Transmural Distribution of Coronary Perfusion and Myocardial Work Density Due to Alterations in Ventricular Loading, Geometry and Contractility

Myocardial supply changes to accommodate the variation of myocardial demand across the heart wall to maintain normal cardiac function. A computational framework that couples the systemic circulation of a left ventricular (LV) finite element model and coronary perfusion in a closed loop is developed to investigate the transmural distribution of the myocardial demand (work density) and supply (perfusion) ratio. Calibrated and validated against measurements of LV mechanics and coronary perfusion, the model is applied to investigate changes in the transmural distribution of passive coronary perfusion, myocardial work density, and their ratio in response to changes in LV contractility, preload, afterload, wall thickness, and cavity volume. The model predicts the following: (1) Total passive coronary flow varies from a minimum value at the endocardium to a maximum value at the epicardium transmurally that is consistent with the transmural distribution of IMP; (2) Total passive coronary flow at different transmural locations is increased with an increase in either contractility, afterload, or preload of the LV, whereas is reduced with an increase in wall thickness or cavity volume; (3) Myocardial work density at different transmural locations is increased transmurally with an increase in either contractility, afterload, preload or cavity volume of the LV, but is reduced with an increase in wall thickness; (4) Myocardial work density-perfusion mismatch ratio at different transmural locations is increased with an increase in contractility, preload, wall thickness or cavity volume of the LV, and the ratio is higher at the endocardium than the epicardium. These results suggest that an increase in either contractility, preload, wall thickness, or cavity volume of the LV can increase the vulnerability of the subendocardial region to ischemia.

Fetal Hemodynamic Responses to Arterial Occlusion of Acardiac Twins

The objective of this study was to comprehensively assess fetal hemodynamic adaptions to occlusive procedures. Twin pregnancies complicated with acardiac twin and hydrops fetalis of the pump twin were recruited. The occlusive procedures — either alcoholization, radiofrequency ablation, coil embolization or occlusive glue — were performed under ultrasound guidance. Various hemodynamic parameters were assessed before, shortly after, then every 6 h for 48 h and 2−4 weeks after the procedures. Seven pregnancies were recruited. The median (range) gestational age of intervention was 21 (17−26) weeks of gestation. Before the procedures, all cases showed normal cardiac function. Just after the procedures, all cases showed an increase in Tei index and isovolumic relaxation time but returned to preocclusion levels within 6−48 h, except for two cases that were persistently high. Increased preload and poor shortening fraction were observed in two cases, leading to heart failure, with one recovery and one death in utero. Five out of the seven cases got through the critical period with a gradual return to normal hemodynamics, ending with the disappearance of hydrops and successful outcomes. It was concluded that the occlusive procedure could aggravate the overworked heart, leading to heart failure. Preocclusion preload index and Tei index may predict risk of heart failure due to the occlusion. This small series strongly suggests that the occlusion should be performed before the deterioration of cardiac function.

Advances in Cardiotoxicity Induced by Altered Mitochondrial Dynamics and Mitophagy

Mitochondria are the most abundant organelles in cardiac cells, and are essential to maintain the normal cardiac function, which requires mitochondrial dynamics and mitophagy to ensure the stability of mitochondrial quantity and quality. When mitochondria are affected by continuous injury factors, the balance between mitochondrial dynamics and mitophagy is broken. Aging and damaged mitochondria cannot be completely removed in cardiac cells, resulting in energy supply disorder and accumulation of toxic substances in cardiac cells, resulting in cardiac damage and cardiotoxicity. This paper summarizes the specific underlying mechanisms by which various adverse factors interfere with mitochondrial dynamics and mitophagy to produce cardiotoxicity and emphasizes the crucial role of oxidative stress in mitophagy. This review aims to provide fresh ideas for the prevention and treatment of cardiotoxicity induced by altered mitochondrial dynamics and mitophagy.

