24-Hour Blood Pressure Patterns and Blood Pressure Medicine in Men After Heart Transplant

A retrospective analysis of data extracted from medical records encompassed 73 male participants, comprising 33 heart transplant recipients and 40 individuals serving as the control group without comorbid conditions. In the HTX group, the underlying etiologies of heart failure leading to transplantation were heterogeneous and included ischemic cardiomyopathy (n = 7), alcohol-related/environmental cardiomyopathy (n = 3), post-inflammatory cardiomyopathy (n = 3), familial/genetic cardiomyopathy (n = 9), and arrhythmogenic cardiomyopathy (n = 4). All patients in the HTX group had advanced heart failure and, prior to transplantation, were receiving full guideline-directed medical therapy, which typically included angiotensin-converting enzyme inhibitors (ACE inhibitors) or angiotensin receptor-neprilysin inhibitors (ARNI), beta-blockers, mineralocorticoid receptor antagonists, sodium-glucose cotransporter 2 inhibitors (SGLT2 inhibitors), and diuretics. Consequently, their blood pressure values before heart transplantation were typically low, reflecting both the severity of heart failure and the effects of pharmacological treatment. The control group consisted of male patients without a history of heart failure or heart transplantation, free of significant cardiovascular disease, and matched for age as closely as possible to the HTX group. Inclusion criteria stipulated an age range of 30 to 70 years and male sex. Exclusion criteria from the beginning included allograft dysfunction, valvular heart disease, other conditions requiring cardiac surgery, congestive heart failure classified as NYHA class III or IV, and chronic kidney disease at stages IV or V. In addition, during chart review, 7 patients from the heart transplant group and 1 patient from the control group were excluded due to unstable renal function with episodes of estimated glomerular filtration rate below 30 mL/min/1.73 m². Finally, 26 HTXr and 39 controls were included in the analysis (Figure 1). Before performing ABPM, antihypertensive treatment was carefully optimized according to current clinical guidelines, in order to ensure reliable interpretation of blood pressure control and to avoid misclassification of resistant hypertension. The primary objective of the study was to evaluate the 24-hour blood pressure profile and hypertension management in post-heart transplant patients, with comparative analysis to the control group.

During routine visits, medical histories and laboratory samples were collected, and the general condition was assessed. Information regarding the date of heart transplantation, as well as current antihypertensive and immunosuppressive treatments, was obtained from individual medical records. The quantity and classification of antihypertensive and immunosuppressive medications were analyzed. Laboratory assessments encompassed blood count parameters, graft function indicators, electrolyte levels, lipid profile measurements, and blood glucose concentrations.

Ambulatory 24-hour blood pressure monitoring was conducted utilizing the SpaceLabs Model 90207 device (Spacelabs Inc., Richmond, Washington, DC, USA), employing the oscillometric technique. The data obtained included mean systolic and diastolic pressures over a 24-hour period, as well as mean pressures during daytime (6:00 AM to 10:00 PM, with measurements every 20 min) and nighttime (12:00 AM to 6:00 AM, with measurements every 30 min). This division of monitoring periods was adapted from O'Brien's methodology. Additionally, the magnitude of the nocturnal dip was recorded. Hypertension diagnosed via ambulatory blood pressure monitoring (ABPM) was defined as daytime blood pressure exceeding 135/85 mmHg, nighttime blood pressure exceeding 120/75 mmHg, or 24-hour blood pressure exceeding 130/80 mmHg. Based on the percentage reduction in circadian blood pressure, patients were categorized as dippers (ΔSBP ≥ 10%), non-dippers (0 < ΔSBP < 10%), and reverse dippers (individuals exhibiting a nocturnal rise in SBP), in accordance with European Society of Hypertension (ESH) criteria [22,23].

For comparisons of two qualitative variables, the following Chi-square tests, depending on table size, number of observations, and expected observations, were applied: the Maximum Likelihood Chi-square test (Chi²_ML), Pearson's Chi-square test, V-square test, and Yates' corrected Chi- square test. The Shapiro–Wilk test was used to assess the normality of the distribution of quantitative variables, and Levene's test was used to examine the homogeneity of variances. To determine whether quantitative variables differed between two groups, the following tests were applied: the independent samples Student's t-test when the quantitative variable in both groups had a normal distribution and the variances were homogeneous, the Student's t-test with variance estimation when the quantitative variable in both groups had a normal distribution but the variances were not homogeneous, and the Mann–Whitney U test when the quantitative variable in at least one group did not have a normal distribution. Effect size (Cohen's d) was also calculated in variables that showed significant differences between groups, in order to present the strength of differences.

