Human cytochrome P450 (CYP) is a superfamily of hemoproteins which oxidize a number of endogenous compounds and xenobiotics. The human CYP2C subfamily consists of four members: CYP2C8, CYP2C9, CYP2C18 and CYP2C19. CYP2C9 and CYP2C19 are important drug-metabolizing enzymes and together metabolize approximately 20% of therapeutically used drugs. Forty-two allelic variants for CYP2C9 and 34 for CYP2C19 have been reported. The frequencies of these variants show marked inter-ethnic variation. The functional consequences of genetic polymorphisms have been examined, and many studies have shown the clinical importance of these polymorphisms. Current evidence suggests that taking the genetically determined metabolic capacity of CYP2C9 and CYP2C19 into account has the potential to improve individual risk/benefit relationships. However, more prospective studies with clinical endpoints are needed before the paradigm of "personalized medicine" based on the variants can be established. This review summarizes the currently available important information on this topic.

Edited by Roger J. Colbran Extracellular vesicles (EVs) have emerged as key mediators of intercellular communication that have the potential to improve cardiac function when used in cell-based therapy. However, the means by which cardiomyocytes respond to EVs remains unclear. Here, we sought to clarify the role of exosomes in improving cardiac function by investigating the effect of cardiomyocyte endocytosis of exosomes from mesenchymal stem cells on acute myocardial infarction (MI). Exposing cardiomyocytes to the culture supernatant of adipose-derived regenerative cells (ADRCs) prevented cardiomyocyte cell damage under hypoxia in vitro. In vivo, the injection of ADRCs into the heart simultaneous with coronary artery ligation decreased overall cardiac infarct area and prevented cardiac rupture after acute MI. Quantitative RT-PCR-based analysis of the expression of 35 known anti-apoptotic and secreted microRNAs (miRNAs) in ADRCs revealed that ADRCs express several of these miRNAs, among which miR-214 was the most abundant. Of note, miR-214 silencing in ADRCs significantly impaired the anti-apoptotic effects of the ADRC treatment on cardiomyocytes in vitro and in vivo. To examine cardiomyocyte endocytosis of exosomes, we cultured the cardiomyocytes with ADRC-derived exosomes labeled with the fluorescent dye PKH67 and found that hypoxic culture conditions increased the levels of the labeled exosomes in cardiomyocytes. Chlorpromazine, an inhibitor of clathrin-mediated endocytosis, significantly suppressed the ADRC-induced decrease of hypoxia-damaged cardiomyocytes and also decreased hypoxia-induced cardiomyocyte capture of both labeled EVs and extracellular miR-214 secreted from ADRCs. Our results indicate that clathrin-mediated endocytosis in cardiomyocytes plays a critical role in their uptake of circulating, exosome-associated miRNAs that inhibit apoptosis.

Prognosis of patients with chronic heart failure remains poor, emphasizing the need to identify additional pathophysiological factors. Tsuda et al. show that Crhr2 activation causes cardiac dysfunction and suggest Crhr2 blockade is a promising therapeutic strategy for chronic heart failure.

Background: Heart failure is a complex syndrome that results from structural or functional impairment of ventricular filling or blood ejection. Protein phosphorylation is a major and essential intracellular mechanism that mediates various cellular processes in cardiomyocytes in response to extracellular and intracellular signals. The RHOA-associated protein kinase (ROCK/Rho-kinase), an effector regulated by the small GTPase RHOA, causes pathological phosphorylation of proteins, resulting in cardiovascular diseases. RHOA also activates protein kinase N (PKN); however, the role of PKN in cardiovascular diseases remains unclear. Methods: To explore the role of PKNs in heart failure, we generated tamoxifen-inducible, cardiomyocyte-specific PKN1- and PKN2-knockout mice by intercrossing the αMHC-CreERT2 line with Pkn1 flox/flox and Pkn2 flox/flox mice and applied a mouse model of transverse aortic constriction– and angiotensin II–induced heart failure. To identify a novel substrate of PKNs, we incubated GST-tagged myocardin-related transcription factor A (MRTFA) with recombinant GST-PKN-catalytic domain or GST-ROCK-catalytic domain in the presence of radiolabeled ATP and detected radioactive GST-MRTFA as phosphorylated MRTFA. Results: We demonstrated that RHOA activates 2 members of the PKN family of proteins, PKN1 and PKN2, in cardiomyocytes of mice with cardiac dysfunction. Cardiomyocyte-specific deletion of the genes encoding Pkn1 and Pkn2 (cmc-PKN1/2 DKO) did not affect basal heart function but protected mice from pressure overload– and angiotensin II–induced cardiac dysfunction. Furthermore, we identified MRTFA as a novel substrate of PKN1 and PKN2 and found that MRTFA phosphorylation by PKN was considerably more effective than that by ROCK in vitro. We confirmed that endogenous MRTFA phosphorylation in the heart was induced by pressure overload– and angiotensin II–induced cardiac dysfunction in wild-type mice, whereas cmc-PKN1/2 DKO mice suppressed transverse aortic constriction– and angiotensin II–induced phosphorylation of MRTFA. Although RHOA-mediated actin polymerization accelerated MRTFA-induced gene transcription, PKN1 and PKN2 inhibited the interaction of MRTFA with globular actin by phosphorylating MRTFA, causing increased serum response factor–mediated expression of cardiac hypertrophy– and fibrosis-associated genes. Conclusions: Our results indicate that PKN1 and PKN2 activation causes cardiac dysfunction and is involved in the transition to heart failure, thus providing unique targets for therapeutic intervention for heart failure.

