Pharmacogenetics of therapy effectiveness for anthracycline-induced cardiotoxicity

Objective To evaluate role of genetic factors (polymorphisms of ADRB1 gene (Arg389Gly, rs1801253) and ACE gene (I/D, rs4343) for effectiveness assessment of β-blocker (carvedilol) and angiotensin-converting enzyme inhibitor (enalapril) therapy in women with anthracycline- induced cardiotoxicity during 12-month follow-up period. Methods A total of 82 women, median age of 45.0 (42.0; 50.0) years with anthracycline-induced cardiotoxicity and without prior cardiovascular diseases were enrolled in the study. All patients received chemotherapy for the treatment of breast cancer included a combination of doxorubicin and cyclophosphamide, or combination of doxorubicin, cyclophosphamide and docetaxel. The cumulative dose of doxorubicin was 300–360 mg/m2. Criteria for the development of cardiotoxicity were a decrease in the left ventricle ejection fraction (LVEF) at the 12 months after chemotherapy completion by >10%, the development of heart failure (HF) with symptoms and clinical signs, and NT-proBNP levels ≥125 pg/mL. Echocardiography and serum levels of NT-proBNP were performed at baseline and at 12 months after enrollment. Average up-titrated dosage of carvedilol was 50 (25; 50) mg per day and enalapril was 10 (10; 20) mg per day. Evaluation of gene polymorphisms of ADRB1 gene and ACE gene were carried out by polymerase chain reaction at baseline before treatment initiation. Results The baseline LVEF, end-systolic and end-diastolic dimension indexes, NT-proBNP levels, 6-minute walk test distance did not differ among patients with different genotypes of ADRB1 and ACE genes. However, carriers of T/T genotype of ADRB1 gene had a significant increasing in LVEF (<0.001) by 11% from 50.0 (48.0; 51.0) to 56.0 (53.0; 57.0)% and decreasing in end-systolic dimension index (p<0.001) by 27.7% and end-systolic dimension index (p<0.001) by 6% within 12 months of follow-up period. The levels of NT-proBNP decreased (p=0.001) by 34.2% from 327.5 (260.1; 381.8) to 213.5 (195.3; 256.7) pg/mL and 6-minute walk test distance increased (0.008) by 10%. Carriers of G/G genotype of ACE gene had the same benefits from this therapy: LVEF (<0.001) increased by 6.5% from 50.5 (47.0; 51.0) to 54.0 (50.0; 57.0)%, end-systolic dimension index (p<0.001) decreased by 5.3% and end-systolic dimension index (p<0.001) by 3% within 12 months of follow-up period. The levels of NT-proBNP decreased (p=0.005) by 20.3 from 314.1 (279.6; 372.9) to 249.9 (197.3; 267.8) pg/mL and 6-minute walk test distance increased (0.008) by 5%. Carriers of other genotypes had decreasing in LVEF, increasing in LV dimensions and NT-proBNP, and further progression of HF. Conclusion Our data suggest that evaluation of gene polymorphisms of ADRB1 (Arg389Gly, rs1801253) and ACE gene (I/D, rs4343) can be recommended before treatment initiation of anthracycline- induced cardiotoxicity in women without prior cardiovascular diseases to determine who will benefit of carvedilol and enalapril therapy. FUNDunding Acknowledgement Type of funding sources: None.

Two novel mutations in the CLCNKB gene leading to classic Bartter syndrome presenting as syncope and hypertension in a 13-year-old boy

Classic Bartter syndrome is a rare condition caused by mutations in the CLCNKB gene and characterised by metabolic alkalosis, hypokalaemia, hyper-reninaemia and hyperaldosteronism. Early signs and symptoms usually occur before a child’s sixth birthday and include polyuria and developmental delay. We treated a 13-year-old Vietnamese boy with this syndrome presenting with atypical presentations including syncope and hypertension, but normal growth and development. All common causes of hypertension were ruled out. Genetic testing found two novel mutations in the CLCNKB gene, that is, Ser12Ala (exon 2) and Glu192Ter (exon 6). His estimated glomerular filtration rate was 61 mL/min/1.73 m2 and a kidney biopsy showed focal segmental glomerulosclerosis. He was well managed with long-term enalapril therapy instead of non-steroidalanti-inflammatory drugs which are recommended in managing the increased prostaglandin E2 production in Bartter syndrome. Paediatricians should be alerted with the variability in its presentation. To preserve the kidney function, treatment must include preventing factors damaging the kidneys.

