Genotype-Phenotype Taxonomy of Hypertrophic Cardiomyopathy.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is an important cause of sudden cardiac death associated with heterogeneous phenotypes, but there is no systematic framework for classifying morphology or assessing associated risks. Here, we quantitatively survey genotype-phenotype associations in HCM to derive a data-driven taxonomy of disease expression. METHODS: We enrolled 436 patients with HCM (median age, 60 years; 28.8% women) with clinical, genetic, and imaging data. An independent cohort of 60 patients with HCM from Singapore (median age, 59 years; 11% women) and a reference population from the UK Biobank (n=16 691; mean age, 55 years; 52.5% women) were also recruited. We used machine learning to analyze the 3-dimensional structure of the left ventricle from cardiac magnetic resonance imaging and build a tree-based classification of HCM phenotypes. Genotype and mortality risk distributions were projected on the tree. RESULTS: Carriers of pathogenic or likely pathogenic variants for HCM had lower left ventricular mass, but greater basal septal hypertrophy, with reduced life span (mean follow-up, 9.9 years) compared with genotype negative individuals (hazard ratio, 2.66 [95% CI, 1.42-4.96]; P<0.002). Four main phenotypic branches were identified using unsupervised learning of 3-dimensional shape: (1) nonsarcomeric hypertrophy with coexisting hypertension; (2) diffuse and basal asymmetrical hypertrophy associated with outflow tract obstruction; (3) isolated basal hypertrophy; and (4) milder nonobstructive hypertrophy enriched for familial sarcomeric HCM (odds ratio for pathogenic or likely pathogenic variants, 2.18 [95% CI, 1.93-2.28]; P=0.0001). Polygenic risk for HCM was also associated with different patterns and degrees of disease expression. The model was generalizable to an independent cohort (trustworthiness, M1: 0.86-0.88). CONCLUSIONS: We report a data-driven taxonomy of HCM for identifying groups of patients with similar morphology while preserving a continuum of disease severity, genetic risk, and outcomes. This approach will be of value in understanding the causes and consequences of disease diversity.

The addition of genetic testing and cardiovascular magnetic resonance to routine clinical data for stratification of etiology in dilated cardiomyopathy.

Background: Guidelines recommend genetic testing and cardiovascular magnetic resonance (CMR) for the investigation of dilated cardiomyopathy (DCM). However, the incremental value is unclear. We assessed the impact of these investigations in determining etiology. Methods: Sixty consecutive patients referred with DCM and recruited to our hospital biobank were selected. Six independent experts determined the etiology of each phenotype in a step-wise manner based on (1) routine clinical data, (2) clinical and genetic data and (3) clinical, genetic and CMR data. They indicated their confidence (1-3) in the classification and any changes to management at each step. Results: Six physicians adjudicated 60 cases. The addition of genetics and CMR resulted in 57 (15.8%) and 26 (7.2%) changes in the classification of etiology, including an increased number of genetic diagnoses and a reduction in idiopathic diagnoses. Diagnostic confidence improved at each step (p < 0.0005). The number of diagnoses made with low confidence reduced from 105 (29.2%) with routine clinical data to 71 (19.7%) following the addition of genetics and 37 (10.3%) with the addition of CMR. The addition of genetics and CMR led to 101 (28.1%) and 112 (31.1%) proposed changes to management, respectively. Interobserver variability showed moderate agreement with clinical data (κ = 0.44) which improved following the addition of genetics (κ = 0.65) and CMR (κ = 0.68). Conclusion: We demonstrate that genetics and CMR, frequently changed the classification of etiology in DCM, improved confidence and interobserver variability in determining the diagnosis and had an impact on proposed management.

Myocardial edema in Takotsubo syndrome mimicking apical hypertrophic cardiomyopathy: An insight into diagnosis by cardiovascular magnetic resonance.

Myocardial edema is one of the characteristic features in the pathogenesis of Takotsubo syndrome. We report a middle aged man who presented with typical clinical and echocardiographic features of apical variant of Takotsubo syndrome. However, a cardiovascular magnetic resonance study performed 10 days after presentation did not show any apical 'ballooning' but revealed features of an apical hypertrophic cardiomyopathy on cine images. Tissue characterization with T2 weighted images proved severe edema as the cause of significantly increased apical wall thickness. A follow-up cardiovascular magnetic resonance study was performed 5 months later which showed that edema, wall thickening and the appearance of apical hypertrophic cardiomyopathy all resolved, confirming Takotsubo syndrome as the cause of the initial appearance. As the affected myocardium most commonly involves the apical segments, an edema induced increase in apical wall thickness may lead to appearances of an apical hypertrophic cardiomyopathy rather than apical ballooning in the acute to subacute phase of Takotsubo syndrome.

