Renal denervation restores autonomic imbalance and prevents atrial fibrillation in patients with hypertensive heart disease : a pilot study

Thesis (PhD)--Stellenbosch University, 2020.ENGLISH ABSTRACT: Background: Atrial fibrillation (AF) is associated with increased cardiovascular morbidity and mortality, but it is uncertain if catheter-based renal denervation (RD) can reduce AF in patients with hypertensive heart disease (HHD). Methods: Patients who were ≥ 55 years old, in sinus rhythm, taking ≥ 3 anti-hypertensive drugs including a diuretic, with echocardiogram-confirmed HHD and suspected coronary artery disease, were randomised to undergo RD or sham procedure. Patients with renal impairment, significant valvular heart disease and untreated thyroid disease were excluded. The primary endpoint, the first episode of subclinical AF (SAF) lasting ≥ 6 minutes, was detected using an implantable loop recorder which was scanned every six months. Six-month follow-up (6MFU) office systolic blood pressure (SBP), cardiovascular mortality and restoration of autonomic imbalance were secondary endpoints. Results: Eighty patients were randomised: 42 underwent RD and 38 a sham procedure. After an average follow-up of three years, fewer RD patients experienced SAF: 6 of 42 patients (14.3%) vs 15 of 38 (39.5%) sham patients (odds ratio (OR), 0.26; 95% CI, 0.1 to 0.71, p = 0.01). Fast AF (ventricular rate ≥ 100 bpm) occurred in 10 sham patients (26.3%) vs 1 RD patient (2.4%): OR, 14.64; 95% CI, 1.77 to 120.91; p = 0.002). The incidence of cardiovascular death was higher in the sham than RD group (6 of 38 (15.8%) vs 1 of 42 (2.4%): OR, 7.69; 95% CI, 0.88 to 67.12; p = 0.049). Non-ST elevation myocardial infarction (NSTEMI) incidence was lower in the RD than sham group (2.3% vs 18.4%: OR, 0.108; 95% CI, 0.01–0.92; p = 0.02). The 6MFU between-group SBP difference was not significant (−3.8 mmHg; p = 0.49). Resting and one-minute recovery heart rate did not differ between groups at 6MFU. Conclusion: In patients with HHD, RD reduces subclinical and fast AF, NSTEMI and cardiovascular death independent of lowering blood pressure. RD was not associated with improvement of surrogate markers of autonomic imbalance.Doctora

Genetic variation in angiotensin II type 2 receptor gene influences extent of left ventricular hypertrophy in hypertrophic cardiomyopathy independent of blood pressure

Introduction. Hypertrophic cardiomyopathy (HCM), an inherited primary cardiac disorder mostly caused by defective sarcomeric proteins, serves as a model to investigate left ventricular hypertrophy (LVH). HCM manifests extreme variability in the degree and distribution of LVH, even in patients with the same causal mutation. Genes coding for renin—angiotensin—aldosterone system components have been studied as hypertrophy modifiers in HCM, with emphasis on the angiotensin (Ang) II type 1 receptor (AT1R). However, Ang II binding to Ang II type 2 receptors (AT2R) also has hypertrophy-modulating effects. Methods. We investigated the effect of the functional +1675 G/A polymorphism (rs1403543) and additional single nucleotide polymorphisms in the 3' untranslated region of the AT2R gene ( AGTR2) on a heritable composite hypertrophy score in an HCM family cohort in which HCM founder mutations segregate. Results. We find significant association between rs1403543 and hypertrophy, with each A allele decreasing the average wall thickness by ~0.5 mm, independent of the effects of the primary HCM causal mutation, blood pressure and other hypertrophy covariates ( p = 0.020). Conclusion. This study therefore confirms a hypertrophy-modulating effect for AT2R also in HCM and implies that +1675 G/A could potentially be used in a panel of markers that profile a genetic predisposition to LVH in HCM

Long-term follow-up of R403W MYH7 and R92W TNNT2 HCM families : mutations determine left ventricular dimensions but not wall thickness during disease progression

