Cardiac structure and function in resistant hypertension: The beneficial role of blood pressure control

Hypertension (HTN), defined as a blood pressure of greater than or equal to 140/90 mmHg, is the leading risk factor for cardiovascular disease worldwide, and its prevalence has doubled since 1990.1 Despite unmistakable evidence that blood pressure control decreases the morbidity and mortality of HTN and the availability of safe, effective, and affordable pharmacologic medications, the global control rate is only approximately 20%. More ominous is the recent observation that in high-income countries such as the United States (US), the control rate of HTN has declined from approximately 55% to 47% over the last decade. Within individuals with HTN are those with “resistant HTN”, defined as a blood pressure that remains above treatment goal despite the use of three anti-hypertensive medications from recommended classes at maximal doses, including one of which is a thiazide or thiazide-like diuretic. Approximately 10% of US adults with HTN have resistant HTN. Those with resistant HTN are more predisposed to adverse cardiovascular outcomes.2-5 The morbidity and mortality from HTN are primarily related to target organ damage, such as the heart, brain, kidney, and vasculature. Cardiac damage includes coronary artery disease resulting in myocardial infarction, congestive heart failure, and left ventricular hypertrophy (LVH). LVH is often overlooked and is related to cardiac remodeling from pressure-overload. While initially compensatory, LVH is ultimately deleterious by leading to congestive heart failure, arrhythmias, and sudden cardiac death. Initially, the ejection fraction is preserved through processes resulting in diastolic dysfunction and increasing left ventricular filling pressures leading to heart failure with preserved ejection. If the elevated blood pressure remains untreated or poorly controlled, this eventually progresses to a reduction in ejection fraction. The prolonged exposure to an elevated blood pressure increases left ventricular afterload and peripheral vascular resistance leading to structural remodeling.6, 7 Increased left ventricular mass (LVM) causes increased myocardial stiffness, increased left ventricular end-diastolic pressure, impaired relaxation, and left atrial dilation.8 These structural changes result in diastolic dysfunction, which can be quantified using echocardiography9 and, more accurately, with cardiac MRI.10 In this issue of the journal, Matanes and colleagues contribute to our body of knowledge regarding cardiac structure and function in resistant HTN and the potential beneficial role of blood pressure reduction. The authors hypothesized that resistant HTN is associated with higher LVM resulting in an increased prevalence of LVH, larger intracardiac volumes, and thus, chamber dilation, and greater diastolic dysfunction when compared to those with controlled non-resistant HTN. Controlled resistant HTN was defined as an office blood pressure less than or equal to 135/85 mmHg on at least three consecutive follow up visits while taking four or more antihypertensive medications, including a thiazide or thiazide-like diuretic. Importantly, this group of controlled resistant HTN was compared to a group of patients with controlled HTN without resistant HTN. A total of 182 patients met inclusion criteria after appropriate screening for secondary causes of HTN. The final cohort comprised of 132 patients after excluding those with masked HTN. Those with masked HTN, defined as having a high out of office blood pressure but normal office blood pressure, was studied separately. Blood pressure readings were taken unattended with appropriate technique. A total of six readings were performed, each 1 minute apart, and the average of the last five readings was used as the final reading. In addition to determining LVH and left ventricular mass index (LVMI), cardiac MRI was used to assess left ventricular peak filling rate (PFR), diastolic volume recovery (DVR), left atrial volume index (LAVI), and E (early) and A (atrial) wave filling velocities, all of which are measures of diastolic function.10 The results demonstrated that a higher prevalence of type 2 diabetes mellitus (42% vs. 15.9%, p = .001), a higher 24-hour ambulatory pulse pressure (61.5 ± 12.1 vs. 56.8 ± 10.8, p = .020), and a lower estimated glomerular filtration rate (56.8 ± 25.3 vs. 72.6 ± 26.5, p = .004) were observed in the controlled resistant HTN group as compared to the controlled non-resistant HTN group. Of interest, left ventricular systolic function and diastolic function were similar between the two groups. There also was no significant difference in left ventricular end-diastolic and end-systolic volume index, left atrial volumes, left ventricular stroke volume/pulse pressure ratio, and brain natriuretic peptide levels between the two groups after controlling for those with masked HTN. The authors hypothesized that the administration of more intensive thiazide, or thiazide-like diuretic, and mineralocorticoid antagonist administration in the controlled resistant HTN group improved volume status and/or contributed to a further reduction