Hypertension and heart failure: insights from exercise stress testing.

Abstract

This article refers to ‘Haemodynamic and metabolic phenotyping of hypertensive patients with and without heart failure by combining cardiopulmonary and echocardiographic stress test’ by N.R. Pugliese et al., published in this issue on pages 458–468. Systemic hypertension is the most common chronic disease among older adults, with a worldwide prevalence exceeding 1 billion. In fact, the term ‘essential’ hypertension is still commonly used to describe this condition, implying its virtually inevitable occurrence with aging. Similarly, heart failure with preserved ejection fraction (HFpEF) has now become the most common cause of heart failure worldwide, with a striking increase in prevalence among older adults. The time-honoured paradigm describing HFpEF development is that systemic arterial hypertension leads to left ventricular (LV) pressure overload, promoting hypertrophy, interstitial fibrosis and LV diastolic dysfunction. However, numerous randomized trials of antihypertensive therapies have been unsuccessful in HFpEF, despite meaningful reductions in arterial pressure, which would be difficult to explain if hypertension was the exclusive pathophysiological driver of the syndrome.1 Longitudinal studies have shown that age-related LV stiffening progresses even when blood pressure is well-controlled or lowered, particularly among patients with obesity, which has emerged as the most potent risk factor for HFpEF in the current era.2, 3 Thus, while patients usually develop HFpEF in the background of hypertension, the clinical factors associated with this progression from hypertension to HFpEF remain only partially understood.4-6 In this issue of the Journal, Pugliese et al.7 report the results of a prospective study using non-invasive exercise stress echocardiography (ESE) with cardiopulmonary exercise testing (CPET) to explore these questions. The authors recruited 63 asymptomatic hypertensives, 50 patients with hypertension and HFpEF, and 32 healthy controls. All participants underwent state-of-the-art, non-invasive CPET with simultaneous echocardiography and lung ultrasound to evaluate for pulmonary congestion. Oxygen consumption (VO2) was measured by expired gas analysis, stroke volume (SV) was measured from pulsed wave Doppler echocardiography, and cardiac output (CO) calculated as the product of SV and heart rate. Arterio-venous oxygen difference (AVO2D) was then calculated according to the Fick principle. At rest, the major differences between the hypertension and HFpEF groups were greater number of hypertensive drugs needed in HFpEF, higher left atrial volumes, and more severely impaired LV diastolic function and right ventricular–pulmonary artery coupling. The estimated probability of HFpEF progressively increased across the three groups.8 With exercise, there was a gradient of worsening exercise capacity, higher estimates of filling pressure and extravascular lung water moving from controls to hypertension to HFpEF, implying a worsening of LV diastolic reserve with stress. Some of the hypertension patients even developed pulmonary oedema during exercise, suggesting the presence of unrecognized HFpEF.9 There were changes in patterns of ventilatory control consistent with increased dead space ventilation, earlier anaerobic metabolism and development of lung congestion,10 with progressive decreases in ventilatory efficiency and oxygen uptake efficiency slope across groups. Graded impairments in exercise CO were observed, but CO was only statistically lower in the HFpEF group. Notably, and in striking contrast to prior studies, there were no differences in HFpEF compared to the hypertension or control groups in SV reserve with exercise.6, 11, 12 Right and left ventricular reserve were most impaired in the HFpEF group, manifest by lower global longitudinal strain (GLS), and the hypertension group displayed subtle abnormalities of GLS when compared to controls, supporting a continuum with HFpEF. Calculated AVO2D was lower in HFpEF and hypertension than controls. The authors conclude from these data that impairments in peak VO2 in hypertension and HFpEF may be the result of a decreased AVO2D, and that CPET with echocardiography can help identify deficits in LV functional reserve and pulmonary congestion in hypertension patients at risk for HFpEF. This study provides valuable confirmation of earlier studies evaluating the continuum from aging to hypertension to HFpEF, showing a generalized and graded reduction in cardiac functional reserve across this spectrum.5, 6 In addition, there are important new findings, including the demonstration of increases in lung congestion