Microstructural and Microvascular Phenotype of Sarcomere Mutation Carriers and Overt Hypertrophic Cardiomyopathy.

BACKGROUND: In hypertrophic cardiomyopathy (HCM), myocyte disarray and microvascular disease (MVD) have been implicated in adverse events, and recent evidence suggests that these may occur early. As novel therapy provides promise for disease modification, detection of phenotype development is an emerging priority. To evaluate their utility as early and disease-specific biomarkers, we measured myocardial microstructure and MVD in 3 HCM groups-overt, either genotype-positive (G+LVH+) or genotype-negative (G-LVH+), and subclinical (G+LVH-) HCM-exploring relationships with electrical changes and genetic substrate. METHODS: This was a multicenter collaboration to study 206 subjects: 101 patients with overt HCM (51 G+LVH+ and 50 G-LVH+), 77 patients with G+LVH-, and 28 matched healthy volunteers. All underwent 12-lead ECG, quantitative perfusion cardiac magnetic resonance imaging (measuring myocardial blood flow, myocardial perfusion reserve, and perfusion defects), and cardiac diffusion tensor imaging measuring fractional anisotropy (lower values expected with more disarray), mean diffusivity (reflecting myocyte packing/interstitial expansion), and second eigenvector angle (measuring sheetlet orientation). RESULTS: Compared with healthy volunteers, patients with overt HCM had evidence of altered microstructure (lower fractional anisotropy, higher mean diffusivity, and higher second eigenvector angle; all P<0.001) and MVD (lower stress myocardial blood flow and myocardial perfusion reserve; both P<0.001). Patients with G-LVH+ were similar to those with G+LVH+ but had elevated second eigenvector angle (P<0.001 after adjustment for left ventricular hypertrophy and fibrosis). In overt disease, perfusion defects were found in all G+ but not all G- patients (100% [51/51] versus 82% [41/50]; P=0.001). Patients with G+LVH- compared with healthy volunteers similarly had altered microstructure, although to a lesser extent (all diffusion tensor imaging parameters; P<0.001), and MVD (reduced stress myocardial blood flow [P=0.015] with perfusion defects in 28% versus 0 healthy volunteers [P=0.002]). Disarray and MVD were independently associated with pathological electrocardiographic abnormalities in both overt and subclinical disease after adjustment for fibrosis and left ventricular hypertrophy (overt: fractional anisotropy: odds ratio for an abnormal ECG, 3.3, P=0.01; stress myocardial blood flow: odds ratio, 2.8, P=0.015; subclinical: fractional anisotropy odds ratio, 4.0, P=0.001; myocardial perfusion reserve odds ratio, 2.2, P=0.049). CONCLUSIONS: Microstructural alteration and MVD occur in overt HCM and are different in G+ and G- patients. Both also occur in the absence of hypertrophy in sarcomeric mutation carriers, in whom changes are associated with electrocardiographic abnormalities. Measurable changes in myocardial microstructure and microvascular function are early-phenotype biomarkers in the emerging era of disease-modifying therapy.

Circulating c-Met-Expressing Memory T Cells Define Cardiac Autoimmunity.

BACKGROUND: Autoimmunity is increasingly recognized as a key contributing factor in heart muscle diseases. The functional features of cardiac autoimmunity in humans remain undefined because of the challenge of studying immune responses in situ. We previously described a subset of c-mesenchymal epithelial transition factor (c-Met)-expressing (c-Met+) memory T lymphocytes that preferentially migrate to cardiac tissue in mice and humans. METHODS: In-depth phenotyping of peripheral blood T cells, including c-Met+ T cells, was undertaken in groups of patients with inflammatory and noninflammatory cardiomyopathies, patients with noncardiac autoimmunity, and healthy controls. Validation studies were carried out using human cardiac tissue and in an experimental model of cardiac inflammation. RESULTS: We show that c-Met+ T cells are selectively increased in the circulation and in the myocardium of patients with inflammatory cardiomyopathies. The phenotype and function of c-Met+ T cells are distinct from those of c-Met-negative (c-Met-) T cells, including preferential proliferation to cardiac myosin and coproduction of multiple cytokines (interleukin-4, interleukin-17, and interleukin-22). Furthermore, circulating c-Met+ T cell subpopulations in different heart muscle diseases identify distinct and overlapping mechanisms of heart inflammation. In experimental autoimmune myocarditis, elevations in autoantigen-specific c-Met+ T cells in peripheral blood mark the loss of immune tolerance to the heart. Disease development can be halted by pharmacologic c-Met inhibition, indicating a causative role for c-Met+ T cells. CONCLUSIONS: Our study demonstrates that the detection of circulating c-Met+ T cells may have use in the diagnosis and monitoring of adaptive cardiac inflammation and definition of new targets for therapeutic intervention when cardiac autoimmunity causes or contributes to progressive cardiac injury.

