INTRODUCTION
Hypertrophic cardiomyopathy (HCM) is a relatively common genetic clinical syndrome characterized by left ventricular (LV) hypertrophy in the absence of other cardiac, systemic, or metabolic disease (1). Its origin mainly lies in gene mutations of the sarcomere, and it is inherited in an autosomal dominant manner in most cases. (2) It presents a broad clinical spectrum, ranging from asymptomatic patients to those with advanced heart failure or sudden death. (3)
However, prognostic stratification in HCM remains challenging, given the heterogeneity in disease progression and the limited ability of conventional parameters to predict functional decline (3-5). Peak oxygen consumption (peak VO2 ), obtained through cardiopulmonary exercise testing, is a robust marker of functional capacity and an independent predictor of morbidity and mortality in various heart diseases, including HCM (6). Thus, peak VO2 was proposed as the primary endpoint in the main studies on this condition. (7-9) However, the clinical and imaging variables that determine lower peak VO2 in this population are not clearly defined.
Cardiac magnetic resonance imaging (CMR) has become the gold standard for LV morphological and functional assessment, also allowing accurate quantification of fibrosis using late gadolinium enhancement (LGE) (1,2). Recently, the incorporation of global longitudinal strain analysis by cardiac magnetic resonance imaging (GLS-CMR) through feature tracking detects earlier stages of ventricular involvement, which are not evident with conventional techniques such as volumetric left ventricular ejection fraction (LVEF) measurement (10,11). It should be noted that GLS was used in this study because it is the most reproducible parameter and the most widely used in clinical practice, with less variability than radial or circumferential strain (12,13).
However, the prognostic value of this parameter in relation to functional capacity in HCM still requires further evidence. (14-17)
OBJECTIVES
We evaluated the association between GLS-CMR and other clinical, echocardiographic, and CMR variables with peak VO2 measured in the cardiopulmonary exercise test in a contemporary cohort of patients with confirmed diagnosis of HCM, with the aim of identifying independent predictors of functional limitation that would optimize prognostic stratification in this group of patients.
METHODS
A retrospective, observational, single-center cohort study was conducted including patients belonging to an institutional HCM registry between January 2017 and March 2025. All patients gave informed consent prior to inclusion in the study. The data for the present analysis were obtained from a review of the institutional electronic medical records.
Hypertrophic cardiomyopathy was defined as the presence of increased thickness in any LV segment >15mm or >13mm in first-degree relatives diagnosed with this disease, in the absence of any other justifiable cause. (1) Whenever possible, genetic studies were performed to confirm the sarcomeric etiology. Patients over 18 years of age with a confirmed diagnosis of sarcomeric HCM were included in the study, and phenotypes or other causes of ventricular hypertrophy were excluded.
For this study, only those patients who had echocardiogram, CMR, and cardiopulmonary exercise testing performed within an interval ≤ 12 months from each other were selected.
The following variables were collected: demographic (age, sex, height), clinical (NYHA functional class, treatment received), echocardiographic (LVEF, maximum intraventricular gradient, presence of obstructive HCM defined by a gradient ≥ 30mmHg at rest and/or systolic anterior movement of the anterior mitral valve), and CMR-derived parameters (indexed ventricular volumes and mass, LVEF, and right ventricular ejection fraction, maximum wall thickness, presence and quantification of LGE, and LV GLS-CMR).
Cardiac magnetic resonance imaging was performed using a 1.5 T scanner (Avanto, Siemens Medical Solutions, Erlangen, Germany) and LGE quantification (using a 5-threshold technique) and GLS-CMR were acquired using Circle Cardiovascular Imaging software (Tissue Tracking, cvi42, Figure 1). Peak VO2 was obtained by cardiopulmonary testing on a cycle ergometer using an incremental protocol, expressed in mL/kg/min.
Statistical analysis
Continuous variables were expressed as mean ± standard deviation (SD) or as median and interquartile range (IQR), depending on their distribution as assessed by the Shapiro-Wilk test, and were compared using Student's t-test or the Mann-Whitney test, depending on data distribution. Categorical variables were presented as absolute frequencies and percentages and were compared using the Chi² test or Fisher's exact test, as appropriate.
