Gender Differences in Cardiac Organ Damage in Arterial Hypertension: Assessing the Role of Drug Nonadherence

Uncontrolled systolic BP is the most common type of uncontrolled hypertension and was used as basis for inclusion in our study [1]. The present study included 523 patients with confirmed uncontrolled hypertension (daytime systolic BP ≥ 135 mmHg) despite prescription of ≥ 2 antihypertensive drugs that participated in a national multicenter study performed at the four largest university hospitals in Norway in 2017–2022 [17]. To identify suitable participants, the primary study recruited a total of 1156 individuals aged ≥ 18 years with uncontrolled office systolic BP despite being prescribed ≥ 2 antihypertensive drugs and with a stable treatment regimen for at least 4 weeks (42% women). 24-hour (24-h) ambulatory BP recording at the baseline visit revealed that surprisingly many of the recruited patients (45%) had controlled daytime systolic BP (Fig. 1). The remaining 562 patients with uncontrolled daytime systolic BP between ≥ 135 mmHg and <170 mmHg (safety threshold), were invited to the follow-up visit which included echocardiography (Fig. 1). Of those, 548 showed up for echocardiography (Fig. 1). For the present analysis, 21 of these were excluded due to poor image quality precluding analysis, and 5 due to myocardial infarct scarring in the left ventricle (LV) (Fig. 1). Thus, 523 patients with uncontrolled treated hypertension are included in the present pre-specified sub-study (Fig. 1). Most patients (57%) were referred by primary care physicians, 15% were referred by secondary medical centers and 27% were self-referred through newspaper advertisements and public media discussion. A detailed description of the study inclusion and protocol has been previously published [17]. The study was approved by the Regional Ethical Committee (2017/804) and was conducted in accordance with the Helsinki Declaration.

Attended office BP was measured in triplets in the seated position after 5 minutes of initial rest, using a validated device, and the office BP was taken as the average of the two last measurements [1]. Ambulatory 24-h BP was measured on the non-dominant arm using a validated device [1]. BP was measured every 20 min during daytime and every 30 minutes during nighttime. If < 70% of the BP measurements were technically successful, the ambulatory BP recording was repeated.

Self-reported medical history data was collected through a structured physician-patient interview. CV disease was defined as history of any of the following events: Myocardial infarction, angina pectoris, percutaneous coronary intervention, coronary bypass grafting, transient ischemic attack, or stroke.

The patient’s weight and height were measured. Obesity was defined as body mass index (BMI) ≥ 30 kg/m². Albumin-creatinine ratio (ACR) was measured in morning spot urine. ACR ≥ 3 mg/mmol was considered elevated [18]. eGFR was calculated from serum creatinine using the Chronic Kidney Disease Epidemiology Collaboration equation [19].

The aldosterone-to-renin ratio (ARR) was calculated using aldosterone and direct renin concentration measurements, without adjusting for interfering antihypertensive medication. ARR > 35 pmol/mIU was considered a positive screening test for primary aldosteronism [20].

Serum drug concentrations were measured using ultra-high-performance liquid chromatography coupled with tandem mass spectrometry (UHLPC-MS/MS), and was available for the 23 most commonly prescribed antihypertensive drugs in Norway, as previously described [17, 21, 22]. An experienced pharmacologist interpreted the adherence status based on information about dosage, time since the last intake, and predefined serum reference ranges [17, 21, 22]. To minimize the influence on patient behaviour, no instructions regarding the administration of BP medication were given prior to the study visits, and patients were not informed about the serum drug measurement. Patients were defined as nonadherent if serum drug concentrations measured at the primary visit documented that at least one prescribed antihypertensive agent was undetectable or below the defined serum reference range [22].

Transthoracic echocardiography was performed using a standardized imaging protocol at all study centers. Echocardiograms were digitally stored and transferred for analyses at the Echocardiography Core Laboratory at the University of Bergen, Norway, which uses Tomtec Arena Software (TomTec Imaging Systems GmbH, Unterschleissheim, Germany) and dedicated workstations. The images were initially analyzed by a junior investigator (AA) and proofread by a senior investigator (EG) in accordance with the current recommendations for echocardiographic core laboratory procedures [23, 24]. Cardiac organ damage was considered present if left ventricular (LV) hypertrophy and/or enlarged left atrium (LA) volume was found in the individual patient. LV hypertrophy was identified by gender-specific cut-off values for LV mass index (> 47.0 g/m^2.7 in women and > 50.0 g/m^2.7 in men).[1] LV hypertrophy was considered concentric if relative wall thickness (RWT) > 0.42, and eccentric if RWT ≤ 0.42 [1]. LA systolic volume was estimated by the biplane Simpsons’s method combining the apical four and two-chamber views [23]. The LA volume was indexed for height squared meter² and defined as enlarged if ≥ 16.5ml/m² in women and ≥ 18.5 ml/m² in men [1]. The presence of mitral valve regurgitation was assessed by colour Doppler echocardiography and severity was graded as mild, moderate, or severe [25].

