The mechanical and cellular relationships between systole and diastole during left ventricular (
LV) dysfunction remain to be established. LV contraction-relaxation coupling was examined during LV
hypertrophy induced by chronic
hypertension. Chronically instrumented pigs received
angiotensin II infusion for4weeks to induce chronic
hypertension (133 ± 7 mmHg vs 98 ± 5 mmHg for mean arterial pressure at Day 28 vs 0, respectively) and LV
hypertrophy. LV function was investigated with the instrumentation and echocardiography for LV twist-untwist assessment before and after
dobutamine infusion. The cellular mechanisms were investigated by exploring the intracellular Ca2+ handling. At Day 28, pigs exhibited LV
hypertrophy with
LV diastolic dysfunction (impaired LV isovolumic relaxation, increased LV end-diastolic pressure, decreased and delayed LV untwisting rate) and
LV systolic dysfunction (impaired LV isovolumic contraction and twist) although LV ejection fraction was preserved. Isolated cardiomyocytes exhibited altered shortening and lengthening. Interestingly, contraction-relaxation coupling remained preserved both in vivo and in vitro during LV
hypertrophy. LV systolic and diastolic dysfunctions were associated to post-translational remodeling and dysfunction of the type 2 cardiac
ryanodine receptor/Ca2+ release channel (
RyR2), i.e., PKA hyperphosphorylation of
RyR2, depletion of calstabin 2 (
FKBP12.6),
RyR2 leak and
hypersensitivity of
RyR2 to cytosolic Ca2+ during both contraction and relaxation phases. In conclusion, LV contraction-relaxation coupling remained preserved during chronic
hypertension despite LV systolic and diastolic dysfunctions. This implies that
LV diastolic dysfunction is accompanied by
LV systolic dysfunction. At the cellular level, this is linked to sarcoplasmic reticulum Ca2+ leak through PKA-mediated
RyR2 hyperphosphorylation and depletion of its stabilizing partner.