Author's summary
Clinical characteristics and outcomes related to hypertension in patients with hypertrophic cardiomyopathy (HCM) are poorly defined. This study demonstrated that HCM patients with coexisting hypertension were older, had more cardiovascular comorbidities, and exhibited lower left ventricular global longitudinal strain (LV-GLS) compared to those without hypertension. A lower LV-GLS was independently associated with a higher risk of adverse cardiovascular events in hypertensive patients, including cardiovascular death, heart failure, and stroke. The findings highlight the prognostic value of LV-GLS in HCM patients with hypertension, suggesting it could be a critical marker for identifying high-risk individuals and guiding treatment strategies.
Keywords: Cardiomyopathy, hypertrophic; Hypertension; Global longitudinal strain
Abstract
Background and Objectives
The prognostic implication of coexisting hypertension in patients with hypertrophic cardiomyopathy (HCM) is poorly defined. This study aimed to evaluate the association between left ventricular global longitudinal strain (LV-GLS) and adverse cardiovascular (CV) events in patients with HCM and coexisting hypertension.
Methods
We analyzed consecutive patients with HCM from 2 tertiary HCM referral centers. The primary outcome was CV events, defined as a composite of CV death, heart failure, and stroke. All LV-GLS measurements were conducted in a core laboratory.
Results
Of 1,139 patients with HCM, 522 (45.8%) had hypertension. Patients with hypertension were older, had more CV comorbidities, and showed a lower LV-GLS (13.7% vs. 14.4%, p=0.001). During a median 6.6-year follow-up, 155 CV events occurred, with a significantly higher crude incidence in patients with hypertension than in those without (p=0.005). Lower LV-GLS was independently associated with a higher risk of CV events in patients with hypertension (per 1% decrease in LV-GLS, adjusted hazard ratio [HR], 1.07; 95% confidence interval [CI], 1.01–1.13; p=0.013). When stratified by four groups based on hypertension and LV-GLS, CV events most frequently occurred in patients with both hypertension and a lower LV-GLS (<13.1%), with a significantly higher risk compared to those without hypertension and a higher LV-GLS (≥13.1%) (adjusted HR, 1.60; 95% CI, 1.01–2.54; p=0.044).
Conclusions
Patients with HCM and coexisting hypertension were older, had more prevalent CV comorbidities, and exhibited a lower LV-GLS compared to those without hypertension. LV-GLS provides important prognostic information in patients with both HCM and hypertension.
Graphical Abstract
INTRODUCTION
Hypertrophic cardiomyopathy (HCM) is the most common and inheritable form of cardiomyopathy and affects 1 in every 200–500 individuals worldwide.1),2) Although contemporary management strategies can effectively reduce the incidence of sudden cardiac death (SCD), the rates of progressive heart failure (HF), atrial fibrillation with an increased risk of stroke, and cardiovascular (CV) death remain high.3),4),5),6) Stratifying patients according to their risk of adverse CV events is often challenging given the significant heterogeneity within the HCM population, which varies widely in terms of symptoms, clinical presentations, and cardiac remodeling patterns.7),8),9) Therefore, it is clinically important to identify prognostic markers to predict adverse events in the HCM population to guide the implementation of tailored management strategies.
Left ventricular global longitudinal strain (LV-GLS) has been established as a superior imaging marker for detecting early or subclinical left ventricular (LV) systolic dysfunction when compared with LV ejection fraction (EF).10) Specifically, in patients with HCM, LV-GLS has been reported to fall below the normal reference value, even when the LVEF is preserved,10),11),12),13) indicating that this marker reflects subclinical myocardial contractile dysfunction at an early stage. More importantly, LV-GLS provides powerful prognostic information regarding adverse CV and SCD-related events in HCM.11),12),13),14) Therefore, the assessment of LV-GLS has the potential to improve risk stratification and optimize management in patients with HCM.