in blood pressure resulting in improved diastolic dysfunction in the controlled resistant HTN group. The findings also demonstrated similar intracardiac volumes between the controlled resistant HTN and controlled non-resistant HTN groups. Those with controlled resistant HTN did have a significantly higher LVM versus the controlled non-resistant HTN group (135.5 g ± 55.7 vs. 118.2 g ± 32.8, p = .031, respectively) and posterior wall thickness (8.5 mm ± 2.2 vs. 7.6 mm ± 1.5, p = .005, respectively), as measured by cardiac MRI. Further analysis was performed on the subgroup determined to have masked HTN. Individuals were categorized as having either masked uncontrolled non-resistant hypertension (MUCH) or masked uncontrolled resistant hypertension (MRHTN). Individuals with MUCH or MRHTN were found to have higher LVM (in grams) when compared to those with controlled HTN. Additionally, MRHTN was associated with higher LVMI when compared to those with controlled resistant HTN. The only cases of LVH found in the study were found in the MRHTN group. MRHTN patients also had higher BMIs (34.4 ± 4.7 vs. 31.4 ± 5.4, p = .019) and a higher prevalence of type 2 diabetes mellitus (54.1% vs. 28.1%, p = .030). This paper demonstrates that when blood pressure in individuals diagnosed with resistant HTN is controlled and those with masked HTN are excluded, there is no difference in mean LVM, LVH, and systolic or diastolic dysfunction when compared to patients with controlled non-resistant HTN. This implies that controlling blood pressure in resistant HTN may reverse an existing increase in LVM and improve diastolic function. It is important to note that the blood pressures achieved in this paper were remarkable in that the systolic blood pressure of those with controlled resistant HTN and controlled HTN were approximately equal at 118 and 117 mmHg, respectively. The results seen in this study are like those seen in SPRINT, which demonstrated that intensive blood pressure reduction significantly reduced morbidity and mortality greater than in those with standard blood pressure reduction.11 Of note, SPRINT enrolled individuals had higher cardiac risk, were older (approximately 68 years old), and had a higher prevalence of chronic kidney disease. Furthermore, they were on an average of two anti-hypertensive medications at baseline and typically required on average an additional third medication to achieve a further reduction of systolic blood pressure in the intensive group. Additionally, most of the benefit from intensive blood pressure reduction was in a reduction of congestive heart failure, likely due to a reduction of diastolic dysfunction and heart failure with preserved ejection fraction. Thus, the degree of blood pressure control, especially in those with resistant HTN and other high-risk individuals with HTN including older individuals who are also at risk for diastolic dysfunction, may be the most crucial finding in the beneficial results seen in this present study. The intensively controlled blood pressures seen may also limit the application of these findings to centers with more experience and expertise in the management of resistant HTN. Limitations of the study include a small sample size and patients’ self-reported non-adherence to anti-hypertensive medications. Internal validity, however, was maintained with subgroup analysis and controlling for other clinical factors that promote LVH. Increased LVM is a significant predictor of cardiovascular adverse events and mortality,12-14 and this study highlights the utility of using cardiac MRI to evaluate hypertensive cardiac disease. Cardiac MRI, however, is not available in every clinical setting, is time-consuming, and costly which limits external validity. Cardiac doppler echocardiography may also be more readily available in these settings. This study emphasizes further the importance and benefit of achieving blood pressure control in all individuals with the diagnoses of HTN and potentially establishing a lower blood pressure treatment threshold and target as control for those at elevated risk. The recent World Health Organization 2021 Guidelines for the Pharmacological Treatment of the Adult with HTN emphasize a lower blood pressure treatment threshold (> or = to 130 mmHg) and target (<130 mmHg) in those with known cardiovascular disease as well as those with high cardiovascular risk by calculation, diabetes mellitus, and chronic kidney disease.15 Furthermore, controlled resistant hypertensive patients can improve cardiac structure and function to those with controlled non-resistant hypertensive levels. Finally, the results of this paper demonstrate that patients with dyslipidemia had diastolic filling patterns suggestive of diastolic dysfunction regardless of the degree of blood pressure control. This emphasizes the importance of controlling all present cardiovascular risk factors in an integrated approach together with the control of HTN. Neil D. Mehta, Sean J. Battle and Donald J. DiPette: authors, editors. Donald J. DiPette MD, FAHA, FACP is a Distinguished Health Sciences Professor at the University of South Carolina, School of Medicine, Columbia South Carolina. None to disclose.