Dilated cardiomyopathy and chronic cardiac inflammation: Pathogenesis, diagnosis and therapy.

Dilated cardiomyopathy (DCM) is typically defined by left ventricular dilation and systolic dysfunction in the absence of a clear precipitant. Idiopathic disease is common; up to 50% of patients with DCM have no cause found despite imaging, genetic and biopsy assessments. Treatment remains focused on managing symptoms, reducing the risk of sudden cardiac death and ameliorating the structural and electrical complications of disease progression. In the absence of aetiology-specific treatments, the condition remains associated with a poor prognosis; mortality is approximately 40% at 10 years. The role of immune-mediated inflammatory injury in the development and progression of DCM was first proposed over 30 years ago. Despite the subsequent failures of three large clinical trials of immunosuppressive treatment (ATTACH, RENEWAL and the Myocarditis Treatment Trial), evidence for an abnormal adaptive immune response in DCM remains significant. In this review, we summarise and discuss available evidence supporting immune dysfunction in DCM, with a specific focus on cellular immunity. We also highlight current clinical and experimental treatments. We propose that the success of future immunosuppressive treatment trials in DCM will be dependent on the deep immunophenotyping of patients, to identify those with active inflammation and/or an abnormal immune response who are most likely to respond to therapy.

The mitral valve in hypertrophic cardiomyopathy.

PURPOSE OF REVIEW: Whilst abnormally increased left ventricular wall thickness is the hallmark feature of hypertrophic cardiomyopathy (HCM), anomalies of the mitral valve and supporting apparatus are well documented. This review addresses the clinical importance of mitral valve abnormalities in HCM, their mechanistic associations with symptoms, and therapeutic strategies targeting mitral valve and apparatus abnormalities. RECENT FINDINGS: The normal mitral valve possesses anatomical features facilitating unrestricted blood flow during LV filling, preventing regurgitation during LV systole, and avoiding obstruction of LV ejection. In HCM, a variety of structural and functional abnormalities can conspire to cause deranged mitral valve function, with implications for management strategy. Identification and characterization of these abnormalities is facilitated by multimodality imaging. Alcohol septal ablation (ASA) cannot address primary mitral valve abnormalities, and so is not preferred to surgical intervention if mitral valve abnormalities are present and are judged to make dominant contributions to LV outflow tract obstruction (LVOTO). Two broadly opposing surgical intervention strategies exist, one advocating isolated septal myectomy and the other including adjuvant mitral apparatus modification. Newer, less invasive surgical and transcatheter techniques will expand interventional options. SUMMARY: Mitral valve abnormalities are a central pathological feature of HCM. Multimodality imaging is crucial for their identification and characterization prior to therapeutic intervention.

Catheter ablation of atrial fibrillation in patients with hypertrophic cardiomyopathy: a European observational multicentre study.

AIMS: Atrial fibrillation (AF) is common in hypertrophic cardiomyopathy (HCM). Data on the efficacy of catheter ablation of AF in HCM patients are sparse. METHODS AND RESULTS: Observational multicentre study in 137 HCM patients (mean age 55.0 ± 13.4, 29.1% female; 225 ablation procedures). We investigated (i) the efficacy of catheter ablation for AF beyond the initial 12 months; (ii) the available risk scores, stratification schemes and genotype as potential predictors of arrhythmia relapse, and (iii) the impact of cryoballoon vs. radiofrequency in procedural outcomes. Mean follow-up was 43.8 ± 37.0 months. Recurrences after the initial 12-month period post-ablation were frequent, and 24 months after the index procedure, nearly all patients with persistent AF had relapsed, and only 40% of those with paroxysmal AF remained free from arrhythmia recurrence. The APPLE score demonstrated a modest discriminative capacity for AF relapse post-ablation (c-statistic 0.63, 95% CI 0.52-0.75; P = 0.022), while the risk stratification schemes for sudden death did not. On multivariable analysis, left atrium diameter and LV apical aneurysm were independent predictors of recurrence. Fifty-eight patients were genotyped; arrhythmia-free survival was similar among subjects with different gene mutations. Rate of procedural complications was high (9.3%), although reducing over time. Outcome for cryoballoon and radiofrequency ablation was comparable. CONCLUSION: Very late AF relapses post-ablation is common in HCM patients, especially in those with persistent AF. Left atrium size, LV apical aneurysm, and the APPLE score might contribute to identify subjects at higher risk of arrhythmia recurrence. First-time cryoballoon is comparable with radiofrequency ablation.