Continuous variables are expressed as mean ± standard deviation and categorical variables are expressed as absolute numbers and percentages. Differences between women and men were tested by the student’s unpaired t-test, Mann-Whitney U test, and Pearson’s chi-square test as appropriate.

Covariables of LV hypertrophy and LA enlargement were identified in univariable and multivariable logistic regression analysis. All variables in Table 1 were evaluated in univariable analysis (p < 0.1). The enter method was used for the multivariable analysis, including covariables with significant univariable associations and clinical relevance while accounting for collinearity. A variance inflation factor > 1.4 was used to identify collinearity. When multiple variables represented similar aspects, we selected the variable with the strongest univariable association. Age and nonadherence were included in all multivariable models. Interaction analyses between gender and nonadherence in the models for LV hypertrophy/LA enlargement were performed by adding the product gender × drug nonadherence to the multivariable models. Logistic regression results are reported as odds ratio (OR), corresponding 95% confidence interval (CI), and p-value. A 2-sided p-value < 0.05 was considered statistically significant in all analyses.

The study had statistical power 0.80 with an alpha 0.05 to detect a 13% difference in the prevalence of LV hypertrophy between genders.

Nonadherence to antihypertensive drugs was unexpectedly low in the study with no difference between women and men (8% vs. 9%, p = 0.51) (Table 1). The prevalence of obesity was high in both women and men (43% vs. 50%, p = 0.126) (Table 1). Women were older and had a longer duration of hypertension than men (Table 1). Women had lower direct renin concentration and higher ARR (Table 1). While women had higher office systolic BP, their 24-h systolic BP was similar to men’s, indicating a more pronounced white-coat effect in women (9.8 ± 14.4 mmHg) than in men (4.5 ± 14.4 mmHg, p < 0.001). On average, women and men were prescribed the same number of antihypertensive agents, but women were prescribed less calcium channel blockers (Table 1).

Compared to adherent patients, nonadherent patients were younger and had a shorter duration of hypertension (both p < 0.05) (Table 1). Furthermore, they had higher 24-h diastolic BP and a higher eGFR (both p < 0.05), while 24-h systolic BP, BMI, and prevalences of comorbidities were similar in the drug-adherent and nonadherent groups (Table 1).

LV hypertrophy was common in both genders, with a higher prevalence in women than men (46% vs. 33%, p = 0.004) (Table 1). Women had more concentric LV hypertrophy than men, whereas the prevalence of eccentric LV hypertrophy was comparable (Fig. 2). The majority of patients had LA enlargement with a higher prevalence in women (70% vs. 65%, p < 0.001) (Table 1). Furthermore, women had a higher prevalence of mitral valve regurgitation than men (Table 1). The prevalence of LV hypertrophy did not differ between adherent and non-adherent patients (Table 1).

Drug nonadherence was not associated with LV hypertrophy in either gender (Table 2, Panel A). In the total study cohort, female gender was associated with a two-fold increased risk of LV hypertrophy (OR 2.01 [95% CI 1.30–3.10], p = 0.002) independent of significant associations with higher age, 24-h systolic BP, higher BMI and elevated ACR (Table 2, Panel A; Fig. 3). Interaction analysis showed no interaction between gender and drug nonadherence with the presence of LV hypertrophy. In gender-specific analyses, LV hypertrophy was only associated with higher BMI in women and with higher BMI, age, and 24-h systolic BP in men (Table 2, Panel A). Secondary models based on significant covariables identified separately in women and men yielded consistent results (Table S1). When adding elevated ARR to the primary model, elevated ARR was associated with presence of LV hypertrophy in men (OR 2.12 [95% CI 1.12–4.00], p = 0.02) but not in women (OR 1.48 [95% CI 0.67–3.28], p = 0.338) (Table S2).

Drug nonadherence was not associated with higher prevalence of LA enlargement in either gender (Table 2, Panel B). Female gender was associated with an increased prevalence of LA enlargement (OR 1.90 [95% CI 1.17–3.10], p = 0.010) after adjusting for confounding factors (Table 2, Panel B; Fig. 3). Interaction analysis showed no interaction between gender and drug nonadherence with the presence of LA enlargement. In gender-specific analyses, LA enlargement was associated with higher BMI and LV hypertrophy in both genders, with mitral valve regurgitation in women, and with older age in men (Table 2, Panel B). Secondary models based on significant covariables identified separately in women and men yielded consistent results (Table S3). Adding elevated ARR to the primary models did not alter the results, and elevated ARR was not associated with LA enlargement in any group.