An increasing number of individuals with HCM are diagnosed at an older age.15),16),17),18) Hypertension, a well-known and significant risk factor for CV events in the general population, affects approximately 30–50% of the HCM population.18),19),20) In patients with hypertension, a longitudinal reduction in LV-GLS has been associated with a higher rate of major adverse CV events (death or admission for HF, myocardial infarction, or stroke).21) However, only limited data are available on the phenotypes and outcomes associated with hypertension in patients with HCM. Moreover, whether LV-GLS measurements can effectively provide prognostic information for hypertensive patients with HCM has yet to be established. Given the high prevalence of hypertension and the associated increased risk of CV events, understanding the prognostic significance of LV-GLS in HCM patients with hypertension is clinically important.
We hypothesized that LV-GLS may present an independent prognostic variable for patients with HCM and hypertension. We aimed: 1) to characterize the clinical and echocardiographic features of patients with HCM based on hypertension and 2) to investigate the association between LV-GLS and adverse events in patients with HCM and coexisting hypertension.
METHODS
Ethical statement
This study adhered to the principles of the Declaration of Helsinki (2013) and was approved by an Institutional Review Board (IRB) at Seoul National University Hospital (IRB number: H-2403-107-1523). The requirement for written informed consent was waived due to the use of retrospective and anonymized data. The data underlying this article will be made available upon reasonable request to the corresponding authors.
Cohort characteristics
The patient cohort included those diagnosed with HCM between 2007 and 2020 at two tertiary referral centers (Seoul National University Hospital and the Samsung Medical Center). Consecutive patients who met the standard diagnostic criteria for HCM were enrolled in the study. HCM was defined as a maximal wall thickness of ≥15 mm or a wall thickness of ≥13 mm with a family history of HCM.22) In patients with long-standing hypertension, the diagnosis of HCM was further evaluated based on clinical and imaging findings. These included a family history or genetic evidence of HCM, the evaluation of serial echocardiography examinations with information on blood pressure control, morphological patterns of LV hypertrophy, and the presence of systolic anterior motion of the mitral valve.2) We excluded patients younger than 19 years, as well as those with congenital heart disease, significant valvular heart disease (including moderate or greater mitral regurgitation), end-stage renal disease, or infiltrative cardiomyopathy, such as Fabry disease, mitochondrial cardiomyopathy, or cardiac amyloidosis. Patients with poor-quality echocardiographic images inadequate for LV-GLS measurement were also excluded.
Variable definitions
Clinical information was collected at the time of HCM diagnosis. Hypertension was defined as a previously confirmed diagnosis meeting the standard diagnostic criteria, with repeated measurements of systolic blood pressure ≥140 mmHg or diastolic blood pressure ≥90 mmHg at rest.23) White-coat hypertension, defined as elevated office blood pressure but normal ambulatory or home blood pressure, was not classified as hypertension. The 5-year SCD risk score was calculated according to the 2014 European Society of Cardiology guidelines.24)
All patients underwent standard echocardiography at the time of HCM diagnosis. The maximum myocardial thickness at end-diastole was recorded. Left atrial volume was calculated using the area-length method and indexed to the body surface area. Septal tissue Doppler velocities were recorded at the medial portion of the mitral annulus. The maximal LV outflow tract gradient was reported as the largest value of pressure gradient measured by continuous wave Doppler, either at rest or during the Valsalva maneuver. An LV apical aneurysm was defined as an akinetic or dyskinetic thin-walled segment of the LV apex. In total, 639 (56%) patients had undergone cardiovascular magnetic resonance imaging at the time of HCM diagnosis. Late gadolinium enhancement was assessed 10–15 min after contrast injection and was defined as areas with a signal intensity exceeding six standard deviations of the remote myocardium. We reported the percentage of late gadolinium enhancement mass divided by the total myocardial mass.
Left ventricular global longitudinal strain
Myocardial strain was measured using the speckle-tracking method with vendor-independent post-processing software (Imaging Arena 4.6; TomTec Imaging Systems, Munich, Germany), as described previously.11),12) LV-GLS was measured at the central core laboratory by experienced technicians who were blinded to patient information and clinical outcomes. LV endocardial borders were manually traced in 2-, 3-, and 4-chamber images at end-systole and tracked throughout the cardiac cycle. LV-GLS was calculated automatically across all segments. LV-GLS measurements were averaged over 3 cardiac cycles in patients with atrial fibrillation. To facilitate straightforward interpretation, we used the absolute value of LV-GLS.