The original publication is available at http://www.cvja.co.za/CVJA holds the copyrightThe clinical profile and prognosis of patients with hypertrophic cardiomyopathy, a primary cardiac muscle disease caused mostly by mutations in sarcomeric protein-encoding genes, have been linked to particular disease-causing mutations in the past. However, such associations are often based on cross-sectional observations, as longitudinal studies of the progression of the disease in genotypically defined patients are sparse. Most importantly, the relative contribution of age, gender and genetic cause to disease profile and progression has not yet been reported, and the question remains whether one or more of these factors could mask the effect of the other(s). Methods: We previously described cross-sectional family studies of two hypertrophic cardiomyopathy (HCM)-causing mutations, R92WTNNT2 and R403WMYH7, both associated with minimal hypertrophy, but with widely different life expectancies. We re-investigated 22 and 26 R92WTNNT2 and R403WMYH7 mutation carriers in these and additional South African R92WTNNT2 families after a mean 11.08 ± 2.79 years, and compared the influence of the two mutations, in the context of age and gender, on disease progression. Results: We demonstrated a positive correlation between age and interventricular septal thickness for both mutations, with more than a third of all mutation carriers developing clinically recognised hypertrophy only after the age of 35 years. This period of hypertrophically silent HCM also coincided with the years in which most sudden cardiac deaths occurred, particularly in male R92WTNNT2 carriers. Statistical analyses indicated that the particular mutation was the strongest determinant of left ventricular remodelling; particularly, LVESD increased and EF reduction was noted in the majority of R403WMYH7 carriers, which may require clinical follow-up over the longer term. Conclusions: Statistical modelling of follow-up data suggests that an interplay between unidentified, possibly genderassociated factors, and the causal mutation are the determinants of eventual cardiac function and survival, but not of the extent of hypertrophy, and emphasises the need for long-term follow-up even in individuals with apparently mild disease.Publishers' Versio

Genetic variation in angiotensin-converting enzyme 2 gene is associated with extent of left ventricular hypertrophy in hypertrophic cardiomyopathy

Hypertrophic cardiomyopathy, a common, inherited cardiac muscle disease, is primarily caused by mutations in sarcomeric protein-encoding genes and is characterized by overgrowth of ventricular muscle that is highly variable in extent and location. This variability has been partially attributed to locus and allelic heterogeneity of the disease-causing gene, but other factors, including unknown genetic factors, also modulate the extent of hypertrophy that develops in response to the defective sarcomeric functioning. Components of the renin-angiotensin-aldosterone system are plausible candidate hypertrophy modifiers because of their role in controlling blood pressure and biological effects on cardiomyocyte hypertrophy

Renal denervation : mechanisms and clinical aspects

CITATION: Heradien, M. J., Van Der Bijl, P. & Brink, P. A. 2020. Renal denervation : mechanisms and clinical aspects. African Journal of Nephrology, 23(1):19-24, doi:10.21804/23-1-3974.The original publication is available at http://www.journals.ac.za/index.php/ajn/ENGLISH ABSTRACT: Hypertension is a global health issue of paramount importance, which has not spared the African continent where an unacceptably high prevalence of uncontrolled blood pressure prevails among its population. Renal denervation (RD) represents an invasive management option for resistant hypertension, acting via several different physiological pathways – mostly predicated on modification of the renal autonomic nervous system. The evidence base for RD has recently been expanded by three randomised, sham-controlled clinical trials, which demonstrated significant blood pressure reductions under a variety of clinical conditions. In this review, both the renal mechanisms underlying RD, as well as the clinical aspects of its application to hypertension, are discussed.https://www.journals.ac.za/index.php/ajn/article/view/3974Publisher's versio

Genetic Modifiers for the Long-QT Syndrome: How Important Is the Role of Variants in the 3′ Untranslated Region of KCNQ1?

BACKGROUND: Long-QT syndrome is an inherited cardiac channelopathy characterized by delayed repolarization, risk of life-threatening arrhythmia, and significant clinical variability even within families. Three single-nucleotide polymorphisms (SNPs) in the 3' untranslated region of KCNQ1 were recently suggested to be associated with suppressed gene expression and hence decreased disease severity when located on the same haplotype with a disease-causing KCNQ1 mutation. We sought to replicate this finding in a larger and a genetically more homogeneous population of KCNQ1 mutation carriers. METHODS AND RESULTS: The 3 SNPs (rs2519184, rs8234, and rs10798) were genotyped in a total of 747 KCNQ1 mutation carriers with A341V, G589D, or IVS7-2A>G mutation. The SNP haplotypes were assigned based on family trees. The SNP allele frequencies and clinical severity differed between the 3 mutation groups. The different SNP haplotypes were neither associated with heart rate-corrected QT interval duration (QTc) nor cardiac events in any of the 3 mutation groups. When the mutation groups were combined, the derived SNP haplotype of rs8234 and rs10798 located on the same haplotype with the mutation was associated with a shorter QTc interval (P<0.05) and a reduced occurrence of cardiac events (P<0.01), consistent with the previous finding. However, when the population-specific mutation was controlled for, both associations were no longer evident. CONCLUSIONS: 3' Untranslated region SNPs are not acting as genetic modifiers in a large group of LQT1 patients. The confounding effect of merging a genetically and clinically heterogeneous group of patients needs to be taken into account when studying disease modifiers