Non-vitamin K oral anticoagulants in hypertrophic cardiomyopathy patients undergoing catheter ablation of atrial fibrillation.

INTRODUCTION: Patients with hypertrophic cardiomyopathy (HCM) and atrial fibrillation (AF) require chronic anticoagulation due to high thromboembolic risk. Evidence supporting the use of non-vitamin K oral anticoagulants (NOACs) in patients with HCM remains sparse, and there are no data regarding the use of NOACs in patients with HCM undergoing catheter ablation of AF. METHODS: Observational nonrandomized study in four European centers. We aimed to investigate the safety and efficacy of NOACs compared with vitamin K antagonists (VKAs) in patients with HCM undergoing catheter ablation for AF. RESULTS: A total of 137 patients with HCM (mean age: 55.0 ± 13.4, 29.1% female) underwent 230 catheter ablations for AF (1.7 ± 1.0 per patient). A total of 55 patients (39.4%) underwent 70 procedures (30.4%) on NOAC, while the remaining were on VKA. Warfarin (97.6%) and rivaroxaban (56.4%) were the most frequently used agents in the respective groups. No procedure-related deaths were reported. We observed no significant difference in the rate of thromboembolism (VKA: 0.6%; NOAC: 0%; p = 1.0) or minor bleeding (VKA: 0.6%; NOAC: 1.4%; p = .54). There was a nonsignificant trend towards a lower incidence of major bleeding (VKA: 6.9%; NOAC: 1.4%; p = .09). CONCLUSION: These preliminary data suggest that NOACs are at least as safe and effective as VKAs in patients with HCM undergoing catheter ablation for AF.

International External Validation Study of the 2014 European Society of Cardiology Guidelines on Sudden Cardiac Death Prevention in Hypertrophic Cardiomyopathy (EVIDENCE-HCM).

BACKGROUND: Identification of people with hypertrophic cardiomyopathy (HCM) who are at risk of sudden cardiac death (SCD) and require a prophylactic implantable cardioverter defibrillator is challenging. In 2014, the European Society of Cardiology proposed a new risk stratification method based on a risk prediction model (HCM Risk-SCD) that estimates the 5-year risk of SCD. The aim was to externally validate the 2014 European Society of Cardiology recommendations in a geographically diverse cohort of patients recruited from the United States, Europe, the Middle East, and Asia. METHODS: This was an observational, retrospective, longitudinal cohort study. RESULTS: The cohort consisted of 3703 patients. Seventy three (2%) patients reached the SCD end point within 5 years of follow-up (5-year incidence, 2.4% [95% confidence interval {CI}, 1.9-3.0]). The validation study revealed a calibration slope of 1.02 (95% CI, 0.93-1.12), C-index of 0.70 (95% CI, 0.68-0.72), and D-statistic of 1.17 (95% CI, 1.05-1.29). In a complete case analysis (n= 2147; 44 SCD end points at 5 years), patients with a predicted 5-year risk of <4% (n=1524; 71%) had an observed 5-year SCD incidence of 1.4% (95% CI, 0.8-2.2); patients with a predicted risk of ≥6% (n=297; 14%) had an observed SCD incidence of 8.9% (95% CI, 5.96-13.1) at 5 years. For every 13 (297/23) implantable cardioverter defibrillator implantations in patients with an estimated 5-year SCD risk ≥6%, 1 patient can potentially be saved from SCD. CONCLUSIONS: This study confirms that the HCM Risk-SCD model provides accurate prognostic information that can be used to target implantable cardioverter defibrillator therapy in patients at the highest risk of SCD.