Outcome assessment
The primary outcome was a CV event, defined as a composite of CV death, HF hospitalization, and ischemic or hemorrhagic stroke. CV death was defined as SCD, death from HF, myocardial infarction, major vascular disease, or stroke. The secondary outcome was SCD-related events, defined as either SCD, aborted SCD, or appropriate implantable cardioverter-defibrillator shock. Data on clinical events were collected based on electronic medical records and official national death records.
Statistical analysis
Continuous variables are expressed as median values with interquartile ranges, and categorical variables as frequencies with percentages. The Kruskal-Wallis test was used to compare continuous variables between groups, and the χ2 test was used to compare categorical variables. The optimal cutoff of LV-GLS for predicting CV events was determined using maximally selected log-rank statistics (Supplementary Figure 1). Based on this analysis, patients were categorized according to an LV-GLS threshold of 13.1% (<13.1% vs. ≥13.1%). Kaplan-Meier survival curves were plotted, and group comparisons were performed using the log-rank test. Cox proportional hazard regression analysis was used to evaluate the association between LV-GLS and outcomes, which was reported as hazard ratios (HRs) and 95% confidence intervals (CIs). The variables included in the multivariable Cox analysis were selected based on their clinical significance and their significance in the univariable Cox analysis: 1) baseline characteristics (age and sex), 2) symptoms and cardiovascular comorbidities (New York Heart Association functional class, hypertension, diabetes mellitus, and atrial fibrillation), and 3) cardiovascular risk factors in the HCM population (syncope and LVEF).
All statistical analyses were performed using R software (version 4.3.0; R Foundation for Statistical Computing, Vienna, Austria), and a 2-tailed value of p<0.05 was considered statistically significant.
RESULTS
Clinical characteristics according to hypertension
Of the 1,139 patients with HCM, 522 (45.8%) had underlying hypertension. The patients with hypertension were significantly older than those without (median 64 vs. 56 years, p<0.001), with a similar proportion of men (73.0% vs. 73.1%, p>0.99) (Table 1). A significantly higher prevalence of cardiovascular comorbidities, including diabetes mellitus, dyslipidemia, atrial fibrillation, and a history of percutaneous coronary intervention, was noted in patients with hypertension than in those without. Patients with hypertension received more frequent medications, including beta-blockers, dihydropyridine calcium channel blockers, renin-angiotensin receptor blockers, and thiazides. With regards to risk factors for SCD, patients with hypertension had a less frequent family history of SCD, and the 5-year SCD risk score was lower in patients with hypertension than in those without (median 1.8% vs. 1.9%, p=0.016).
Table 1. Baseline characteristics of the study participants according to hypertension.
| Characteristics | Patients with hypertension (n=522) | Patients without hypertension (n=617) | p value | |
|---|---|---|---|---|
| Age (years) | 64 (55–71) | 56 (48–65) | <0.001 | |
| Male | 381 (73.0) | 451 (73.1) | >0.99 | |
| Body mass index (kg/m2) | 25.5 (23.5–27.5) | 24.4 (22.8–26.4) | <0.001 | |
