past 30 years, HF still entails overall a poor prognosis, comparable to cancer [1‐3]. The latest European data on outcomes in patients with HF report on an all-cause mortality over 12 months of 14% in hospitalized and 7% in out-patient patients [4]. As such, there is great need for further improvement in HF prevention, diagnosis, and treatment. The newly published guidelines on HF of the European Society of Cardiology classify HF in three distinct subcategories of HF: HF with reduced ejection fraction (HFrEF), defined as a LVEF (left ventricular ejection fraction) of \(\leq\)40%, HF with mildly-reduced EF (HFmrEF), defined as LVEF 41–49%, and HF with preserved EF (HFpEF), defined as LVEF \(\geq\)50% [1]. Currently, HF is defined as a clinical syndrome consisting of symptoms that may be accompanied by signs and which is due to structural or functional heart anomalies resulting in elevated intracardiac filling pressures and/or inadequate cardiac output at rest and/or during exercise [5]. The diagnosis of HFpEF is challenging and supported by two score-based algorithms (H2FPEF and HFA-PEFF) which includes clinical, echocardiographic and blood laboratory values parameters.[6, 7]. Although HFpEF accounts for approximately 50% of all patients with HF, pathophysiological understanding and treatment options are limited [8‐10]. There are a number of hypotheses on the pathogenesis of HFpEF, one of which being the assumption that diastolic dysfunction mainly, but not solely contributes to the development and course of HFpEF [11, 12]. Besides the functional patho-mechanisms, structural changes have been shown in patients with HFpEF: hypertrophic cardiomyocytes appear to be more frequent in HFpEF than in HFrEF [13] and collagen fraction is significantly increased compared to control persons [14]. There have been investigations concerning risk factors for the development of HFpEF, stating that age seems to be the most influencing, together with obesity, metabolic syndrome, sedentary lifestyle and arterial hypertension (aHT) [11].

The diagnosis of arterial hypertension relies upon accurate, reliable, and standardized blood pressure measurements. Indirect, cuff-based blood pressure measurements are typically performed with automated devices based on oscillometric techniques. Office blood pressure is the gold standard for diagnosis arterial hypertension, however, current guidelines recommend to confirm the diagnosis with out-of-office measurements such as ambulatory or home blood pressure monitoring with repeated measurements [15, 16]. In this review we focused on hypertensive response to exercise (HRE), as measured by using both automated and auscultation-based devices during physical effort while performing ergometry. HRE is defined as an exaggerated blood pressure response to exercise (EBPR), and has been shown to be related with a higher risk of development of future aHT [17‐19]. No universally accepted definition of HRE exists today, however, several previous studies have suggested a systolic blood pressure elevation during exercise testing ≥ 210 mm Hg for men and ≥ 190 mm Hg for women or diastolic blood pressure elevation > 110 mm Hg in both genders [20‐24]. According to the current European guidelines for sports cardiology, an exaggerated systolic blood pressure (SBP) to > 200 mm Hg at a workload of 100 W during exercise testing should prompt a clinical evaluation and optimization of antihypertensive medical therapy; whereas in young Olympic athletes a peak SBP > 220 mm Hg in males and > 200 mm Hg in females are beyond the 95th percentile [25]. In a recent review, our group described how HRE is not a normal finding in athletes and, as such, it might represent a risk factor for the future development of cardiovascular complication [26]. The current European guidelines for sports cardiology, although recognizing the under investigated problem of HRE, did not propose any definition for HRE [16].

Estimations about the prevalence of HRE range between 3–4% in a systematic review [27], 18% in a cohort of normotensive, young and healthy men and women [28], and 40% in a study of middle-aged, healthy men [29]. As with prevalence, pathophysiological processes and clinical implications of HRE are poorly understood.

It is the aim of this review to evaluate the available evidence for the hypothesis of a continuum of HRE, aHT and HFpEF.

The systematic literature search was carried out using the PRISMA 2020 guidelines [30]. As for literature extraction, the PubMed database was searched for papers with the use of the following terms: “heart failure”, “diastolic heart failure”, “heart failure with preserved ejection fraction”, “hypertensive response to exercise”, “exercise hypertension”, “exaggerated blood pressure response”, “hypertension”, “arterial hypertension”, “systemic hypertension”. Only articles in English and studies/reviews who were done in humans were included.

Duplicates were systematically studied and removed from the analysis. In order to find the relevant articles, title and abstract were screened and read respectively.

The literature search was implemented in three steps to connect the medical conditions with each other and find evidence for the continuum of disease: HRE and aHT, aHT and HFpEF, as well as HRE and HFpEF. As for the connection between aHT and HFpEF, we had no claim to completeness in this review as the association is well established [31, 32]. Also, a thorough and complete analysis on the pathogenesis of HFpEF with respect to aHT would have gone beyond the scope of this review. Hence, only major articles on this topic were included to demonstrate the association of aHT and HFpEF. Regarding HRE and aHT, the literature search yielded 251 papers. Out of those papers, 3 were excluded due to being duplicates and another 219 after checking the title and reading the abstract. Finally, 29 articles were classified as being relevant to the topic and 10 articles were found to be adequate to address our research question as whether HRE is a possible precursor of aHT (Fig. 1, Table 1). The literature search on a possible association of HRE and HFpEF yielded a total of 53 papers, out of which 13 were excluded being duplicates. Another 32 articles were excluded after screening the title and reading the abstract. Out of the 8 articles left for full-text analysis, 6 were found to be suitable to our research question (Fig. 2, Table 2). All relevant articles were read and included into this narrative review.

This review article aimed to investigate possible associations i.e. a continuum of disease of HRE, aHT and HFpEF. Indeed, if such a continuum exist, HRE would be the earliest detectable pathology in the long term development of HFpEF and therefore would have huge clinical implications.

In conclusion, there is coherent data on the association between HRE and aHT, as well as between aHT and HFpEF—however, long-term data investigating the continuum of disease is scarce (yet promising) and further research is needed. Our comprehensive literature search revealed suggestive data concerning a connection between all three conditions: patients with HRE are at risk of developing aHT [33‐35, 37‐39], aHT itself is known to be one of the main risk factors for the development of HFpEF [46, 59, 60], and HRE being linked to diseases at risk of ending in HFpEF, such as LV diastolic dysfunction and CAD [50, 51, 56‐58]. aHT represents the principal risk factor for the development of HFpEF and, as such, has been intensely studied. Early findings, as well as newer insights, consequently underline the fact that aHT can progress to HFpEF over time. Figure 3 shows a summary of patho-mechanisms and a possible course of disease. Hence, the key question seems to be to which extent HRE in otherwise young and healthy individuals poses a risk to progress to aHT in the future. In this review, we have reported on several studies which support such an association. However, uncertainties still remain: How should HRE be defined? Should we focus more intensely on measuring DBP during exercise, rather than on SBP? Gender and ethnic aspects should be further elucidated in future studies. Long-term prospective studies investigating cardiovascular outcomes in patients with HRE are needed to address these questions and corroborate our hypothesis of a continuum of disease.