Letter by Nikolova et al Regarding Article, “Heart Failure With Preserved Ejection Fraction in Perspective”

To the Editor:

We would like to congratulate Pfeffer et al¹ for their excellent review of the current state of knowledge of the complex syndrome of heart failure with preserved ejection fraction (HFpEF). The authors provide a comprehensive historical and epidemiological perspective on the evolution in our understanding of this syndrome. However, we would like to point out that there is a fundamental pathophysiological process supported by animal and human data that should be included when considering this disorder. In particular, the authors discuss the importance of calcium homeostatic changes as a major contributor to the development of diastolic relaxation abnormalities and myocardial stiffness. A major component of pathological calcium homeostasis is remodeling of the transverse tubule (TT) network. TTs are richly folded membrane structures in cardiomyocytes, which harbor calcium (Ca²⁺) signaling microdomains.^2–4 Synchrony of Ca²⁺ transients and excitation-contraction coupling are dependent on the maintenance of the precise architectural organization of theses Ca²⁺ microdomains, which are disrupted in HFpEF.^5–7

TT changes are observed in the myocardium even at the stage of compensated hypertrophy.^8,9 In the continuum to heart failure progression, in heart failure with reduced ejection fraction and even with HFpEF, TTs exhibit worsening luminal dilation and microdomain loss.^5,6,9 Moreover, adverse TT changes have been proposed to serve as a prognostic tool in left ventricular assist device patients that can predict the potential for left ventricle functional recovery with mechanical unloading.¹⁰ As it is impractical to assay TT integrity via invasive endomyocardial biopsies, cBIN1 (cardiac bridging integrator 1) is emerging as a noninvasive test that reflects TT remodeling and thus has the potential to change the paradigm of HFpEF diagnosis and prognosis.

cBIN1 is a TT scaffolding protein in cardiomyocytes, which is turned over into blood in proportion to TT health, allowing in a sense a liquid biopsy of the myocardium.^11,12 A recent study performed by our group demonstrated that in a cohort of 52 patients experiencing cardiomyopathies with preserved left ventricular ejection fraction, cBIN1 and its log inverse derived score CS (cBIN1 Score) are able to diagnose the heart failure population with an area under the curve of 0.98 (95% CI, 0.96–1.00).¹² CS provides a robust separation of the heart failure and control populations.¹² Additionally, CS is able to prognosticate future cardiovascular hospitalizations over 1 year of follow-up.¹²

The accumulating body of evidence, from both animal and human studies, implicates TT changes in HFpEF pathogenesis. TT remodeling is, therefore, an important frontier in our understanding of this disease and our assessment of its affected patients.