| SBP (mmHg) | 130 (120–141) | 124 (114–134) | <0.001 | |
| DBP (mmHg) | 79 (70–85) | 74 (67–80) | <0.001 | |
| Heart rate (bpm) | 68 (61–76) | 69 (61–77) | 0.334 | |
| NYHA ≥III | 20 (3.8) | 29 (4.7) | 0.566 | |
| Family history of HCM | 21 (4.0) | 71 (11.5) | <0.001 | |
| ICD implantation at baseline | 1 (0.2) | 3 (0.5) | 0.738 | |
| Risk factors for SCD | ||||
| Family history of SCD | 41 (7.9) | 74 (12.0) | 0.027 | |
| Non-sustained VT* | 86 (23.1) | 105 (21.4) | 0.615 | |
| Syncope | 58 (11.1) | 83 (13.5) | 0.269 | |
| 5-year SCD risk score (%) | 1.8 (1.3–2.7) | 1.9 (1.4–3.2) | 0.016 | |
| Comorbidities | ||||
| Diabetes mellitus | 132 (25.3) | 68 (11.0) | <0.001 | |
| Dyslipidemia | 151 (28.9) | 111 (18.0) | <0.001 | |
| Atrial fibrillation | 113 (21.6) | 92 (14.9) | 0.004 | |
| Previous PCI | 19 (3.6) | 7 (1.1) | 0.009 | |
| Previous myocardial infarction | 7 (1.3) | 9 (1.5) | >0.99 | |
| History of cancer | 75 (14.4) | 50 (8.1) | 0.001 | |
| Medications | ||||
| Beta-blockers | 233 (44.6) | 230 (37.3) | 0.014 | |
| Non-DHP CCB | 63 (12.1) | 108 (17.5) | 0.013 | |
| DHP CCB | 162 (31.0) | 6 (1.0) | <0.001 | |
| RAS blockers | 260 (49.8) | 59 (9.6) | <0.001 | |
| Loop diuretics | 27 (5.2) | 21 (3.4) | 0.183 | |
| Thiazide | 68 (13.0) | 21 (3.4) | <0.001 | |
| Spironolactone | 18 (3.4) | 24 (3.9) | 0.813 | |
| Cardiac structure and function | ||||
| LV end-diastolic diameter (mm) | 49 (45–52) | 47 (43–50) | <0.001 | |
| LV end-systolic diameter (mm) | 29 (26–31) | 28 (25–30) | <0.001 | |
| LVEF (%) | 65.0 (60.0–69.0) | 65.0 (60.0–69.0) | 0.619 | |
| Maximal wall thickness (mm) | 18.0 (16.0–20.5) | 18.0 (16.0–20.0) | 0.337 | |
| LV mass index (g/m2) | 121.7 (102.4–150.2) | 121.4 (98.0–147.8) | 0.293 | |
| LA dimension (mm) | 45.0 (41.0–51.0) | 43.0 (39.0–48.0) | <0.001 | |
| LA volume index (mL/m2) | 43.8 (33.3–55.3) | 41.3 (32.0–53.2) | 0.092 | |
| E/A ratio | 0.8 (0.7–1.1) | 0.9 (0.7–1.3) | <0.001 | |
| Septal e’-wave (cm/s) | 4.7 (3.8–5.9) | 5.0 (4.0–6.0) | 0.007 | |
| E/e’ ratio | 12.5 (10.0–16.2) | 11.9 (9.4–15.6) | 0.089 | |
| TR peak velocity (m/s) | 2.4 (2.2–2.6) | 2.3 (2.1–2.6) | 0.158 | |
| Maximal LV outflow tract gradient (mmHg) | 5.4 (3.7–10.1) | 5.0 (3.6–8.9) | 0.199 | |
| Maximal LVOT gradient ≥30 mmHg | 75 (14.4) | 95 (15.4) | 0.687 | |
| LV apical aneurysm | 51 (9.8) | 53 (8.6) | 0.558 | |
| LV-GLS (%) | 13.7 (10.7–16.7) | 14.4 (11.7–17.7) | 0.001 | |
| Late gadolinium enhancement (%)† | 3.1 (0.7–7.8) | 4.5 (1.0–12.1) | 0.005 | |
Continuous variables are expressed as median values with interquartile ranges, and categorical variables as frequencies with percentages.
bpm = beats per minute; CCB = calcium channel blocker; DBP = diastolic blood pressure; DHP = dihydropyridine; HCM = hypertrophic cardiomyopathy; ICD = implantable cardioverter-defibrillator; LA = left atrial; LV = left ventricular; LVEF = left ventricular ejection fraction; LV-GLS = left ventricular global longitudinal strain; LVOT = left ventricular outflow tract; NYHA = New York Heart Association; PCI = percutaneous coronary intervention; RAS = renin-angiotensin system; SBP = systolic blood pressure; SCD = sudden cardiac death; TR = tricuspid regurgitation; VT = ventricular tachycardia.
*Data available in 864 patients (75.9%); 373 patients with hypertension (71.5%) and 491 patients without hypertension (79.6%).
