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 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

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

Disappearance of isocapnic buffering period during increasing work rate exercise at high altitude

Background At sea level, ventilation kinetics are characterized during a ramp exercise by three progressively steeper slopes, the first from the beginning of exercise to anaerobic threshold, the second from anaerobic threshold to respiratory compensation point, and the third from respiratory compensation point to peak exercise. In the second ventilation phase, body CO2 stores are used to buffer acidosis owing to lactate production; it has been suggested that this extra CO2 production drives the ventilation increase. At high altitude, ventilation increases owing to hypoxia. We hypothesize that ventilation increase reduces body CO2 stores affecting ventilation kinetics during exercise. Design In eight healthy participants, we studied the ventilation kinetics during an exercise performed at sea level and at high altitude (4559 m). Methods We used 30 W/2 min step incremental protocol both at sea level and high altitude. Tests were done on a cycloergometer with breath-by-breath ventilation and inspiratory and expiratory gas measurements. We evaluated cardiopulmonary data at anaerobic threshold, respiratory compensation point, peak exercise and the VE/VCO2 slope. Results At high altitude: (a) peak Vo(2) decreased from 2595 +/- 705 to 1745 +/- 545mi/min (P < 0.001); (b) efficiency of ventilation decreased (VE/VCO2 slope from 25 +/- 2 to 38 +/- 4, P < 0.0001); (c) at each exercise step end-tidal pressure change for CO2 was lower; and (d) the isocapnic buffering period disappeared in seven over eight participants and was significantly shortened in the remaining participant. Conclusion Exercise performed at high altitude is characterized by two, instead of three, ventilation slopes

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

Prognostic value of chromogranin A in chronic heart failure: data from the GISSI-Heart Failure trial

Aims To assess the association between circulating levels of chromogranin A (CgA) and outcome in a large population of patients with chronic heart failure (HF). Methods and results Plasma CgA levels were measured at randomization and after 3 months in 1233 patients (median age 68 years, 80% male) with chronic, stable HF from the GISSI-HF trial. Circulating CgA levels were associated with several established risk markers in HF, including increased age, diabetes, reduced renal function, and heart rate variability. During a median follow-up of 3.9 years, 333 patients (27%) died. By univariable analysis, plasma CgA levels at baseline were strongly associated with all-cause mortality during follow-up; 2nd vs. 1st tertile: HR 1.58 (1.17–2.11), P ¼ 0.002; and 3rd vs. 1st tertile: HR 2.35 (1.78–3.10), P , 0.0001. After adjustment for established risk factors of mortality, this association was attenuated and no longer significant. Randomized treatments with n-3 polyunsaturated fatty acid or rosuvastatin did not significantly change plasma CgA concentration over 3 months. Conclusion Measurement of circulating CgA levels in patients with chronic, stable HF does not provide incremental prognostic information to that obtained from physical examination, routine biochemical analysis, and contemporary HF biomarkers

Schematic representation of the sequence of data collection in studies A and B.

<p>Sp_O2, blood oxygen saturation; Pt_O2, transcutaneous oxygen partial pressure; Pt_CO2, transcutaneous CO₂ partial pressure; HR, heart rate; BP, blood pressure; RF, respiratory frequency; PAP, pulmonary artery pressure; Vt, tidal volume; VE, minute ventilation; Dl_CO, pulmonary CO diffusion; VA = alveolar volume; TFC, thoracic fluid content; Pet_CO2, end tidal CO₂ pressure in the exhaled air.</p