In the heart, fatty acid is a major energy substrate to fuel contraction under aerobic conditions. Ischemia downregulates fatty acid metabolism to adapt to the limited oxygen supply, making glucose the preferred substrate. However, the mechanism underlying the myocardial metabolic shift during ischemia remains unknown. Here, we show that lipoprotein lipase (LPL) expression in cardiomyocytes, a principal enzyme that converts triglycerides to free fatty acids and glycerol, increases during myocardial infarction (MI). Cardiomyocyte‐specific LPL deficiency enhanced cardiac dysfunction and apoptosis following MI. Deficiency of aquaporin 7 (AQP7), a glycerol channel in cardiomyocytes, increased the myocardial infarct size and apoptosis in response to ischemia. Ischemic conditions activated glycerol‐3‐phosphate dehydrogenase 2 (GPD2), which converts glycerol‐3‐phosphate into dihydroxyacetone phosphate to facilitate adenosine triphosphate (ATP) synthesis from glycerol. Conversely, GPD2 deficiency exacerbated cardiac dysfunction after acute MI. Moreover, cardiomyocyte‐specific LPL deficiency suppressed the effectiveness of peroxisome proliferator‐activated receptor alpha (PPARα) agonist treatment for MI‐induced cardiac dysfunction. These results suggest that LPL/AQP7/GPD2‐mediated glycerol metabolism plays an important role in preventing myocardial ischemia‐related damage.

CB ablation may reduce the acute narrowing of the left-sided PVs as compared to RF ablation.

The rapid rise in the prevalence of type 2 diabetes mellitus (T2DM) poses a huge healthcare burden across the world. Although there are several antihyperglycaemic agents (AHAs) available including addition of new drug classes to the treatment algorithm, more than 50% of patients with T2DM do not achieve glycaemic targets, suggesting an urgent need for treatment strategies focusing on prevention and progression of T2DM and its long‐term complications. Lifestyle changes including implementation of healthy diet and physical activity are cornerstones for the management of T2DM. The positive effects of diet and exercise on incretin hormones such as glucagon‐like peptide‐1 (GLP‐1) have been reported. We hypothesize an IDEP concept (Interaction between Diet/Exercise and Pharmacotherapy) aimed at modifying the diet and lifestyle, along with pharmacotherapy to enhance the GLP‐1 levels, would result in good glycaemic control in patients with T2DM. Consuming protein‐rich food, avoiding saturated fatty acids and making small changes in eating habits such as eating slowly with longer mastication time can have a positive impact on the GLP‐1 secretion and insulin levels. Further the type of physical activity (aerobic/resistance training), intensity of exercise, duration, time and frequency of exercise have shown to improve GLP‐1 levels. Apart from AHAs, a few antihypertensive drugs and lipid‐lowering drugs have also shown to increase endogenous GLP‐1 levels, however, due to quick degradation of GLP‐1 by dipeptidyl peptidase‐4 (DPP‐4) enzyme, treatment with DPP‐4 inhibitors would protect GLP‐1 from degradation and prolong its activity. Thus, IDEP concept can be a promising treatment strategy, which positively influences the GLP‐1 levels and provide additive benefits in terms of improving metabolic parameters in patients with T2DM and slowing the progression of T2DM and its associated complications.

Myocarditis is a clinically important disease because of the high mortality. From the perspective of treatment strategy, eosinophilic myocarditis should be distinguished from other types of myocarditis. Toxocariasis, caused by Toxocara canis or Toxocara cati, is known as a cause of eosinophilic myocarditis but is considered rare. As it is an unpopular disease, eosinophilic myocarditis due to toxocariasis may be underdiagnosed. We experienced two cases of eosinophilic myocarditis due to toxocariasis from different geographical areas in quick succession between 2013 and 2014. Case 1 is 32-year-old man. Case 2 is 66-year-old woman. In both cases, diagnosis was done by endomyocardial biopsy and IgG-ELISA against Toxocara excretory-secretory antigen. Only a corticosteroid was used in Case  1, whereas a corticosteroid and albendazole were used in Case  2 as induction therapy. Both patients recovered. Albendazole was also used in Case  1 to prevent recurrence after induction therapy. Eosinophilic myocarditis by toxocariasis may in actuality not be a rare disease, and corticosteroid is an effective drug as induction therapy even before use of albendazole.