†Data available in 639 patients (56.1%); 259 patients with hypertension (49.6%) and 380 patients without hypertension (61.6%).
Patients with hypertension had a significantly larger LV cavity size than those without, although the LVEF was similar between the groups (median 65.0% vs. 65.0%, p=0.619) (Table 1). There was no significant difference in LV maximal wall thickness between patients with and without hypertension (median 18.0 vs. 18.0 mm, p=0.337). Patients with hypertension had larger LA volume indices and higher E/e’ ratios, although the differences were of borderline statistical significance. The percentage of late gadolinium enhancement was higher in patients without hypertension (median 4.5% vs. 3.1%, p=0.005).
Left ventricular global longitudinal strain in hypertrophic cardiomyopathy based on hypertension
The median LV-GLS across the entire cohort was 14.0% (interquartile range, 11.3–17.3%). The distribution of LV-GLS across the hypertension subgroups is shown in Figure 1A and B. LV-GLS was significantly lower in patients with hypertension (median 13.7%) compared to those without (median 14.4%, p=0.001) (Table 1). In a linear regression analysis, hypertension was associated with a significantly lower LV-GLS after adjusting for multiple risk factors (standardized regression coefficient = −0.075±0.030, p=0.013) (Supplementary Table 1).
Figure 1. Distribution of LV-GLS and its association with cardiac structure and function according to hypertension status.
Distribution of LV-GLS in patients (A) with hypertension and (B) without hypertension, with the data grouped in 1% intervals. Association of LV-GLS with (C) maximal wall thickness, (D) LVEF, and (E) LA volume index according to hypertension.
IQR = interquartile range; LA = left atrial; LVEF = left ventricular ejection fraction; LV-GLS = left ventricular global longitudinal strain.
Clinical and echocardiographic characteristics of two LV-GLS groups (≥13.1% vs. <13.1%) are presented in Supplementary Table 2. Compared to patients with higher LV-GLS, those with lower LV-GLS more frequently had atrial fibrillation and exhibited lower LVEF, greater LV maximal wall thickness, and a larger LA volume index. In both patients with and without hypertension, those with a lower LV-GLS (<13.1%) had a significantly higher maximal wall thickness, lower LVEF, and higher LA volume index compared to those with a higher LV-GLS (≥13.1%) (Figure 1C-E).
Cardiovascular events in the entire cohort
Over a median follow-up of 6.6 years (interquartile interval 2.8–9.8 years), 155 CV events occurred, including 56 CV deaths, 74 hospitalizations due to HF, and 59 strokes. The annualized rate of CV events was 22.4 events per 1,000 patient years. Univariable Cox analysis showed that age, female sex, New York Heart Association class ≥III, syncope history, a higher 5-year SCD risk score, hypertension, diabetes mellitus, atrial fibrillation, a lower LVEF, a higher LV mass index, a higher LA dimension or volume index, a higher E/e’ ratio, a higher TR peak velocity, and a lower LV-GLS were significantly associated with an increased risk of CV events (Supplementary Table 3). However, in the multivariable Cox model, hypertension was not independently associated with a higher risk of CV event (p=0.761) (Supplementary Table 4).
Cardiovascular events according to hypertension and left ventricular global longitudinal strain
CV events occurred more frequently in patients with hypertension than in those without (89 [17.0%] vs. 66 [10.7%], p=0.005) (Figure 2A). When stratified by LV-GLS, patients with a lower LV-GLS (<13.1%) had significantly higher CV events compared to those with a higher LV-GLS (≥13.1%) (80 [17.7%] vs. 75 [10.9%], p<0.001) (Figure 2B).
Figure 2. Adverse CV events according to hypertension and LV-GLS.
CV event-free survival according to (A) underlying hypertension and (B) LV-GLS groups (≥13.1% vs. <13.1%).
CV = cardiovascular; LV-GLS = left ventricular global longitudinal strain.
