Commentary Chasing the Pathophysiological Footprint in Hypertrophic Cardiomyopathy: Beyond Global Strain

Hypertrophic cardiomyopathy (HCM) remains one of the most diagnostically challenging conditions in contemporary cardiology. Despite substantial structural abnormalities, many patients maintain a normal left ventricular ejection fraction (LVEF) and appear clinically stable at rest. Yet these same patients frequently report exertional limitations, reduced stamina, or disproportionate fatigue during daily activities. This disconnection between resting imaging and lived experience underscores the need for more sensitive tools capable of detecting early mechanical and physiological impairment. In this context, the study by Lin et al. [1], published in this issue of the journal, offers a compelling integrated approach, combining left ventricular pressure-strain loop (LV‐PSL)‐derived myocardial work indices with cardiopulmonary exercise testing (CPET) to illuminate the hidden burden of disease in non‐obstructive HCM. It is known that irrespective of whether a dynamic obstruction along the outflow tract is present or not, the condition more often than not may lead to sudden death, heart failure, and atrial fibrillation-related stroke [2].Echocardiography remains the most fundamental, accessible, and cost-effective imaging modality in cardiovascular medicine. It is portable, bedside-ready, and universally regarded as the first-line tool for evaluating patients with suspected HCM. To overcome the inherent limitations of two-dimensional imaging, particularly in diseases characterized by increased wall thickness such as HCM and cardiac amyloidosis, speckle tracking echocardiography has emerged as a valuable extension, offering a more comprehensive assessment of myocardial deformation. The recent document by the Americal society of Echocardiography [3], further enhances this approach by providing practical guidance on image acquisition, including optimized imaging protocols to improve reproducibility, and emphasizing the added value of strain imaging, particularly myocardial strain, in detecting subtle myocardial dysfunction. Strain imaging, especially global longitudinal strain, offers sensitive detection of early myocardial impairment that may precede changes in ejection fraction. Yet even with these advances, the information derived from conventional echocardiography and strain imaging does not fully capture the functional status of an individual patient in daily clinical practice. Myocardial work and cardiopulmonary exercise testing (CPET) provide complementary physiological perspectives, linking the phenotypic expression of the disease to its real-world functional consequences and clinical outcome [4].Lin et al. [1] enrolled 55 patients with non‐obstructive HCM and 55 matched controls, performing comprehensive echocardiography, speckle‐tracking strain analysis, myocardial work assessment, and CPET. Their findings reveal a consistent and physiologically coherent pattern: even in the presence of preserved LVEF, patients with HCM exhibit impaired myocardial mechanics at rest, an abnormal mechanical response to exercise, and measurable reductions in aerobic capacity and metabolic efficiency, as summarized in Figure 1.At baseline, the HCM cohort demonstrated significantly reduced global longitudinal strain, global work index (GWI), global constructive work (GCW), and global work efficiency, accompanied by increased global wasted work (GWW) and prolonged peak strain dispersion (PSD). These abnormalities reflect a myocardium that is less effective, less efficient, and less synchronous, despite maintaining a normal ejection fraction. As the authors note, this pattern likely arises from the combined effects of myocyte hypertrophy, fibrosis, microvascular dysfunction, and impaired myocardial energetics. Importantly, these abnormalities were detectable at rest, reinforcing the sensitivity of myocardial work as an early marker of subclinical systolic dysfunction.Beyond the quantitative abnormalities, the morphology of the LV‐PSL loops themselves offers a striking visual signature of the disease. In the HCM cohort, the loops assume a narrow, cone‐shaped configuration with steep pressure-strain trajectories, reflecting a ventricle that is stiff, energetically constrained, and unable to generate the broad, rounded work loops seen in healthy myocardium. This geometric “tightening” of the loop is consistent with impaired compliance and increased myocardial stiffness, despite the preserved structural integrity of the left ventricle on conventional imaging. The loop morphology therefore reinforces the central message of the study: that myocardial work captures pathophysiological features of HCM that remain invisible to standard echocardiography and even to speckle‐tracking strain alone.The study’s most striking insights emerge from the post‐exercise myocardial work analysis. In healthy controls, exercise appropriately increased GWI and GCW, reflecting enhanced contractile performance under physiological stress. In contrast, patients with HCM failed to augment constructive work and instead exhibited significant increases in GWW and PSD. This divergence highlights a fundamental limitation of the hypertrophied myocardium: when challenged, it cannot generate additional effective work (global work efficiency) and instead becomes more dyssynchronous and energetically wasteful. The authors aptly describe this as a manifestation of a “structural–functional–metabolic” triple disorder, in which hypertrophy and fibrosis impair synchrony, microvascular ischemia limits oxygen delivery, and metabolic inefficiency constrains ATP availability during stress.The CPET findings align seamlessly with the myocardial