Increased Chamber Resting Tone Is a Key Determinant of Left Ventricular Diastolic Dysfunction
María Tamargo, Pablo Martínez-Legazpi, M. Ángeles Espinosa, Aurore Lyon, Irene Méndez, Enrique Gutiérrez-Ibañes, Ana I. Fernández, Raquel Prieto-Arévalo, Ana González-Mansilla, Theo Arts, Tammo Delhaas, Teresa Mombiela, Ricardo Sanz-Ruiz, Jaime Elízaga, Raquel Yotti, Carsten Tschöpe, Francisco Fernández-Avilés, Joost Lumens, Javier Bermejo- Cardiology and Cardiovascular Medicine
BACKGROUND:
Twitch-independent tension has been demonstrated in cardiomyocytes, but its role in heart failure (HF) is unclear. We aimed to address twitch-independent tension as a source of diastolic dysfunction by isolating the effects of chamber resting tone (RT) from impaired relaxation and stiffness.
METHODS:
We invasively monitored pressure-volume data during cardiopulmonary exercise in 20 patients with hypertrophic cardiomyopathy, 17 control subjects, and 35 patients with HF with preserved ejection fraction. To measure RT, we developed a new method to fit continuous pressure-volume measurements, and first validated it in a computational model of loss of cMyBP-C (myosin binding protein-C).
RESULTS:
In hypertrophic cardiomyopathy, RT (estimated marginal mean [95% CI]) was 3.4 (0.4–6.4) mm Hg, increasing to 18.5 (15.5–21.5) mm Hg with exercise ( P <0.001). At peak exercise, RT was responsible for 64% (53%–76%) of end-diastolic pressure, whereas incomplete relaxation and stiffness accounted for the rest. RT correlated with the levels of NT-proBNP (N-terminal pro-B-type natriuretic peptide; R=0.57; P =0.02) and with pulmonary wedge pressure but following different slopes at rest and during exercise (R 2 =0.49; P <0.001). In controls, RT was 0.0 mm Hg and 1.2 (0.3–2.8) mm Hg in HF with preserved ejection fraction patients and was also exacerbated by exercise. In silico, RT increased in parallel to the loss of cMyBP-C function and correlated with twitch-independent myofilament tension (R=0.997).
CONCLUSIONS:
Augmented RT is the major cause of LV diastolic chamber dysfunction in hypertrophic cardiomyopathy and HF with preserved ejection fraction. RT transients determine diastolic pressures, pulmonary pressures, and functional capacity to a greater extent than relaxation and stiffness abnormalities. These findings support antimyosin agents for treating HF.