In the univariable Cox analysis, a lower LV-GLS was significantly associated with a higher risk of CV events in the entire cohort, as well as in each group of patients with hypertension (per 1% decrease in LV-GLS: HR, 1.09; 95% CI, 1.04–1.15; p<0.001) and without hypertension (per 1% decrease in LV-GLS: HR, 1.06; 95% CI, 1.00–1.13; p=0.041) (p-for-interaction=0.503) (Table 2). The 10-year CV events probabilities gradually increased as the LV-GLS decreased in both patients with and without hypertension, with a more pronounced increase observed in those with hypertension (Figure 3). After adjusting for multiple risk factors, the decrease in LV-GLS remained a significant predictor of CV events in patients with hypertension (per 1% decrease in LV-GLS: adjusted HR, 1.07; 95% CI, 1.01–1.13; p=0.013). However, the significance was lost in patients without hypertension, with no significant interaction observed (p-for-interaction=0.566). Similar findings were observed for LV-GLS categorization using a 13.1% cutoff value (Table 2).
Table 2. Association of LV-GLS with adverse cardiovascular events according to hypertension.
| Variables | Entire cohort | Patients with hypertension (n=522) | Patients without hypertension (n=617) | p-for-interaction | ||||
|---|---|---|---|---|---|---|---|---|
| HR (95% CI) | p value | HR (95% CI) | p value | HR (95% CI) | p value | |||
| LV-GLS, per 1% decrease | ||||||||
| Unadjusted analysis | 1.08 (1.04–1.12) | <0.001 | 1.09 (1.04–1.15) | <0.001 | 1.06 (1.00–1.13) | 0.041 | 0.503 | |
| Multivariable analysis* | 1.04 (1.00–1.09) | 0.030 | 1.07 (1.01–1.13) | 0.013 | 1.02 (0.95–1.08) | 0.604 | 0.566 | |
| LV-GLS, <13.1% vs. ≥13.1% | ||||||||
| Unadjusted analysis | 1.96 (1.43–2.69) | <0.001 | 2.12 (1.39–3.23) | <0.001 | 1.63 (0.99–2.66) | 0.050 | 0.426 | |
| Multivariable analysis* | 1.54 (1.09–2.16) | 0.013 | 2.01 (1.27–3.18) | 0.003 | 1.10 (0.64–1.88) | 0.736 | 0.313 | |
CI = confidence interval; HR = hazard ratio; LVEF = left ventricular ejection fraction; LV-GLS = left ventricular global longitudinal strain; NYHA = New York Heart Association.
*Adjusted for age, sex, NYHA functional class, hypertension, diabetes mellitus, atrial fibrillation, syncope, and LVEF. Hypertension was not included in the multivariable model for the subgroups with and without hypertension.
Figure 3. The relationship between LV-GLS and the probability of 10-year CV events according to hypertension.
CV = cardiovascular; LV-GLS = left ventricular global longitudinal strain.
When stratified by 4 groups according to hypertension and LV-GLS, CV events most frequently occurred in those with both hypertension and LV-GLS <13.1%, while the lowest rate of CV events occurred in patients without hypertension and LV-GLS ≥13.1% (Figure 4). Cox analysis demonstrated that patients with both hypertension and LV-GLS <13.1% had a significantly higher risk of CV events than those without hypertension and LV-GLS ≥13.1% (adjusted HR, 1.60; 95% CI, 1.01–2.54; p=0.044) (Table 3).
Figure 4. Adverse CV events stratified by 4 groups based on hypertension status and LV-GLS.
CV = cardiovascular; LV-GLS = left ventricular global longitudinal strain.
Table 3. Risks of adverse cardiovascular events by hypertension status and LV-GLS categories.
| Categories | No. | Event (10-year cumulative incidence, %) | Univariable analysis | Multivariable analysis* | ||
|---|---|---|---|---|---|---|
| HR (95% CI) | p value | HR (95% CI) | p value | |||
| Without hypertension and LV-GLS ≥13.1% | 395 | 38 (15.8) | 1.00 (ref) | 1.00 (ref) | ||
| Without hypertension and LV-GLS <13.1% | 222 | 28 (17.0) | 1.62 (0.99–2.65) | 0.052 | 1.27 (0.77–2.11) | 0.353 |
| With hypertension and LV-GLS ≥13.1% | 293 | 37 (15.6) | 1.30 (0.82–2.04) | 0.261 | 0.90 (0.56–1.45) | 0.668 |
| With hypertension and LV-GLS <13.1% | 229 | 52 (35.8) | 2.74 (1.80–4.16) | <0.001 | 1.60 (1.01–2.54) | 0.044 |
CI = confidence interval; HR = hazard ratio; LVEF = left ventricular ejection fraction; LV-GLS = left ventricular global longitudinal strain; NYHA = New York Heart Association.