ANGIOTENSIN CONVERTING ENZYME INHIBITOR SEBAGAI TERAPI PASIEN HIPERTENSI PRIMER DENGAN OBESITAS

Hypertension and obesity are the diseases that’s corelate to each other. The Bridge thatconnects between hypertension and obesity lies on Renin Angiotensin System (RAS) andleptin and adiponectin hormone system. RAS function to regulate the osmolarity of theblood circulation to control blood pressure. Leptin is a hormone that inhibit food intake.Adiponectin secreted by adipose cells to regulate blood glucose and performing theoxidation of fatty acid. In recent studies found that there’s a correlation betweenangiotensinogen with adiponectin. Then the question emerge about an intervention on RAScould have an effect on adiponectin, the hormone that’s corelate to obesity. A study fromFontana et.al found that there’s a correlation on using ACE inhibitor with leptin andadiponectin. Subjects with primary hypertension with 8 weeks enalapril therapy shows anincrease in adiponectin level, whilst the control group didnt show any significant change.There isn’t any correlation between subject and control on leptin level. This journal maypresent the theories that may lead to explaining about the correlation between hypertensionand obesity, and if ACE Inhibitor is the right therapy for primary hypertension patient withan obesity or not.

LCZ696 Therapy Reduces Ventricular Tachyarrhythmia Inducibility in a Myocardial Infarction-Induced Heart Failure Rat Model

Background. LCZ696 (valsartan/sacubitril) therapy significantly reduced mortality in patients with heart failure (HF). Although a clinical trial (PARADISE-MI Trial) has been ongoing to examine the effects of LCZ696 in myocardial infarction (MI) patients, the effects of LCZ696 on remodeling of cardiac electrophysiology in animal models remain largely unclear. Methods. We performed coronary artery ligation to create MI in Sprague-Dawley rats. Echocardiography was performed one week after MI to confirm the development of HF with left ventricular ejection fraction ≤ 40%. MI rats were randomly assigned to receive medical therapy for 4 weeks: LCZ696, enalapril, or vehicle. The sham-operation rats received sham operation without MI creation. In vivo electrophysiological exams were performed under general anesthesia. Western blot analyses were conducted to quantify ion channel proteins. Results. The HF-vehicle group did not show significant changes in LVEF. Both enalapril and LCZ696 therapy significantly improved LVEF. The HF-vehicle group had higher ventricular arrhythmia (VA) inducibility than the sham group. As compared with the HF-vehicle group, LCZ696 therapy significantly reduced VA inducibility, but enalapril therapy did not. Western blot analyses showed significant downregulation of NaV1.5, ERG, KCNE1, and KCNE2 channel proteins in the HF vehicle group compared with the sham group. LCZ696 therapy upregulated protein expression of ERG, KCNE1, and KCNE2. Conclusion. As compared with enalapril therapy, LCZ696 therapy led to improvement of LVEF, reduced VA inducibility, and upregulated expression of K+ channel proteins.

Curcumin and enalapril ameliorate renal failure by antagonizing inflammation in ⅚ nephrectomized rats: role of phospholipase and cyclooxygenase

Previously, we showed that curcumin prevents chronic kidney disease (CKD) development in ⅚ nephrectomized (Nx) rats when given within 1 wk after Nx (Ghosh SS, Massey HD, Krieg R, Fazelbhoy ZA, Ghosh S, Sica DA, Fakhry I, Gehr TW. Am J Physiol Renal Physiol 296: F1146–F1157, 2009). To better mimic the scenario for renal disease in humans, we began curcumin and enalapril therapy when proteinuria was already established. We hypothesized that curcumin, by blocking the inflammatory mediators TNF-α and IL-1β, could also reduce cyclooxygenase (COX) and phospholipase expression in the kidney. Nx animals were divided into untreated Nx, curcumin-treated, and enalapril-treated groups. Curcumin (75 mg/kg) and enalapril (10 mg/kg) were administered for 10 wk. Renal dysfunction in the Nx group, as evidenced by elevated blood urea nitrogen, plasma creatinine, proteinuria, segmental sclerosis, and tubular dilatation, was comparably reduced by curcumin and enalapril, with only enalapril significantly lowering blood pressure. Compared with controls, Nx animals had higher plasma/kidney TNF-α and IL-1β, which were reduced by curcumin and enalapril treatment. Nx animals had significantly elevated kidney levels of cytosolic PLA2, calcium-independent intracellular PLA2, COX 1, and COX 2, which were comparably reduced by curcumin and enalapril. Studies in mesangial cells and macrophages were carried out to establish that the in vivo increase in PLA2 and COX were mediated by TNF-α and IL-1β and that curcumin, by antagonizing the cytokines, could significantly reduce both PLA2 and COX. We conclude that curcumin ameliorates CKD by blocking inflammatory signals even if it is given at a later stage of the disease.