PRMT7 Ablation in Cardiomyocytes Causes Cardiac Hypertrophy and Fibrosis Through β-Catenin Dysregulation

Angiotensin II (AngII) has potent cardiac hypertrophic effects mediated through activation of hypertrophic signaling like Wnt/b-Catenin signaling. In the current study, we examined the role of protein arginine methyltransferase 7 (PRMT7) in cardiac function. PRMT7 was greatly decreased in hypertrophic hearts chronically infused with AngII and cardiomyocytes treated with AngII. PRMT7 depletion in rat cardiomyocytes resulted in hypertrophic responses. Consistently, mice lacking PRMT7 exhibited displayed the cardiac hypertrophy and fibrosis. PRMT7 overexpression abrogated the cellular hypertrophy elicited by AngII, while PRMT7 depletion exacerbated the hypertrophic response caused by AngII. Similar with AngII treatment, the cardiac transcriptome analysis of PRMT7-deficient hearts revealed the alteration in gene expression profile related to Wnt signaling pathway. Inhibition of PRMT7 by gene deletion or an inhibitor treatment enhanced the activity of b-Catenin. PRMT7 deficiency decreases symmetric dimethylation of b-Catenin. Mechanistic studies reveal that methylation of arginine residue 93 in b-Catenin decreases the activity of b-Catenin. Taken together, our data suggest that PRMT7 is important for normal cardiac function through suppression of b-Catenin activity.

PDGFRα-Signaling Is Dispensable for the Development of the Sinoatrial Node After Its Fate Commitment

Palate-derived growth factor receptor α (Pdgfrα) signaling has been reported to play important roles in the cardiac development. A previous study utilizing Pdgfrα conventional knockout mice reported hypoplasia of the sinus venous myocardium including the sinoatrial node (SAN) accompanied by increased expression of Nkx2.5. This mouse line embryos die by E11.5 due to embryonic lethality, rendering them difficult to investigate the details. To elucidate the underlying mechanism, in this study, we revisited this observation by generation of specific ablation of Pdgfrα in the SAN by Shox2-Cre at E9.5, using a Shox2-Cre;Pdgfrαflox/flox conditional mouse line. Surprisingly, we found that resultant homozygous mutant mice did not exhibit any malformation in SAN morphology as compared to their wild-type littermates. Further analysis revealed the normal cardiac function in adult mutant mice assessed by the record of heart rate and electrocardiogram and unaltered expression of Nkx2.5 in the E13.5 SAN of Pdgfrα conditional knockout mice. Our results unambiguously demonstrate that Pdgfrα is dispensable for SAN development after its fate commitment in mice.

Comparison of QRSarea and left ventricular activation time during left bundle branch pacing and left ventricular septal pacing

Funding Acknowledgements Type of funding sources: None. Background Left bundle branch area pacing (LBBAP) has recently been introduced as a novel physiological pacing strategy. Within LBBAP, distinction is made between left bundle branch pacing (LBBP) and left ventricular septal pacing (LVSP, no left bundle capture). Objective To compare acute electrocardiographic (ECG) and vectorcardiographic (VCG) effects of LBBP and LVSP as compared to intrinsic conduction. Methods In 50 patients with normal cardiac function and pacemaker indication for bradycardia, ECG characteristics of LBBP and LVSP were evaluated during RVSP and pacing at various depths in the septum: starting at the RV side of the septum: the last position with QS morphology, the first position with r’ morphology, LVSP and – in patients where LBB capture was achieved – LBBP. From the ECG’s QRS duration and QRS morphology in V1, and the stimulus-LVAT interval were measured. After conversion of the ECG into VCG (Kors conversion matrix), QRS area was calculated. Results In LVSP, QRS area significantly decreased from 82 ± 29 µVs during RVSP to 46 ± 12 µVs during LVSP. In patients where LBB capture was achieved QRS area significantly decreased from 78 ± 23 µVs to 38 ± 15 µVs in LBBP. In patients with LBB capture, QRS area was significantly smaller during LBBP compared to LVSP (figure A), but LVAT was not significantly different (figure B, p = 0.138). In patients with normal ventricular activation where LBBP was achieved (n = 20), QRS area was significantly larger during LVSP (48 ± 17) compared to LBBP (37 ± 16), the latter being not significantly different from normal intrinsic ventricular activation (35 ± 19 µVs). Conclusions ECG and VCG indices demonstrate that ventricular dyssynchrony is comparable but slightly more synchronous during LBBP compared to LVSP. Abstract Figure. QRS area and S-LVAT in LVSP and LBBP

Cardiac Cell Therapy for Heart Repair: Should the Cells Be Left Out?