Mutation location and I-Ks requlation in the arrhythmic risk of long QT syndrome type 1:the importance of the KCNQ1 S6 region

AIMS: Mutation type, location, dominant-negative I(Ks) reduction, and possibly loss of cyclic adenosine monophosphate (cAMP)-dependent I(Ks) stimulation via protein kinase A (PKA) influence the clinical severity of long QT syndrome type 1 (LQT1). Given the malignancy of KCNQ1-p.A341V, we assessed whether mutations neighbouring p.A341V in the S6 channel segment could also increase arrhythmic risk. METHODS AND RESULTS: Clinical and genetic data were obtained from 1316 LQT1 patients [450 families, 166 unique KCNQ1 mutations, including 277 p.A341V-positive subjects, 139 patients with p.A341-neighbouring mutations (91 missense, 48 non-missense), and 900 other LQT1 subjects]. A first cardiac event represented the primary endpoint. S6 segment missense variant characteristics, particularly cAMP stimulation responses, were analysed by cellular electrophysiology. p.A341-neighbouring mutation carriers had a QTc shorter than p.A341V carriers (477 ± 33 vs. 490 ± 44 ms) but longer than the remaining LQT1 patient population (467 ± 41 ms) (P < 0.05 for both). Similarly, the frequency of symptomatic subjects in the p.A341-neighbouring subgroup was intermediate between the other two groups (43% vs. 73% vs. 20%; P < 0.001). These differences in clinical severity can be explained, for p.A341V vs. p.A341-neighbouring mutations, by the p.A341V-specific impairment of I(Ks) regulation. The differences between the p.A341-neighbouring subgroup and the rest of LQT1 mutations may be explained by the functional importance of the S6 segment for channel activation. CONCLUSION: KCNQ1 S6 segment mutations surrounding p.A341 increase arrhythmic risk. p.A341V-specific loss of PKA-dependent I(Ks) enhancement correlates with its phenotypic severity. Cellular studies providing further insights into I(Ks)-channel regulation and knowledge of structure-function relationships could improve risk stratification. These findings impact on clinical management

Abnormal blood pressure response to exercise occurs more frequently in hypertrophic cardiomyopathy patients with the R92W troponin T mutation than in those with myosin mutations

Abnormal blood pressure response to exercise is reported to occur in up to a third of hypertrophic cardiomyopathy (HCM) cases and is associated with an increased risk of death, particularly in the young, but it is not known whether the HCM-causing mutation influences blood pressure response to exercise. The purpose of this article is to ascertain whether the blood pressure response to exercise differs among carriers of the R92W mutation in the cardiac troponin T gene (TNNT2), which has been associated with an increased risk of sudden cardiac death in young males; carriers of mutations in the cardiac β-myosin heavy chain gene (MYH7); and their noncarrier relatives. Thirty R92WTNNT2 carriers, 51 MYH7 mutation carriers, and 68 of their noncarrier relatives were subjected to bicycle ergonometric exercise testing to assess blood pressure response to, as well as heart rate recovery after, exercise. Additional echocardiographic and demographic details were documented for all participants. R92WTNNT2 carriers demonstrated significantly more abnormal blood pressure responses to exercise (P = .021; odds ratio 3.03; confidence interval 1.13–8.12) and smaller increases in systolic blood pressure than MYH7 mutation carriers or related noncarrier control individuals. Although abnormal blood pressure response occurred at similar frequencies in males in all groups (23%–26%), the percentage of R92WTNNT2 females with abnormal blood pressure response was 64%, compared with 25% for MYH7 and 22% for noncarriers. Therefore, these results show that blood pressure response to exercise is influenced by genotype and gender in patients with HCM