A repeated measures ANOVA was conducted to compare variables describing blood pressure simultaneously over time (during the day and the night) and between groups (HTXr and control group). Additionally, Tukey's HSD test was employed for post hoc analysis.

Statistical analyses were performed utilizing TIBCO software (TIBCO Software Inc., Palo Alto, CA, USA ), as well as Statistica (data analysis software system, version 13). A p-value of less than 0.05 was regarded as statistically significant.

Patients after heart transplantation often exhibit poorer BP control despite comparable pharmacotherapy. It has been identified that post-transplant patients predominantly utilize antihypertensive medications from the following categories: calcium channel blockers (CCB), angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers (ACEi/ARB), and alpha-blockers. In selecting a specific therapeutic agent, both the drug's impact on graft function and the potential for interactions with immunosuppressive medications must be carefully considered.

In our study, calcium channel blockers and angiotensin-converting enzyme inhibitors were the first-line agents in the treatment of arterial hypertension in patients after heart transplantation. Calcium channel blockers remain the most commonly used antihypertensive medications, partly due to the high frequency of renal dysfunction in the early post-heart transplant phase and concerns about potential hyperkalemia associated with the use of renin-angiotensin-aldosterone system (RAAS) blockers [24]. The benefits of using RAAS blockers are not fully understood in heart transplant patients. A recent study conducted by Masarone et al. [25] highlights the pleiotropic effects of ACE inhibitors in patients, including improvement of the peripheral vascular system, regulation of fluid and sodium balance, as well as the prevention of graft rejection and heart failure. The first randomized study comparing diltiazem and lisinopril as antihypertensive agents after heart transplantation revealed that both drugs were equivalently effective in achieving blood pressure control, and both were safe for treating hypertension after heart transplantation. Although titrated monotherapy with either of these drugs caused good blood pressure control in less than 50% of treated patients, it was suggested that a combination of both classes of drugs may result in larger effects [26].

Another group of medications frequently used in the studied HTXr group were beta-blockers. Similarly for non-transplant patients, beta-blockers are not regarded as first-line treatments for hypertension, although they may be beneficial when blood pressure is not well controlled with other therapies. A considerable number of patients required multi-drug regimens, and the common prescription of loop diuretics is indicative of the substantial burden of resistant hypertension among heart transplant recipients. Retrospective studies have demonstrated that beta-blockers are safe and particularly useful in heart transplant patients with resistant arterial hypertension [27]. Furthermore, the studied HTXr group showed statistically higher heart rate values than the Cx group. Abnormal heart rate control in patients after heart transplantation may be an independent factor affecting both graft and patient survival, and could contribute to the development of heart failure [28,29]. In our clinical practice, beta-blockers are avoided in the early years following heart transplantation and are only used in specific clinical scenarios, including atrial or ventricular arrhythmias and left ventricular dysfunction, particularly in the late phase post-transplantation [27].

In our study, we observed that loop diuretics were more frequently used in the HTXr patient cohort compared to the control group (HTXr: 61.54% versus 2.56%, p < 0.001). Diuretics are administered to manage fluid overload subsequent to cardiac transplantation. Cardiac transplant recipients exhibit abnormal responses to volume overload, demonstrating a propensity for salt and water retention despite a normal cardiac index.