Doppler echocardiography underestimates the prevalence and magnitude of mid-cavity obstruction in patients with symptomatic hypertrophic cardiomyopathy.

OBJECTIVES: To evaluate utility of Doppler echocardiography in the assessment of left ventricular (LV) mid-cavity obstructive (LVMCO) hypertrophic cardiomyopathy (HCM). BACKGROUND: LVMCO is a relatively under-diagnosed complication of HCM and may occur alone or in combination with LV outflow tract obstruction (LVOTO). Identifying and quantifying LVMCO and differentiating it from LVOTO has important implications for patient management. We aimed to assess diagnostic performance of Doppler echocardiography in the assessment of suspected LV obstruction. METHODS: Forty symptomatic HCM patients with suspected obstruction underwent cardiac catheterization, and comparison of location and magnitude of Doppler derived gradients with synchronous invasive measurements (reference standard), at rest and isoprenaline stress (IS). RESULTS: Doppler's diagnostic accuracy for any obstruction (≥30 mmHg) in this cohort was 75% with false positive and false negative rates of 2.5 and 22.5%, respectively. During subanalysis, Doppler's diagnostic accuracy for isolated LVOTO in this selected cohort is 83% with false positive and false negative rates of 4 and 12.5%, respectively. For LVMCO, the accuracy is only 50%, with false positive and false negative rates of 10 and 40%, respectively. Doppler gradients for isolated LVOTO were similar to invasive: 85 ± 51 and 87 ± 35 mmHg, respectively (P = 0.77). Doppler gradients in LVMCO were consistently lower than invasive: 45 ± 38 and 81 ± 31 mmHg, respectively (P = 0.0002). Mid-systolic flow cessation and/or contamination of spectral signals were identified as causes of Doppler-derived inaccuracies. CONCLUSIONS: Doppler echocardiography under-diagnoses and underestimates severity of LVMCO in symptomatic HCM patients. Recognition of abrupt mid-systolic flow cessation and invasive measurements may improve detection of LVMCO in HCM.

Sudden adult death syndrome in m.3243A>G-related mitochondrial disease: an unrecognized clinical entity in young, asymptomatic adults.

AIMS: To provide insight into the mechanism of sudden adult death syndrome (SADS) and to give new clinical guidelines for the cardiac management of patients with the most common mitochondrial DNA mutation, m.3243A>G. These studies were initiated after two young, asymptomatic adults harbouring the m.3243A>G mutation died suddenly and unexpectedly. The m.3243A>G mutation is present in ∼1 in 400 of the population, although the recognized incidence of mitochondrial DNA (mtDNA) disease is ∼1 in 5000. METHODS AND RESULTS: Pathological studies including histochemistry and molecular genetic analyses performed on various post-mortem samples including cardiac tissues (atrium and ventricles) showed marked respiratory chain deficiency and high levels of the m.3243A>G mutation. Systematic review of cause of death in our m.3243A>G patient cohort showed the person-time incidence rate of sudden adult death is 2.4 per 1000 person-years. A further six cases of sudden death among extended family members have been identified from interrogation of family pedigrees. CONCLUSION: Our findings suggest that SADS is an important cause of death in patients with m.3243A>G and likely to be due to widespread respiratory chain deficiency in cardiac muscle. The involvement of asymptomatic relatives highlights the importance of family tracing in patients with m.3243A>G and the need for specific cardiac arrhythmia surveillance in the management of this common genetic disease. In addition, these findings have prompted the derivation of cardiac guidelines specific to patients with m.3243A>G-related mitochondrial disease. Finally, due to the prevalence of this mtDNA point mutation, we recommend inclusion of testing for m.3243A>G mutations in the genetic autopsy of all unexplained cases of SADS.

Cardiovascular magnetic resonance imaging of myocardial oedema following acute myocardial infarction: Is whole heart coverage necessary?