*Adjusted for age, sex, NYHA functional class, diabetes mellitus, atrial fibrillation, syncope, and LVEF.
Sudden cardiac death-related events according to hypertension and left ventricular global longitudinal strain
During the follow-up, there were 32 SCD-related events. There was no significant difference in the cumulative incidence of SCD-related events according to hypertension (Supplementary Figure 2A). However, patients with a lower LV-GLS had a significantly higher incidence of SCD-related events than those with a higher LV-GLS (Supplementary Figure 2B). In both hypertensive and non-hypertensive patients, those with a lower LV-GLS had a higher incidence of SCD-related events (Supplementary Figure 3).
DISCUSSION
This study investigated clinical features, and cardiac structural and functional characteristics in relation to hypertension in patients with HCM, using a large strain imaging database. Compared with those without hypertension, patients with hypertension were significantly older, exhibited more frequent CV comorbidities, had a lower LV-GLS, and subsequently experienced higher adverse CV events. Lower LV-GLS was associated with thicker myocardium, reduced LV systolic function (as indicated by LVEF), and LA enlargement, and was identified as a strong independent predictor of CV events in hypertensive patients with HCM. Importantly, patients with both hypertension and a lower LV-GLS had the worst long-term CV outcomes. Collectively, our findings provide important insights into the characteristics and outcomes of patients with HCM based on their hypertension status and emphasize the critical role of LV-GLS in risk stratification.
Although numerous studies have established that hypertension increases the risk of adverse CV events, specific data involving patients with HCM are scarce and contradictory. A previous study conducted in the United Kingdom demonstrated that hypertension was an independent predictor of adverse CV outcomes in 425 patients with HCM of different ethnicities.25) However, a more recent study showed that hypertensive patients with HCM exhibited a non-significantly lower survival rate.26) In the present study, patients with hypertension experienced a significantly higher incidence of CV events, but hypertension was not independently associated with the outcomes after adjustment for multiple CV comorbidities. This finding suggests that the increased incidence of CV events in hypertensive patients with HCM may be linked to their overall cardiovascular health and related comorbidities, such as ischemic heart disease.16) It also underscores the necessity of closely monitoring and controlling CV comorbidities in HCM patients, similar to practices in other populations across various clinical settings.
Hypertension induces various forms of LV remodeling, including progressive myocardial systolic dysfunction. While LVEF was similar between patients with and without hypertension, LV-GLS was significantly lower in those with hypertension, and hypertension was independently associated with lower LV-GLS. These findings suggest that LV-GLS is a more sensitive and precise marker of LV systolic function compared to LVEF. In HCM, LV systolic dysfunction is known to be closely associated with myocardial fibrosis, ischemia, and cardiomyocyte apoptosis.27) Although the guideline uses an LVEF below 50% to stratify the risk of SCD,22) individuals with a low-normal LVEF of 50–60% also have a higher incidence of HF-related hospitalizations and CV death.28) Notably, LV-GLS provides effective risk stratification for adverse CV outcomes in patients with HCM and a low-normal EF, highlighting its significant predictive role.11) Therefore, the information provided by LV-GLS has the potential to redefine disease stages and serve as a surrogate marker for identifying high-risk patients beyond traditional risk factors.14)
Our analysis demonstrated a strong association between LV-GLS and CV events in patients with HCM and hypertension. In the multivariable analysis, the association remained significant only within the hypertensive group. Moreover, the probability of CV events with decreasing LV-GLS increased more steeply in those with hypertension compared to those without. These findings suggest that LV-GLS is a composite marker of myocardial dysfunction, likely influenced by various factors, and has a greater prognostic significance in patients with HCM who have additional CV conditions. However, the exact mechanisms underlying the impact of hypertension remain unclear. While hypertension may induce fibrosis in the myocardium,29) in our cohort, it was surprisingly not associated with an increased late gadolinium enhancement. The lower extent of late gadolinium enhancement in hypertensive HCM patients may suggest a higher prevalence of non-familial HCM in this population, which is associated with a later onset of HCM and a milder phenotype.8)