during exertion that was observed even in the hypertension group. While LV ejection fraction was similar in all three groups, LV GLS was 25% lower in the HFpEF cohort at rest and during exercise, also consistent with earlier studies showing deficits in LV contractility and contractile reserve in HFpEF.5, 6 To specifically probe the continuum of hypertensive patients, the authors excluded patients with atrial fibrillation and diabetes. This does affect the generalizability of the results, because these comorbidities are present in 40–50% of patients.1 While the assessment of cardiac function was extremely comprehensive, left atrial function was not assessed in this study, limiting the ability to identify a potential relationship between hypertension and HFpEF. Despite exclusion of atrial fibrillation, patients with HFpEF display differing left atrial function13, 14 and it is probable that impairment in left atrial reserve may contribute to the transition from hypertension to HFpEF as suggested by a prior study.4 Finally, it is notable that the study cohort included predominantly men (81%). This differs from what is seen in the community where women outnumber men with HFpEF by a 2:1 ratio.1 In addition to the findings of abnormal cardiac reserve that were unmasked by exercise, the authors also observed that AVO2D was lower in both HFpEF and hypertensives when compared to controls, which they interpret to reflect a peripheral deficit common to both hypertension and HFpEF patients early in the course of disease progression. AVO2D reflects the difference in oxygen content between the arterial blood departing the left ventricle and the mixed venous blood returning to the lungs, measured in the pulmonary artery. Therefore, AVO2D is determined by measuring arterial saturation, haemoglobin and pulmonary artery saturation. In the current study, AVO2D was not directly measured but calculated from the Fick principle (AVO2D = VO2/CO). What explained the differences in AVO2D observed in the current study? There was no evidence of a reduction in arterial oxygen content or haemoglobin in any cohort. Therefore, differences in calculated AVO2D would have to be related to venous oxygen content. Normally, AVO2D increases with exercise to a level that numerically approximates the plasma haemoglobin concentration, because oxygen removal in skeletal muscle increases several fold. This was exactly the case in the hypertension and HFpEF groups (exercise AVO2D 13.3–13.5 mL/dL). However, in the control group, the calculated AVO2D at peak exercise was extremely high (16.9 ± 2 mL/dL), far exceeding the haemoglobin. Based upon the reported arterial saturations and haemoglobin levels in the control group, this would correspond to an average pulmonary artery saturation of only 7% in the control group with exercise, approaching the lowest value ever recorded in man. Since this seems implausible, and because AVO2D was calculated and not directly measured, its mathematical determinants (VO2/CO) bear scrutiny. VO2 was directly measured using robust techniques, pointing to a problem with CO estimation. SV was measured using pulsed wave Doppler, which can be technically challenging during exercise, due to greater respiratory motion with poor Doppler alignment with the outflow tract, high ejection flow rates exceeding the Nyquist limit causing aliasing artefact, and possible violations of the assumption that the LV outflow tract diameter remains constant during exercise (with an error that is squared). If SV and CO were underestimated in controls, this would explain how their AVO2D was much higher than expected, and also why HFpEF patients in this study did not display a reduction in SV compared to controls during exercise, despite impairments in LV systolic function, contradicting several studies.6, 11, 12 Exercise stress echocardiography and CPET can be a valued asset in clinical care and scientific investigation, and this modality has substantially advanced our understandings of heart failure.15, 16 The data by Pugliese et al.7 support the utility of CPET testing and add to the growing body of literature demonstrating the potential added value of lung ultrasonography9 and exercise E/e'17 in evaluating HFpEF among hypertension patients at risk. However, given the discrepancies and potential error in estimating CO during exercise with ESE (and all variables calculated from CO), we need to remember to maintain a healthy degree of skepticism. ESE represents a valuable and powerful tool in the care of patients with hypertension, but we must always be mindful of its strengths and weaknesses. Dr. Borlaug is supported by RO1 HL128526 and U10 HL110262. Conflict of interest: none declared.