Review of Journal of Cardiovascular Magnetic Resonance 2013.

There were 109 articles published in the Journal of Cardiovascular Magnetic Resonance (JCMR) in 2013, which is a 21% increase on the 90 articles published in 2012. The quality of the submissions continues to increase. The editors are delighted to report that the 2012 JCMR Impact Factor (which is published in June 2013) has risen to 5.11, up from 4.44 for 2011 (as published in June 2012), a 15% increase and taking us through the 5 threshold for the first time. The 2012 impact factor means that the JCMR papers that were published in 2010 and 2011 were cited on average 5.11 times in 2012. The impact factor undergoes natural variation according to citation rates of papers in the 2 years following publication, and is significantly influenced by highly cited papers such as official reports. However, the progress of the journal's impact over the last 5 years has been impressive. Our acceptance rate is <25% and has been falling because the number of articles being submitted has been increasing. In accordance with Open-Access publishing, the JCMR articles go on-line as they are accepted with no collating of the articles into sections or special thematic issues. For this reason, the Editors have felt that it is useful once per calendar year to summarize the papers for the readership into broad areas of interest or theme, so that areas of interest can be reviewed in a single article in relation to each other and other recent JCMR articles. The papers are presented in broad themes and set in context with related literature and previously published JCMR papers to guide continuity of thought in the journal. We hope that you find the open-access system increases wider reading and citation of your papers, and that you will continue to send your quality manuscripts to JCMR for publication.

T2* imaging of the heart: methods, applications, and outcomes.

This review describes and discusses the rationale, technique, applications, and impact of cardiovascular magnetic resonance (CMR) T2* imaging, principally in the assessment of iron loading within the heart, and highlights how this robust imaging strategy has transformed disease outcome.Until recently, no simple noninvasive measurement was available to reliably indicate severe cardiac iron loading before the development of overt cardiac dysfunction or heart failure. Consequently, the majority of patients with transfusion-dependent anemias, such as ß-thalassemia major, died prematurely of cardiovascular complications of severe iron overload.The magnetic properties of particulate iron disrupt magnetic field homogeneity in the CMR environment and consequently influence the CMR parameter T2*, which describes signal decay relating to both field inhomogeneity and loss of spin coherence. There is a direct relationship between T2* and myocardial iron concentration, enabling this to be used to identify and quantify myocardial iron load. Single breath-hold gradient-echo sequences in which a single midventricular short-axis myocardial slice is acquired at multiple echo times enables a myocardial T2* value to be measured from the rate of exponential decay. The application of T2* CMR to assessing cardiac iron loading is rapid, reproducible, extensively validated, and now widely performed. Data have highlighted the profound predictive power of this imaging technique and moreover its ability to inform management strategies such that, over a relatively short duration, outcome has been dramatically improved, and the disease course in ß-thalassemia major transformed.

A phase II, randomized, placebo-controlled, double-blind, multi-dose study of SRT2104, a SIRT1 activator, in subjects with type 2 diabetes.

AIM: SRT2104 is a selective activator of SIRT1. In animal models, SRT2104 improves glucose homeostasis and increases insulin sensitivity. We evaluated the tolerability and pharmacokinetics of SRT2104, and its effects on glycaemic control, in adults with type 2 diabetes mellitus. METHOD: Type 2 diabetics with glycosylated haemoglobin (HbA1c) ≥ 7.5% and ≤10.5%, fasting glucose ≥160 and ≤240 mg dl(-1) , and on stable doses of metformin were evenly randomized to placebo or SRT2104 0.25 g, 0.5 g, 1.0 g or 2.0 g, administered orally once daily for 28 days. Changes in fasting and post-prandial glucose and insulin were analyzed. RESULTS: Safety evaluation found no major differences between groups in the frequency of adverse events. SRT2104 concentrations did not increase in a dose-proportional fashion. Significant variability in exposure was observed. Treatment with SRT2104 did not lead to any consistent, dose-related changes in glucose or insulin. Day 28 change from baseline (mean (SD)): fasting glucose (mmol l(-1) ) = -1.17 (2.42), -1.11 (3.45), -0.52 (2.60), -0.97 (2.83) and -0.15 (2.38) for placebo, 0.25 g, 0.5 g, 1.0 g and 2.0 g, respectively. Day 28 change from baseline (mean (SD)): fasting insulin (mmol l(-1) ) = 1.0 (51.66), 8.9 (95.04), -6.9 (41.45), 4.1 (57.16) and 15.2 (138.79) for placebo, 0.25 g, 0.5 g, 1.0 g and 2.0 g, respectively) Treatment with SRT2104 was associated with improvement in lipid profiles. CONCLUSION: Treatment with SRT2104 for 28 days did not result in improved glucose or insulin control which is likely due to the observed pharmacokinetics which were not dose proportional and had large between subject variability.