Linear regression models were applied to explore the associations between clinical, echocardiographic, and CMR variables with peak VO2 . In the univariate analysis, each predictor was evaluated individually to identify significant correlations with peak VO2 . Subsequently, those variables with statistical significance (p < 0.05) or clinical relevance were incorporated into a multivariate linear regression model to identify independent predictors of lower peak VO2 . All statistical analyses were performed using STATA software version 13.1 (StataCorp LP, College Station, TX, USA), and p values < 0.05 were considered as statistically significant.
Ethical considerations
The study protocol follows the ethical guidelines of the Declaration of Helsinki, (18) and the design of the institutional hypertrophic cardiomyopathy registry from which the data were obtained was approved by the institutional ethics committee.
RESULTS
A total of 54 patients diagnosed with sarcomeric HCM were included in the study. Mean age was 53± 18 years, and 59.2% (n = 32) were men. The obstructive form of the disease was recorded in 26 patients (48.1%) . Mean peak VO2 in the population was 23.5± 9.6mL / kg / min .
Cardiac magnetic resonance parameters
Mean LVEF was 72 ± 10% and mean maximum wall thickness 17 ± 4 mm . Late gadolinium enhancement was present in 94.4% (n = 51) of patients, with a median mass of 15 grams and a 95% confidence interval (CI) of 6.84-33.59 (no discrimination was made according to LGE percentage). Mean LV GLS-CMR was -13 ± 3.3% . Figure 1 shows an example of GLS-CMR measurement in one cohort patient. The remaining clinical, echocardiographic, CMR, and cardiopulmonary exercise test variables are detailed in Table 1.
Fig. 1.
Example of left ventricular global longitudinal strain analysis using Circle Cardiovascular Imaging (Tissue Tracking, cvi42).
Table 1.
General characteristics of the population
| Clinical variables | |
|---|---|
| Age at diagnosis, years, mean ± SD | 53 ± 18 |
| Male sex, n (%) | 32 (59.3) |
| Height, centimeters, mean ± SD | 161 ± 33 |
| NYHA functional class* ≥ 2, n (%) | 16 (29.6) |
| BMI*, kg/m², mean ± SD | 28.4 ± 5.1 |
| Hypertension, n (%) | 21 (38.9) |
| Diabetes mellitus, n (%) | 6 (11.1) |
| Atrial fibrillation, n (%) | 7 (13.0) |
| Dyspnea, n (%) | 31 (57.4) |
| Angina, n (%) | 12 (22.2) |
| Atrial fibrillation, n (%) | 7 (13.0) |
| Beta-blockers, n (%) | 38 (70.4) |
| Calcium channel blockers, n (%) | 7 (13.0) |
| Myosin inhibitors, n (%) | 3 (5.6) |
| ICD*, n (%) | 6 (11.1) |
| Septal myectomy, n (%) | 3 (5.6) |
| Septal alcoholism, n (%) | 2 (3.7) |
| Ecocardiographic variables | |
| Wall thickness, mm, mean ± SD | 17.4 ± 3.9 |
| Left atrial anteroposterior diameter, mm, median (IQR) | 42 [38-46] |
| Intraventricular gradient, mmHg, median (IQR) | 30 [6-58] |
| SAM, n (%) | 25 (46.3) |
| LVOTO, n (%) | 32 (59.3) |
| Cardiac resonance variables | |
| LVEF, %, mean ± SD | 72 ± 10 |
| Indexed LV end-diastolic volume, mL/m², mean ± SD | 72 ± 18 |
| Indexed LV end-systolic volume, mL/m², median (IQR) | 69 [60-78] |
| Maximum thickness, mm, mean ± SD | 17 ± 4 |
| Presence of LGE, n (%) | 51 (94.4) |
| LGE mass, grams, median (IQR) | 15 [6.84-33.59] |
| Left ventricular GLS, %, mean ± SD | -13 ± 3.3 |
| Right ventricular ejection fraction, %, mean ± SD | 66 ± 7 |
| RV end-diastolic volume, mL, mean ± SD | 71 ± 15 |
| RV end-systolic volume, mL, mean ± SD | 27 ± 24 |
| LV mass, grams | 86 ± 24 |
| Oxygen consumption variables | |
| Peak VO₂ (mL/kg/min), mean ± SD | 23.5 ± 9.6 |
| VO₂ (% of predicted), mean ± SD | 83.3 ± 19.5 |
| Heart rate at peak VO₂ (bpm), mean ± SD | 133.7 ± 30.7 |
| OUES, [(mL/min)/log10], mean ± SD | 2156.8 ± 954.7 |
BMI: body mass index; ICD: implantable cardioverter defibrillator; IQR: interquartile range; LGE: late gadolinium enhancement; LV: left ventricular; LVEF: left ventricular ejection fraction; LVOTO: left ventricular outflow tract obstruction; NYHA: New York Heart Association; OUES: oxygen uptake efficiency slope; RV: right ventricular; SAM: systolic anterior mitral valve movement; SD: standard deviation.