Further therapies for blood pressure regulation may encompass alpha-adrenergic antagonists. These drugs can reduce blood pressure by diminishing peripheral vascular resistance and may result in a decrease in triglyceride (TG) levels, alongside an increase in high-density lipoprotein (HDL) cholesterol levels and the HDL cholesterol-to-total cholesterol ratio [30]. In our study, we observed significantly higher triglyceride levels in the group of heart transplant patients compared to the control group. According to the modified and revised Third Report of the National Cholesterol Education Program (NCEP-ATP III) [31] criteria, components of metabolic syndrome (MetS) include elevated TG levels, decreased HDL, presence of diabetes, elevated blood pressure values, or the use of antihypertensive medications. A retrospective study by Sponga et al. [32] demonstrated that the presence of MetS before and 1 year after heart transplantation (HTx) was associated with markedly worse survival, additionally identifying these factors as risk factors for mortality in univariate analysis. Furthermore, MetS 1 year post-Htx was linked to a significantly increased risk of developing cardiac allograft vasculopathy (CAV). The administration of alpha-blocker medications, which positively influence certain aspects of MetS, may potentially reduce the prevalence of metabolic syndrome among heart transplant recipients.

Heart transplant recipients frequently present abnormal circadian BP patterns, including non-dipping and reverse-dipping profiles. From a therapeutic perspective, this highlights the importance of tailoring antihypertensive regimens to circadian variability. These abnormalities are associated with increased cardiovascular risk and graft dysfunction. However, data on interventions aimed at normalizing abnormal circadian blood pressure rhythms in heart transplant recipients are lacking. Clinically, evening dosing and prioritizing long-acting agents with sustained 24-hour efficacy (high smoothness index) may improve nighttime BP control more than conventional morning administration [33,34,35].

In our cohort, nocturnal hypertension and isolated nighttime BP elevation were markedly more frequent in HTXr than in controls, suggesting a high burden of masked hypertension. The high prevalence of masked hypertension in HTXr emphasizes the need for systematic use of 24-hour ABPM in follow-up, as office BP may underestimate risk.

In addition to the currently used treatment regimens, changing the timing of administering antihypertensive drugs should be considered. Introducing new antihypertensive medications in heart transplant patients to control blood pressure should be evaluated. One of the groups of drugs worth mentioning may be sodium-glucose cotransporter-2 inhibitors (SGLT2i). SGLT2 inhibitors have recently been recommended as an essential element of therapy for patients with heart failure and reduced ejection fraction (HFrEF) due to their favorable effects on mortality, clinical events, and quality of life [36]. Moreover, preliminary data indicate that the use of SGLT2 inhibitors appears to be well-tolerated and may provide benefits in both blood pressure and glucose level control in heart transplant recipients. A study by Kairo et al. [37] in patients with type 2 diabetes and uncontrolled nocturnal hypertension showed a significant reduction in both nighttime ambulatory systolic blood pressure and 24-hour ambulatory systolic blood pressure. Another retrospective study by Muir et al. [38] demonstrated that among 19 heart transplant patients treated with empagliflozin, systolic blood pressure was reduced by 12 mmHg (p = 0.03), and diastolic blood pressure by 7 mmHg (p = 0.03). In contrast, a study by Cehic et al. [39] involving 22 heart transplant patients with type 2 diabetes did not show a significant decrease in systolic blood pressure in patients treated with empagliflozin, although heart transplant patients treated with empagliflozin were more likely to use lower doses of diuretics after 12 months of treatment compared to patients that did not use empagliflozin. Both studies indicated that the use of SGLT2 inhibitors, particularly empagliflozin, appears to be safe and effective in treating selected heart transplant patients with diabetes.

We present the assessment of 24-hour blood pressure only in male heart transplant recipients. Currently, there are few studies evaluating blood pressure in heart transplant patients with gender stratification. Over the years, we have learned about numerous differences in macro- and microcirculation between men and women due to various physiological factors, including hormonal regulation. We believe that blood pressure assessment without gender stratification is inadequate, especially considering that women physiologically have lower blood pressure than men. None of our patients declared difference between gender identity and biological sex.

The most significant limitations of this study are its single-center, retrospective design. The results may not be as representative as those of multi-center reports; however, they could provide valuable data on a topic not extensively described in the literature—the assessment of 24-hour blood pressure profiles, variability (24-hour ABPM), and treatment in heart transplant patients, although frequently encountered in clinical practice. The true prevalence of hypertension in heart transplant patients is still unknown. Additionally, there is a continuing debate regarding optimal blood pressure goals and suggested pharmacologic regimens. Another important limitation is the absence of long-term outcome data, such as cardiac allograft vasculopathy (CAV) graft loss, or survival, directly linked to abnormal BP patterns. Prospective longitudinal studies are warranted to establish their prognostic relevance.