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EDITORIAL COMMENTARIES

Hypertension and aortic stenosis

no strangers, not anymore!

Manolis, Athanasios J.; Kallistratos, Manolis.S.; Poulimenos, Leonidas E.

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doi: 10.1097/HJH.0000000000002226
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Aortic stenosis, the most common valvular heart disease, is closely related to the traditional cardiovascular disease (CVD) risk factors. Hypertension (HTN) dyslipidaemia, diabetes mellitus and smoking roughly account for 30–40% of the lifetime risk for aortic stenosis, and their presence and duration exerts a positive dose–response to the risk of developing aortic stenosis [1]. Not only the presence of a past medical history of HTN, but also elevated blood pressure levels per se increases the risk of aortic stenosis as it does with stroke or ischemic heart disease [2,3]. In a UK biobank population-based cohort of 502 602 patients, aged 40–96 years, the authors evaluated through Mendelian randomization using individual participant data the association between SBP and major valvular heart disease. For each 20 mmHg increase in SBP, there was an increased risk of aortic stenosis [odds ratio (OR), 3.26; 95% confidence interval (CI) 1.50-7.10], aortic regurgitation (OR 2.59; 95% CI 0.75-8.92), and mitral regurgitation (OR 2.19; 95% CI 1.07-4.47), with no evidence for heterogeneity by type of valvular heart disease (P = 0.90) [3]. HTN accounts for one-quarter for the population – attributable risk for incident aortic stenosis [4] and the prevalence of HTN in aortic stenosis patients is estimated from 30 to 70% in different cohorts [5]. The vascular damage induced by HTN and degenerative aortic valve stenosis are age-related diseases that frequently coexist as they share many common pathophysiologic mechanisms [6]. Both conditions are characterized by a substantial activation of proinflammatory and profibrotic markers that leads to endothelial dysfunction and the development of atherosclerotic like lesions. Osteoblastic transformation of the tissue with subsequent calcification seems the terminal differentiation of aortic stenosis from the common path with atherosclerotic vascular disease [7]. Moreover, other facts as the strong relation of the tissue Renin, angiotensin, aldosterone system to the development of aortic stenosis, only underline this strong liaison [8,9].

Likewise, the presence of HTN alters the progression and natural history of the aortic valve disease. HTN not only induces left ventricular hypertrophy (LVH) but also alters its pattern in patients with aortic stenosis. The latter, have usually higher ventricular mass, relative wall thickness and higher prevalence of LVH [10]. LVH along with the diastolic dysfunction that is already prominent in patients with aortic stenosis, and the increased left ventricular systolic stress also induce neurohumoral activation and inflammation, aggravating both aortic stenosis and HTN burden [11]. Hypertensive patients in the SEAS study, for instance, had 56% higher rate of ischemic cardiovascular events and two-fold increased mortality among patients with aortic stenosis, irrespectively of aortic stenosis severity, abnormal LV geometry, SBP or statin use [12]. LVH and atrial damage in aortic stenosis are on the other hand predictors of hard outcomes [13]. HTN seems to interfere also, with the development of symptoms. The presence of HTN is associated with lower LVH reduction after surgery whereas is considered one of the major independent risk factors for death, postoperative heart failure and worse clinical outcome in general, after aortic valve replacement (AVR) [14–16].

Finally, HTN can strongly interfere with the proper evaluation of aortic stenosis commonly in a nonpredictable way [17]. Blood pressure should be routinely recorded in patients evaluated for aortic stenosis and optimally BP control should be optimal before echocardiography or catheterization. On the other hand, the decline of LV systolic performance because of aortic stenosis (and by the synergistic effect of HTN to LV) especially observed in conditions accompanied with low stroke volume index (SVI) (as in paradoxical low flow low gradient aortic stenosis – PLFLGAS) could lead to SBP pseudonormalization in as many as 30% of hypertensive patients with aortic stenosis. There, the need to calculate vascular resistance or indices as valvuloarterial impedance (Zva) to assess the combined ventricular afterload might be imperative. American College of Cardiology/American Heart Association (ACC/AHA) guidelines underline this phenomenon and consider PLFLGAS diagnosis only in patients properly treated for HTN [18] as both their symptoms and diagnosis could be very different after HTN control [19]

To elucidate the impact of HTN on symptoms and functional capacity during a treadmill exercise test (ETT) in apparently asymptomatic patients with aortic stenosis, Saeed et al.[20] assessed retrospectively 314 patients (age 65 ± 12 years, 68% men) with moderate or severe asymptomatic aortic stenosis. In this study, HTN was defined as a past medical history of elevated blood pressure, past or current treatment with antihypertensive agents or a BP at the baseline clinic visit greater than 140/90 mmHg. The authors found that HTN and clinic SBP were not associated with revealed symptoms in the univariate logistic regression analysis. In a multivariate logistic regression analysis though, lower peak SBP (OR 1.02; 95% CI 1.00–1.04; P = 0.017) and rapid early rise in heart rate (OR 15.03; 95% CI 6.23–36.24; P < 0.001) were associated with a higher risk of revealed symptoms. Moreover, the use of antihypertensive treatment was associated with a lower risk of revealed symptoms (OR 0.40; 95% CI 0.18–0.89; P = 0.025), independently of age, obesity, LV ejection fraction and aortic valve area.