Univariate analysis
In the univariate linear regression model, significant associations were observed between peak VO2 and age at diagnosis (β = -0.35;95% CI: -0.46 to -0.24 ; p < 0.001 ), male sex (β = +8.26;95% CI + 3.37 to +13.14 ; p = 0.001 ), indexed right ventricular end-diastolic volume (β = +0.31;95% CI +0.15 to +0.46 ; p < 0.001 ), and LV GLS-CMR (β = -0.85;95% CI -1.62 to -0.08 ; p = 0.034 ). No significant associations were found with NYHA functional class, the presence of dynamic intraventricular obstruction, maximum intraventricular gradient, LVEF, LV volumes, LV mass, maximum wall thickness, or LGE. Table 2 details the variables included in the univariate analysis and their relationship with peak VO2.
Table 2.
Univariate linear regression model
| Variable | Univariate linear regression β coefficient (95% CI) | p value |
|---|---|---|
| Age at diagnosis | -0.35 (-0.46 to -0.24) | <0.001 |
| Male | +8.26 (+3.37 to +13.14) | 0.001 |
| NYHA dyspnea | -2.59 (-5.35 to +0.17) | 0.065 |
| Maximum intraventricular gradient (mmHg) | -0.06 (-0.15 to +0.02) | 0.110 |
| Obstructive HCM | -1.14 (-6.44 to +4.17) | 0.669 |
| LVEF % | +0.11 (-0.16 to +0.38) | 0.425 |
| Indexed left ventricular end-diastolic volume, (mL/m²) | +0.08 (-0.06 to +0.23) | 0.265 |
| Indexed LV end-systolic volume, (mL/m²) | -0.05 (-0.15 to +0.05) | 0.320 |
| Left ventricular mass (g/m²) | -0.0007 (-0.11 to +0.11) | 0.921\n |
| Maximum wall thickness (mm) | +0.09 (-0.60 to +0.79) | 0.781 |
| Quantitative LGE (%) | -0.004 (-0.10 to +0.09) | 0.934 |
| LGE (present) | +2.35 (-18 to 23.2) | 0.821 |
| RVEF (%) | +0.25 (-0.10 to +0.60) | 0.162 |
| Indexed RV end-diastolic volume (mL/m²) | +0.31 (+0.15 to +0.46) | <0.001 |
| Indexed RV end-systolic volume (mL/m²) | -0.018 (-0.13 to +0.09) | 0.743 |
| CMR strain (%) | -0.85 (-1.6 to -0.08) | 0.034 |
CMR: cardiac magnetic resonance; HCM: hypertrophic cardiomyopathy; LGE: late gadolinium enhancement; LV: left ventricular; LVEF: left ventricular ejection fraction; NYHA: New York Heart Association; RV: right ventricular; RVEF: right ventricular ejection fraction.
Multivariate analysis
In the multivariate linear regression model (Table 3), the independent predictors of lower peak VO2 were: female sex (β = -6.1 ; 95% CI -10.56 to -1.75; p = 0.007) older age at diagnosis (β = -0.26 ; 95% CI: -0.37 to -0.15; p < 0.001), and lower LV GLS-CMR (β = -0.59, 95% CI: -1.14 to -0.04; p = 0.033).