Long-term antihypertensive treatment fails to improve E/e' despite regression of left ventricular mass: an Anglo-Scandinavian cardiac outcomes trial substudy.

Antihypertensive treatment can improve tissue Doppler indices of left ventricular diastolic function in the short term, but little is known about the longer-term effect of different antihypertensive treatments on progression of left ventricular diastolic function and left ventricular hypertrophy. We hypothesized that long-term treatment of hypertension will lead to improvements in left ventricular hypertrophy and diastolic function. We collected detailed cardiovascular phenotypic data on 1006 participants from a substudy of the Anglo-Scandinavian Cardiac Outcomes Trial. Patients randomized to either an amlodipine±perindopril-based or an atenolol±bendroflumethiazide-based regimen underwent conventional and tissue Doppler echocardiography at time of control of blood pressure after randomization (≈1.5 years; phase 1) and after a further 2 years of antihypertensive treatment (phase 2). There were no prerandomization data. Five hundred thirty-six patients had complete data collection at both phases. Left ventricular mass index regressed from phase 1 to 2 with no significant difference between treatment groups (amlodipine: 119.5-116.8; atenolol: 122.9-117.5; P<0.001 for both). Conversely, tissue Doppler diastolic indices did not change in the amlodipine±perindopril-based regimen (E/e', 7.5-7.6 cm/s; P=not significant), but deteriorated in the atenolol±bendroflumethiazide-based regimen (E/e', 8.0-8.5 cm/s; P<0.01). Despite regression of left ventricular hypertrophy, there was no associated improvement in diastolic function. In fact, long-term treatment with atenolol±bendroflumethiazide resulted in a progressive deterioration in E/e'. This may be a factor contributing to the previously described worse clinical outcome in patients treated with atenolol±bendroflumethiazide compared with amlodipine±perindopril.

Clinical utility and prognostic value of left atrial volume assessment by cardiovascular magnetic resonance in non-ischaemic dilated cardiomyopathy.

AIMS: Echocardiographic studies have shown that left atrial volume (LAV) predicts adverse outcome in small heart failure (HF) cohorts of mixed aetiology. However, the prognostic value of LAV in non-ischaemic dilated cardiomyopathy (DCM) is unknown. Cardiovascular magnetic resonance (CMR) allows accurate and reproducible measurement of LAV. We sought to determine the long-term prognostic significance of LAV assessed by CMR in DCM. METHODS AND RESULTS: We measured LAV indexed to body surface area (LAVi) in 483 consecutive DCM patients referred for CMR. Patients were prospectively followed up for a primary endpoint of all-cause mortality or cardiac transplantation. During a median follow-up of 5.3 years, 75 patients died and 9 underwent cardiac transplantation. After adjustment for established risk factors, LAVi was an independent predictor of the primary endpoint [hazard ratio (HR) per 10 mL/m(2) 1.08; 95% confidence interval (CI) 1.01-1.15; P = 0.022]. LAVi was also independently associated with the secondary composite endpoints of cardiovascular mortality or cardiac transplantation (HR per 10 mL/m(2) 1.11; 95% CI 1.04-1.19; P = 0.003), and HF death, HF hospitalization, or cardiac transplantation (HR per 10 mL/m(2) 1.11; 95% CI 1.04-1.18; P = 0.001). The optimal LAVi cut-off value for predicting the primary endpoint was 72 mL/m(2). Patients with LAVi >72 mL/m(2) had a three-fold elevated risk of death or transplantation (HR 3.00; 95% CI 1.92-4.70; P < 0.001). LAVi provided incremental prognostic value for the prediction of transplant-free survival (net reclassification improvement 0.17; 95% CI 0.05-0.29; P = 0.002). CONCLUSIONS: LAVi is a powerful independent predictor of transplant-free survival and HF outcomes in DCM. Assessment of LAV improves risk stratification in DCM and should be incorporated into routine CMR examination.