Although, as discussed previously, the presence of established HTN and even elevated blood pressure levels, are associated with the incidence of aortic stenosis and worse outcomes, it is true that the effect of blood pressure behaviour or peak SBP during ETT has not been well addressed in the past. ETT represents a significant tool to unmask symptoms associated with aortic stenosis, as approximately 50% of the patients with severe and almost 30% with moderate aortic stenosis report no symptoms at initial diagnosis. Nevertheless, the presence of symptoms or ventricular arrhythmias, aggravates significantly their prognosis and dictates surgical AVR or transcatheter AVR [21]. ETT is apparently well tolerated for asymptomatic patients with aortic stenosis unless they have an already established indication for AVR, uncontrolled HTN, symptomatic or hemodynamically significant arrhythmias, and inability to perform the ETT because of orthopaedic or other limitations [20]. The criteria to determine a ETT as abnormal are: aortic stenosis-related symptoms, or a drop in their baseline SBP as per European Society of Cardiology (ESC) guidelines for valvular disease (for some authors insufficient rise in blood pressure, significant ventricular arrhythmias, or ST depressions could also signify a positive result [21,22].

In the study conducted by Saeed et al.[20], lower peak SBP and rapid early rise in heart rate were associated with a higher risk of revealed symptoms. There are studies in the literature reporting similar findings. In a study conducted by Amato et al.[23], rise of blood pressure levels less than 20 mmHg at peak exercise in patients with aortic stenosis were associated with worse outcome. Similar results were reported also from other studies regarding the inotropic incompetence during exercise [24–26]. However, we have to keep in mind that there is established knowledge that in patients with cardiomyopathies, low baseline or peak BP levels at ETT and increased chronotropic responses usually are predictors of worse outcomes: In a study conducted by Kallistratos et al., patients with impaired LV function and higher SBP and DBP at baseline, as well as patients with SBP at least 160 mmHg and pulse pressure (PP) at least 75 mmHg at peak exercise presented the most favourable prognosis. A four-fold increase in cardiac mortality risk for patients with SBP less than 160 mmHg at peak exercise (hazard ratio 3.97; 95% CI 1.60–9.84) and a three-fold increase for patients with PP less than 75 mmHg at peak exercise (hazard ratio 2.96; 95% CI 1.29–6.82) [27]. Likewise, in another study led by the same author, low SBP or peak BP levels at ETT as well as increased chronotropic responses mainly reflect low cardiac output and worse clinical condition (increased plasma NT pro-Brain natriuretic peptide (BNP) levels and low functional capacity as expressed by peak VO2 oxygen consumption) [28]. On the other hand, higher SBP levels and a normal chronotropic competence may indicate higher inotropic reserve [29,30]. Likewise, in the FIT project study [31] that included 44 089 participants without coronary heart disease (83% were hypertensive patients), modest increases in exercise SBP responses were associated with adverse outcomes whereas similar results have been reported by other studies [32,33].

Not only low cardiac output, but also autonomic dysfunction, might explain these results. It is possible that lower peak SBP and rapid early rise in heart rate occurs because of autonomic nervous system dysfunction especially during the ETT, and this imbalance may be linked to the subsequent development of heart failure [34]. The concept of the declining performance of the LV during the clinical course of aortic stenosis, even for patients that are asymptomatic with relatively low transvalvular pressure gradients, has been an established fact during the last decade by the systematic study of complex entities as PLFLGAS, where a ‘normal’ ejection fraction cannot describe adequately the failing LV performance. In such cases more ‘sensitive’ metrics of LV decline as SVI, global longitudinal strain, BNP, or fibrosis as assessed by cardiovascular magnetic resonance have to be sought [35]. For sure, these patients have worse prognosis sometimes even after AVR. It is not surprising again that HTN poses a great diagnostic and therapeutic conundrum in these ‘burnt-out’ left ventricles.

The paradigm shift in aortic stenosis approach is fascinating. It is not anymore a mechanistic valvular constriction but rather a syndrome. Therefore, the complex interplay of LV systolic and diastolic dysfunction, vascular and valvular load, mitral regurgitation, right ventricular performance, autonomic nervous system responses and comorbidities have to be thoroughly sought for its correct pathophysiology understanding, diagnosis and management. Every aspect of hypertensive cardiovascular disease has a prominent role in this integrative approach, and new pieces in the puzzle of thorough understanding of its complex interplay with aortic stenosis, as presented in the well conducted work of Saeed et al.[20], are always more than welcome. HTN and aortic stenosis are nowadays not to be considered as isolated entities. They are no strangers, not anymore.

ACKNOWLEDGEMENTS

Conflicts of interest

There are no conflicts of interest.

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