work abnormalities. Peak VO2, anaerobic threshold (AT), oxygen pulse (VO2/HR), and metabolic equivalents were all significantly reduced in the HCM group. These impairments reflect diminished global aerobic capacity, early metabolic limitation, and blunted stroke volume augmentation – physiological consequences of the mechanical inefficiency demonstrated on LV‐PSL. The VE/VCO2 slope was only mildly elevated and but not statistically different from controls, a finding consistent with the cohort’s predominantly NYHA class I status. This nuance is important: ventilatory inefficiency often emerges later in the disease course, whereas metabolic and stroke‐volume limitations appear earlier.The integration of myocardial work and CPET provides a powerful, multidimensional view of HCM pathophysiology. The inability to increase GCW and GWI during exercise offers a mechanical substrate for the reduced peak VO2, early onset of AT, and diminished oxygen pulse observed on CPET. In fact, the CPET abnormalities validate the clinical relevance of the myocardial work findings, demonstrating that mechanical inefficiency translates into measurable functional limitation. This convergence strengthens the argument that combined imaging and physiological assessment offers a more complete understanding of disease burden than either modality alone.The study also explores the relationship between maximal wall thickness and functional parameters. While maximal wall thickness correlated with several CPET and myocardial work indices in univariable analysis, multivariable modeling identified PSD, GCW, and GWW as the only independent associates. This finding reinforces the concept that myocardial work parameters serve as functional intermediaries between structural remodeling and clinical performance. Hypertrophy begets dyssynchrony (reflected in PSD), reduces effective work (GCW), and increases wasted work (GWW), all of which contribute to impaired exercise capacity.Several strengths of this study merit emphasis. The integrated design, inclusion of matched controls, and incorporation of CPET provide a robust physiological framework. The reproducibility of myocardial work indices, demonstrated through intraclass correlation analysis, supports their reliability in clinical and research settings. Moreover, the focus on non‐obstructive HCM – a subgroup often overshadowed by its obstructive counterpart – adds valuable insight into a population where early detection of dysfunction is particularly important, particularly in a newly diagnosed young individual when both LVEF and diastolic functions are preserved (Fig. 2).The study’s limitations are acknowledged by the authors. The single‐center design and modest sample size limit generalizability, and the absence of phenotype‐specific analyses (e.g., apical vs. septal hypertrophy) precludes more granular interpretation. Longitudinal follow‐up would be necessary to determine whether myocardial work or CPET parameters predict clinical outcomes or disease progression. Another limitation could be mentioned here that left atrial strain analysis was not performed as decreased LA strain could be associated with adverse outcome in HCM including sudden cardiac death worsening or new onset heart failure, new onset atrial fibrillation, and thromboembolic events [5]. LA strain and conventional markers of diastolic dysfunction are generally associated with increased LA pressure, as has recently been highlighted in the most recent ASE guideline [6].Nevertheless, the work by Lin et al. represents an important step toward a more nuanced understanding of non‐obstructive HCM. Their findings suggest that myocardial work and CPET, when used together, can uncover early mechanical and physiological abnormalities that remain invisible on conventional imaging. As the field moves toward more personalized and physiology‐based care, such integrated approaches may help refine risk stratification, guide exercise recommendations, and monitor disease evolution. As we have shown in Figure 3, in busy laboratories the researchers may consider selected LV-PSL parameters like GCW, GWI where CPET may not be easily available.Building on the mechanistic insights provided by Lin and colleagues, who demonstrated a fundamental energetic deficit in the HCM myocardium, it is increasingly clear that therapeutic strategies must extend beyond gradient reduction to address impaired metabolic efficiency. In this regard, Braunwald’s reference to the ongoing SONATA‐HCM phase 3 trial of Sotagliflozin, a dual SGLT1-2 inhibitor, is particularly timely [7]. As he notes, the rationale for sotagliflozin (widely used in diabetes with our without kidney function impairment) lies in its ability to promote a shift toward ketone‐body utilization, a more oxygen‐efficient substrate for the energy‐starved cardiomyocyte. This metabolic approach aligns directly with the energetic abnormalities described in the paper by Lin et al. [1] and may complement sarcomere‐targeted therapies by improving myocardial energetics in non‐obstructive HCM, a population for whom evidence‐based treatments remain limited. If successful, Sotagliflozin could meaningfully expand the therapeutic landscape and reinforce the centrality of metabolic modulation in HCM care.The authors have no conflicts of interest to declare.The authors have not received any financial support.Anatoli Kiotsekglou: designed the commentary and developed the conceptual framework. Aasha S Gopal: performed critical review of the work and created Figure 3. Adnan Rahman: responsible for data collection for Figure 2 and for obtaining informed consent from the patient for publication of anonymized images. Samir K. Saha: supervising author and final review and editing of the work.