Experiences in peer-to-peer training in diabetes mellitus: challenges and implications.

This paper briefly describes the functions of peer advisers in diabetes (PADs) and their training. The formal process used in the assessment of the peer advisers at the completion of the training courses is also stated. The findings of a recent randomized controlled trial to study the effectiveness of peer advisers in delivering a programme of education on self-management are also described. The experience gained after the completion of four courses for the training of peer advisers, in addition to a review of the literature, forms the basis for discussion of the subject of peer-to-peer support activities in diabetes. PADs are effective in the provision of one-to-one psychosocial support and advice on self-management. They are also effective as committee members and advocates for diabetes. More recently, they have been shown to be effective as teachers on self-management to their peers with diabetes. With the imminent explosion in the number of people with diabetes, there will be increased need for psychosocial support and in the requirement for the provision of education on self-management. It is unlikely that health services would be given sufficient resources to cope with this. Society should identify alternative resources. People with diabetes and their close carers are the obvious choice, and we need to commence their training now. The implications for primary care are discussed.

A meta-analysis of the mechanism of blood pressure change with aging.

OBJECTIVES: We undertook a meta-analysis to determine whether changes in wave reflection substantiate the consensus explanation of why blood pressure (BP) changes with aging. BACKGROUND: Consensus documents attribute the aging changes in BP to wave reflection moving progressively from diastole into systole. However, the extensive quantitative data on this phenomenon have never been systematically reviewed. Individual studies have been small, and limited to a narrow age range. METHODS: Using PubMed, Cochrane, and Web of Science databases, we identified 64 studies (including 13,770 subjects, age range 4 to 91 years) reporting the timing of wave reflection, defined as the time from the onset (foot) of the pressure waveform to the shoulder point (anachrotic notch). RESULTS: In subjects of all ages, reflection times were well within systole. There was a small tendency for younger subjects to have later reflection, but this was only 0.7 ms per year, whereas the weighted mean reflection time was 136 ms (99% confidence interval: 130 to 141 ms) and the mean duration of systole was 328 ms (99% confidence interval: 310 to 347 ms). At this rate of change with age, arrival of wave reflection would only be construed to be in diastole at an extrapolated age of -221 years. CONCLUSIONS: These findings challenge the current consensus view that a shift in timing of wave reflection significantly contributes to the changes in the BP waveform with aging. We should re-evaluate the mechanisms of BP elevation in aging.

Comparison of pioglitazone and gliclazide in sustaining glycemic control over 2 years in patients with type 2 diabetes.

OBJECTIVE: The hypothesis that pioglitazone treatment is superior to gliclazide treatment in sustaining glycemic control for up to 2 years in patients with type 2 diabetes was tested. RESEARCH DESIGN AND METHODS: This was a randomized, multicenter, double-blind, double-dummy, parallel-group, 2-year study. Approximately 600 patients from 98 centers participated. Eligible patients had completed a previous 12-month study and consented to continue treatment for a further year. To avoid selection bias, all patients from all centers were included in the primary analysis (a comparison of the time-to-failure distributions of the two groups by using a log-rank test) regardless of whether they continued treatment for a 2nd year. By using repeated-measures ANOVA, time course of least square means of HbA(1c) and homeostasis model of assessment (HOMA) indexes (HOMA-%S and HOMA-%B) were analyzed. RESULTS: A greater proportion of patients treated with pioglitazone maintained HbA(1c) <8% over the 2-year period than those treated with gliclazide. A difference between the Kaplan-Meier curves was apparent as early as week 32 and widened at each time point thereafter, becoming statistically significant from week 52 onward. At week 104, 129 (47.8%) of 270 pioglitazone-treated patients and 110 (37.0%) of 297 gliclazide-treated patients maintained HbA(1c) <8%. Compared with gliclazide treatment, pioglitazone treatment produced a larger decrease in HbA(1c), a larger increase in HOMA-%S, and a smaller increase in HOMA-%B during the 2nd year of treatment. CONCLUSIONS: Pioglitazone is superior to gliclazide in sustaining glycemic control in patients with type 2 diabetes during the 2nd year of treatment.