BACKGROUND: AAR measurement is useful when assessing the efficacy of reperfusion therapy and novel cardioprotective agents after myocardial infarction. Multi-slice (Typically 10-12) T2-STIR has been used widely for its measurement, typically with a short axis stack (SAX) covering the entire left ventricle, which can result in long acquisition times and multiple breath holds. This study sought to compare 3-slice T2-short-tau inversion recovery (T2- STIR) technique against conventional multi-slice T2-STIR technique for the assessment of area at risk (AAR). METHODS: CMR imaging was performed on 167 patients after successful primary percutaneous coronary intervention. 82 patients underwent a novel 3-slice SAX protocol and 85 patients underwent standard 10-slice SAX protocol. AAR was obtained by manual endocardial and epicardial contour mapping followed by a semi- automated selection of normal myocardium; the volume was expressed as mass (%) by two independent observers. RESULTS: 85 patients underwent both 10-slice and 3-slice imaging assessment showing a significant and strong correlation (intraclass correlation coefficient = 0.92;p < 0.0001) and a low Bland-Altman limit (mean difference -0.03 ± 3.21%, 95% limit of agreement,- 6.3 to 6.3) between the 2 analysis techniques. A further 82 patients underwent 3-slice imaging alone, both the 3-slice and the 10-slice techniques showed statistically significant correlations with angiographic risk scores (3-slice to BARI r = 0.36, 3-slice to APPROACH r = 0.42, 10-slice to BARI r = 0.27, 10-slice to APPROACH r = 0.46). There was low inter-observer variability demonstrated in the 3-slice technique, which was comparable to the 10-slice method (z = 1.035, p = 0.15). Acquisition and analysis times were quicker in the 3-slice compared to the 10-slice method (3-slice median time: 100 seconds (IQR: 65-171 s) vs. (10-slice time: 355 seconds (IQR: 275-603 s); p < 0.0001. CONCLUSIONS: AAR measured using 3-slice T2-STIR technique correlates well with standard 10-slice techniques, with no significant bias demonstrated in assessing the AAR. The 3-slice technique requires less time to perform and analyse and is therefore advantageous for both patients and clinicians.

Almanac 2014: cardiomyopathies.

Cardiomyopathies are myocardial disorders that are not explained by abnormal loading conditions and coronary artery disease. They are classified into a number of morphological and functional phenotypes that can be caused by genetic and non-genetic mechanisms. The dominant themes in papers published in 2012-2013 are similar to those reported in Almanac 2011, namely, the use (and interpretation) of genetic testing, development and application of novel non-invasive imaging techniques and use of serum biomarkers for diagnosis and prognosis. An important innovation since the last Almanac is the development of more sophisticated models for predicting adverse clinical events.

Innate and adaptive immunity in acute myocarditis.

Acute myocarditis is an acute inflammatory cardiomyopathy associated with cardiac damage triggered by a virus or a pathological immune activation. It may present with a wide range of clinical presentations, ranging from mild symptoms to severe forms like fulminant myocarditis, characterized by hemodynamic compromise and cardiogenic shock. The immune system plays a central role in the pathogenesis of myocarditis. In fact, while its function is primarily protective, aberrant responses can be detrimental. In this context, both innate and adaptive immunity play pivotal roles; notably, the innate system offers a non-specific and immediate defense, while the adaptive provides specialized protection with immunological memory. However, dysregulation in these systems can misidentify cardiac tissue, triggering autoimmune reactions and possibly leading to significant cardiac tissue damage. This review highlights the importance of innate and adaptive immune responses in the progression and treatment of acute myocarditis.

Cardiovascular involvement in later-onset malonyl-CoA decarboxylase deficiency: Case studies and literature review.

BACKGROUND: Malonyl-CoA decarboxylase deficiency (MLYCDD) is an ultra-rare inherited metabolic disorder, characterized by multi-organ involvement manifesting during the first few months of life. Our aim was to describe the clinical, biochemical, and genetic characteristics of patients with later-onset MLYCDD. METHODS: Clinical and biochemical characteristics of two patients aged 48 and 29 years with a confirmed molecular diagnosis of MLYCDD were examined. A systematic review of published studies describing the characteristics of cardiovascular involvement of patients with MLYCDD was performed. RESULTS: Two patients diagnosed with MLYCDD during adulthood were identified. The first presented with hypertrophic cardiomyopathy and ventricular pre-excitation and the second with dilated cardiomyopathy (DCM) and mild-to-moderate left ventricular (LV) systolic dysfunction. No other clinical manifestation typical of MLYCDD was observed. Both patients showed slight increase in malonylcarnitine in their plasma acylcarnitine profile, and a reduction in malonyl-CoA decarboxylase activity. During follow-up, no deterioration of LV systolic function was observed. The systematic review identified 33 individuals with a genetic diagnosis of MLYCDD (median age 6 months [IQR 1-12], 22 males [67%]). Cardiovascular involvement was observed in 64% of cases, with DCM the most common phenotype. A modified diet combined with levocarnitine supplementation resulted in the improvement of LV systolic function in most cases. After a median follow-up of 8 months, 3 patients died (two heart failure-related and one arrhythmic death). CONCLUSIONS: For the first time this study describes a later-onset phenotype of MLYCDD patients, characterized by single-organ involvement, mildly reduced enzyme activity, and a benign clinical course.