Cardiovascular disease (CVD) is still the leading cause of death worldwide. Coronary arteryocclusion, or myocardial infarction (MI) causes massive loss of cardiomyocytes. The ischemia areais eventually replaced by a fibrotic scar. From the mechanical dysfunctions of the scar in electronictransduction, contraction and compliance, pathological cardiac dilation and heart failure develops.Once end-stage heart failure occurs, the only option is to perform heart transplantation. The sequentialchanges are termed cardiac remodeling, and are due to the lack of endogenous regenerativeactions in the adult human heart. Regenerative medicine and biomedical engineering strategies havebeen pursued to repair the damaged heart and to restore normal cardiac function. Such strategiesinclude both cellular and acellular products, in combination with biomaterials. In addition, substantialprogress has been made to elucidate the molecular and cellular mechanisms underlying heartrepair and regeneration. In this review, we summarize and discuss current therapeutic approachesfor cardiac repair and provide a perspective on novel strategies that holding potential opportunitiesfor future research and clinical translation.

Echocardiographic Characteristics of Cardiac thrombus in Patients With Mycoplasma pneumoniae infection

Right ventricular thrombus in Mycoplasma pneumoniae pneumonia (MPP) patient is rare. Herein we reported 4 cases of right ventricular thrombus. All of them were diagnosed of severe mycoplasma pneumonia, with increased D-dimer. There was no abnormality in the atrial and ventricular diameters with a normal cardiac function during the course of the illness. Every thrombus was closely attached to the tricuspid chordae. Except one thrombus surgically removed, the remaining thrombi dissolved during the follow-ups.

Stress-driven cardiac calcium mishandling via a kinase-to-kinase crosstalk

Calcium homeostasis in the cardiomyocyte is critical to the regulation of normal cardiac function. Abnormal calcium dynamics such as altered uptake by the sarcoplasmic reticulum (SR) Ca2+-ATPase and increased diastolic SR calcium leak are involved in the development of maladaptive cardiac remodeling under pathological conditions. Ca2+/calmodulin-dependent protein kinase II-δ (CaMKIIδ) is a well-recognized key molecule in calcium dysregulation in cardiomyocytes. Elevated cellular stress is known as a common feature during pathological remodeling, and c-jun N-terminal kinase (JNK) is an important stress kinase that is activated in response to intrinsic and extrinsic stress stimuli. Our lab recently identified specific actions of JNK isoform 2 (JNK2) in CaMKIIδ expression, activation, and CaMKIIδ-dependent SR Ca2+ mishandling in the stressed heart. This review focuses on the current understanding of cardiac SR calcium handling under physiological and pathological conditions as well as the newly identified contribution of the stress kinase JNK2 in CaMKIIδ-dependent SR Ca2+ abnormal mishandling. The new findings identifying dual roles of JNK2 in CaMKIIδ expression and activation are also discussed in this review.

Reduced reticulum–mitochondria Ca2+ transfer is an early and reversible trigger of mitochondrial dysfunctions in diabetic cardiomyopathy

Type 2 diabetic cardiomyopathy features Ca2+ signaling abnormalities, notably an altered mitochondrial Ca2+ handling. We here aimed to study if it might be due to a dysregulation of either the whole Ca2+ homeostasis, the reticulum–mitochondrial Ca2+ coupling, and/or the mitochondrial Ca2+ entry through the uniporter. Following a 16-week high-fat high-sucrose diet (HFHSD), mice developed cardiac insulin resistance, fibrosis, hypertrophy, lipid accumulation, and diastolic dysfunction when compared to standard diet. Ultrastructural and proteomic analyses of cardiac reticulum–mitochondria interface revealed tighter interactions not compatible with Ca2+ transport in HFHSD cardiomyocytes. Intramyocardial adenoviral injections of Ca2+ sensors were performed to measure Ca2+ fluxes in freshly isolated adult cardiomyocytes and to analyze the direct effects of in vivo type 2 diabetes on cardiomyocyte function. HFHSD resulted in a decreased IP3R–VDAC interaction and a reduced IP3-stimulated Ca2+ transfer to mitochondria, with no changes in reticular Ca2+ level, cytosolic Ca2+ transients, and mitochondrial Ca2+ uniporter function. Disruption of organelle Ca2+ exchange was associated with decreased mitochondrial bioenergetics and reduced cell contraction, which was rescued by an adenovirus-mediated expression of a reticulum-mitochondria linker. An 8-week diet reversal was able to restore cardiac insulin signaling, Ca2+ transfer, and cardiac function in HFHSD mice. Therefore, our study demonstrates that the reticulum–mitochondria Ca2+ miscoupling may play an early and reversible role in the development of diabetic cardiomyopathy by disrupting primarily the mitochondrial bioenergetics. A diet reversal, by counteracting the MAM-induced mitochondrial Ca2+ dysfunction, might contribute to restore normal cardiac function and prevent the exacerbation of diabetic cardiomyopathy.