Our analysis revealed that the prognosis was worst for patients with both hypertension and reduced LV-GLS. This observation suggests that HCM patients with myocardial systolic dysfunction have an augmented risk of CV events in the setting of hypertension. LV systolic dysfunction in HCM is a progressive condition that ultimately increases the risk of SCD and HF, with hypertension potentially playing a significant role. Our findings indicate that the assessment of LV-GLS may be particularly valuable in patients with HCM and hypertension. More rigorous monitoring and control of hypertension in patients with HCM could offer significant benefits. Since recent advancements in HCM treatment have successfully reduced the incidence of SCD, CV events unrelated to SCD have become a significant concern.30) Future research is essential to confirm the benefits of treatments that improve vascular and metabolic health in this specific population and to establish the role of LV-GLS in risk stratification.
Our study has several limitations. First, this cohort consisted exclusively of the Korean population; therefore, our findings require further validation in an external cohort. Second, patients without hypertension at baseline may have developed hypertension during follow-up. Furthermore, our analysis did not account for potential morphological changes in the LV in hypertensive patients or their effects on the LV-GLS over time. Third, specific data on the characteristics of hypertension treatment were unavailable, including the duration of treatment and the dosage of medication; thus, the effects of hypertension treatment and adequate control of blood pressure over time were not assessed. Further analysis accounting for these factors may provide insights into the effects of treatment intensity on cardiac function and prognosis in patients with HCM.
In conclusion, patients with HCM and coexisting hypertension were older, had more prevalent CV comorbidities, and exhibited a lower LV-GLS compared to those without hypertension. LV-GLS is an important prognosticator in patients with both HCM and hypertension.
Footnotes
Funding: This study was supported by a research grant from the 2021 Seoul National University Research Fund (No. 800-20210548).
Conflict of Interest: The authors have no financial conflicts of interest.
Data Sharing Statement: The data supporting the findings of this study will be available from the corresponding authors upon reasonable request.
- Conceptualization: Kwak S, Kim HK.
- Data curation: Kwak S, Kim J, Park CS, Lee HJ, Park JB, Lee SP.
- Formal analysis: Kwak S.
- Funding acquisition: Kim HK.
- Investigation: Kwak S, Park CS, Lee HJ, Park JB, Lee SP.
- Methodology: Kwak S, Kim J.
- Project administration: Kim HK, Lee SC.
- Resources: Kim HK.
- Software: Kwak S.
- Supervision: Kim YJ, Kim HK, Lee SC, Wang A.
- Visualization: Kwak S.
- Writing - original draft: Kwak S, Kim J, Kim HK.
- Writing - review & editing: Kwak S, Kim HK, Wang A.
SUPPLEMENTARY MATERIALS
Multivariable linear regression model for predicting LV-GLS
Baseline clinical characteristics of the study participants according to LV-GLS
Univariable Cox analysis for CV events in the entire cohort
Multivariable Cox analysis for CV events in the entire study population
Cutoff value of LV-GLS for CV events identified by maximally selected log-rank statistics.
SCD-related events according to hypertension and LV-GLS across the entire cohort.
SCD-related events by LV-GLS in groups of patients with and without hypertension.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Multivariable linear regression model for predicting LV-GLS
Baseline clinical characteristics of the study participants according to LV-GLS
Univariable Cox analysis for CV events in the entire cohort
Multivariable Cox analysis for CV events in the entire study population
Cutoff value of LV-GLS for CV events identified by maximally selected log-rank statistics.
SCD-related events according to hypertension and LV-GLS across the entire cohort.
SCD-related events by LV-GLS in groups of patients with and without hypertension.