Sunil K. Vasireddi

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a genetic disorder of desmosomal and structural proteins that is characterized by fibro-fatty infiltrate in the ventricles and fatal arrhythmia that can occur early before significant structural abnormalities. Most ARVC mutations interfere with β-catenin–dependent transcription that enhances adipogenesis; however, the mechanistic pathway to arrhythmogenesis is not clear. We hypothesized that adipogenic conditions play an important role in the formation of arrhythmia substrates in ARVC. Cardiac myocyte monolayers co-cultured for 2–4 days with mesenchymal stem cells (MSC) were derived from human-induced pluripotent stem cells with the ARVC5 TMEM43 p.Ser358Leu mutation. The TMEM43 mutation in myocyte co-cultures alone had no significant effect on impulse conduction velocity (CV) or APD. In contrast, when co-cultures were exposed to pro-adipogenic factors for 2–4 days, CV and APD were significantly reduced compared to controls by 49% and 31%, respectively without evidence of adipogenesis. Additionally, these arrhythmia substrates coincided with a significant reduction in IGF-1 expression in MSCs and were mitigated by IGF-1 treatment. These findings suggest that the onset of enhanced adipogenic signaling may be a mechanism of early arrhythmogenesis, which could lead to personalized treatment for arrhythmias associated with TMEM43 and other ARVC mutations.

Abnormal Left ventricular mass (LVM) prognosticates adverse cardiovascular events. Conventionally, LVM measured by echo assumes a prolate ellipsoid (PE) shape; however, it poorly correlates with reference standard of cardiac magnetic resonance imaging (CMR) derived LVM. PE model assumes LVL = 2 × LVID. We developed a new echo LVM formula based on LV length and tested for accuracy against CMR. A retrospective study of consecutive patients with an echocardiogram and CMR within 3 months. Derivation (n = 170) and validation cohorts (n = 54) were used to test the new formula. Following analysis of correlation of interventricular septum (IVS), LV internal dimension (LVID), posterior wall (PW) and LVL between echo and CMR, a novel paraboloid-shape linear regression (PLR) model was derived. LVM by both models were compared to CMR. Poor correlation observed between actual and assumed LVL (0.52 with CMR; 0.44 with echo). Strong correlation was noted between echo and CMR measured LVL, LVID, IVS (r > 0.80) and a moderate correlation with PW (r = 0.62). Strong correlation of LVL was harnessed to develop PLR model, which significantly decreased paired error in derivation cohort (from 64 ± 42 to 22 ± 21 gm) and validation cohort (from 63 ± 46 to 25 ± 18 gm). Furthermore, it demonstrates significant reduction in absolute, relative errors and variability along with superior correlation in both cohorts. Between echo and CMR, LVL demonstrates one of the best correlation among LV dimensions. The assumption, LVL = 2 × LVID appears inaccurate. PLR model incorporates LVL and significantly improves accuracy, reduces variability of LVM.