Nanoscale Study of Calcium Handling Remodeling in Right Ventricular Cardiomyocytes Following Pulmonary Hypertension

Abstract

Pulmonary hypertension is a complex disorder characterized by pulmonary vascular remodeling and right ventricular hypertrophy, leading to right heart failure. The mechanisms underlying this process are not well understood. We hypothesize that the structural remodeling occurring in the cardiomyocytes of the right ventricle affects the cytosolic Ca 2+ handling leading to arrhythmias. After 12 days of monocrotaline-induced pulmonary hypertension in rats, epicardial mapping showed electrical remodeling in both ventricles. In myocytes isolated from the hypertensive rats, a combination of high-speed camera and confocal line-scan documented a prolongation of Ca 2+ transients along with a higher local Ca 2+ -release activity. These Ca 2+ transients were less synchronous than in controls, likely due to disorganized transverse-axial tubular system. In fact, following pulmonary hypertension, hypertrophied right ventricular myocytes showed significantly reduced number of transverse tubules and increased number of axial tubules; however, Stimulation Emission Depletion microscopy demonstrated that the colocalization of L-type Ca 2+ channels and RyR2 (ryanodine receptor 2) remained unchanged. Finally, Stimulation Emission Depletion microscopy and super-resolution scanning patch-clamp analysis uncovered a decrease in the density of active L-type Ca 2+ channels in right ventricular myocytes with an elevated open probability of the T-tubule anchored channels. This may represent a general mechanism of how nanoscale structural changes at the early stage of pulmonary hypertension impact on the development of the end stage failing phenotype in the right ventricle.

The complement C3-complement factor D-C3a receptor signalling axis regulates cardiac remodelling in right ventricular failure

“…4k-m). Calcium homeostasis plays a pivotal role in cardiomyocyte excitation-contraction coupling, and its impairment leads to RV failure and arrhythmic events 26 . In isolated RV cardiomyocytes, time to peak Ca 2+ transient was prolonged by PAC in WT mice, and its prolongation was suppressed in C3KO mice (Fig.…”

Ingenuity pathway analysis of the human cardiac cell Atlas identifies differences between right and left ventricular cardiomyocytes

“…Interestingly, many CPVT arrhythmias originate from the RV, 9 and thus the increased expression of RYR2 in the RV may provide a molecular explanation for this clinical observation. Moreover, in PAH‐induced RV dysfunction, there is increased calcium sparks and prolonged calcium transients in RV cardiomyocytes, possibly due to abnormal gating of the RYR2 10 …”

“…Moreover, in PAH-induced RV dysfunction, there is increased calcium sparks and prolonged calcium transients in RV cardiomyocytes, possibly due to abnormal gating of the RYR2. 10 Canonical pathway analysis of the five cardiomyocyte populations revealed eukaryotic initiation factor 2 (EIF2) signaling as an important differentiator between the RV and LV (Figure 1). EIF2 integrates a diverse set of signals including inflammation, stress, and nutritional states to modulate protein synthesis.…”

“…Moreover, in PAH‐induced RV dysfunction, there is increased calcium sparks and prolonged calcium transients in RV cardiomyocytes, possibly due to abnormal gating of the RYR2. 10 …”

Comparative Analysis of Right Ventricular Metabolic Reprogramming in Pre-clinical Rat Models of Severe Pulmonary Hypertension-induced Right Ventricular Failure

“…If left untreated, the life span of an individual with PH is about 2.8 years and the 5-year survival rate is only around 62% 8 . PH-induced RV failure (PH-RVF) is a major determinant of morbidity and mortality in PH [9][10][11] and is characterized by RV myocyte hypertrophy [12][13][14] , extensive extra-cellular matrix (ECM) reorganization [14][15][16] , fibrosis [17][18][19][20][21] and vascular remodeling [22][23][24] .…”