DISCUSSION
In this contemporary cohort of patients with HCM, we observed that a lower LV-GLS-CMR value was independently associated with lower functional capacity, as measured by peak VO2 in the cardiopulmonary exercise test. This finding could provide a relevant pathophysiological perspective, based on the hypothesis that functional limitation in HCM would depend not only on the degree of hypertrophy or the presence of dynamic obstruction, but also on both clinical and subclinical myocardial contractile failure, detectable by GLS-CMR, even in patients with preserved LVEF. Global longitudinal strain, by reflecting the longitudinal deformation capacity of the myocardium, is a sensitive marker of contractile efficiency and allows the detection of early mechanical dysfunction before global LVEF alterations or advanced symptoms become apparent (19,20). It is noteworthy that all patients in our cohort had preserved LVEF.
Abnormal GLS probably represents the functional expression of the distinctive molecular mechanisms of HCM, characterized by a progressive loss of contractile efficiency, which translates into reduced myocardial shortening and, consequently, a limited ability to increase cardiac output during exercise. In other words, reduced GLS implies a lower contractile reserve and, therefore, a limitation in sustaining cardiac output, which translates into decreased peak VO2.(14,19) This phenomenon could explain the association between greater GLS-CMR alteration and lower peak VO2 observed in our study, in accordance with the findings of the STRAIN-HCM study, where GLS behaved as an independent predictor of adverse events. (14,21)
On the other hand, we found no correlation between peak VO2 and the amount of myocardial fibrosis measured by LGE, a finding that reinforces the idea that GLS identifies an earlier functional stage of myocardial damage. (22,23) It should be noted that in our cohort, almost all patients had some degree of LGE, suggesting that the differential prognostic value of GLS does not depend exclusively on the presence or absence of fibrosis, but on the degree of underlying mechanical dysfunction.
The lower functional capacity observed in women in this study is consistent with reports from other series, where female sex is associated with more symptomatic phenotypes, smaller ventricular cavities, and greater predisposition to dynamic obstruction. (24) These anatomical features, combined with a frequently later diagnosis, could partly explain the functional gap observed. Similarly, older age was a negative determinant of peak VO2 probably reflecting the cumulative impact of diffuse fibrosis, myocardial stiffness, and associated comorbidities. (25,26)
From a clinical perspective, incorporating GLS-CMR into the evaluation of HCM may provide additional prognostic value and allow for a more accurate characterization of the functional phenotype. In patients with preserved LVEF, a significant reduction in GLS could anticipate clinical deterioration and guide early interventions. This integrated approach is in line with the current trend in the AHA/ACC international guidelines, (1) which promote personalized pathophysiological stratification, prevailing over a purely morphological approach.
In the future, it will likely be necessary to develop prognostic models that integrate clinical, imaging, and functional variables to refine risk prediction in this population.
Although this study has limitations inherent to its retrospective design and the single-center nature of the sample, the availability of high-quality complementary studies—echocardiogram, CMR, and cardiopulmonary testing— strengthens the robustness of the results. Furthermore, our population represents a clinical profile characteristic of HCM, with the presence of obstructive forms, which reinforces the representativeness of the sample and the applicability of the findings. Taken together, our data consolidate the notion that HCM is essentially a disease of myocardial mechanics rather than hypertrophy per se, and position GLS-CMR as a potentially important marker for understanding, quantifying, and monitoring contractile efficiency in clinical practice.
CONCLUSIONS
In this contemporary cohort of patients with HCM, female sex, older age, and reduced GLS-CMR were independently associated with lower peak VO2
These results highlight the usefulness of GLS-CMR as a complementary tool for prognostic stratification and functional assessment, beyond conventional parameters such as LVEF or LGE. Its systematic implementation could optimize the early identification of patients at higher risk of functional deterioration.
Limitations
The limitations of this study include its retrospective nature and the lack of stratification of peak VO2 according to patient sex. It is also important to note that no comparison was made between strain measured by cardiac magnetic resonance imaging and strain assessed by echocardiography.
Conflicts of interest
None declared. (See authors' conflict of interests forms on the web).
Acknowledgments
To the entire cardiology department of Hospital Italiano de Buenos Aires.
Sources of funding
None.