Excessive Trabeculation of the Left Ventricle: JACC: Cardiovascular Imaging Expert Panel Paper.

Excessive trabeculation, often referred to as "noncompacted" myocardium, has been described at all ages, from the fetus to the adult. Current evidence for myocardial development, however, does not support the formation of compact myocardium from noncompacted myocardium, nor the arrest of this process to result in so-called noncompaction. Excessive trabeculation is frequently observed by imaging studies in healthy individuals, as well as in association with pregnancy, athletic activity, and with cardiac diseases of inherited, acquired, developmental, or congenital origins. Adults with incidentally noted excessive trabeculation frequently require no further follow-up based on trabecular pattern alone. Patients with cardiomyopathy and excessive trabeculation are managed by cardiovascular symptoms rather than the trabecular pattern. To date, the prognostic role of excessive trabeculation in adults has not been shown to be independent of other myocardial disease. In neonates and children with excessive trabeculation and normal or abnormal function, clinical caution seems warranted because of the reported association with genetic and neuromuscular disorders. This report summarizes the evidence concerning the etiology, pathophysiology, and clinical relevance of excessive trabeculation. Gaps in current knowledge of the clinical relevance of excessive trabeculation are indicated, with priorities suggested for future research and improved diagnosis in adults and children.

Characterizing the hypertensive cardiovascular phenotype in the UK Biobank.

AIMS: To describe hypertension-related cardiovascular magnetic resonance (CMR) phenotypes in the UK Biobank considering variations across patient populations. METHODS AND RESULTS: We studied 39 095 (51.5% women, mean age: 63.9 ± 7.7 years, 38.6% hypertensive) participants with CMR data available. Hypertension status was ascertained through health record linkage. Associations between hypertension and CMR metrics were estimated using multivariable linear regression adjusting for major vascular risk factors. Stratified analyses were performed by sex, ethnicity, time since hypertension diagnosis, and blood pressure (BP) control. Results are standardized beta coefficients, 95% confidence intervals, and P-values corrected for multiple testing. Hypertension was associated with concentric left ventricular (LV) hypertrophy (increased LV mass, wall thickness, concentricity index), poorer LV function (lower global function index, worse global longitudinal strain), larger left atrial (LA) volumes, lower LA ejection fraction, and lower aortic distensibility. Hypertension was linked to significantly lower myocardial native T1 and increased LV ejection fraction. Women had greater hypertension-related reduction in aortic compliance than men. The degree of hypertension-related LV hypertrophy was greatest in Black ethnicities. Increasing time since diagnosis of hypertension was linked to adverse remodelling. Hypertension-related remodelling was substantially attenuated in hypertensives with good BP control. CONCLUSION: Hypertension was associated with concentric LV hypertrophy, reduced LV function, dilated poorer functioning LA, and reduced aortic compliance. Whilst the overall pattern of remodelling was consistent across populations, women had greater hypertension-related reduction in aortic compliance and Black ethnicities showed the greatest LV mass increase. Importantly, adverse cardiovascular remodelling was markedly attenuated in hypertensives with good BP control.

Apical Ischemia Is a Universal Feature of Apical Hypertrophic Cardiomyopathy.

BACKGROUND: Apical hypertrophic cardiomyopathy (ApHCM) accounts for ≈10% of hypertrophic cardiomyopathy cases and is characterized by apical hypertrophy, apical cavity obliteration, and tall ECG R waves with ischemic-looking deep T-wave inversion. These may be present even with <15 mm apical hypertrophy (relative ApHCM). Microvascular dysfunction is well described in hypertrophic cardiomyopathy. We hypothesized that apical perfusion defects would be common in ApHCM. METHODS: A 2-center study using cardiovascular magnetic resonance short- and long-axis quantitative adenosine vasodilator stress perfusion mapping. One hundred patients with ApHCM (68 overt hypertrophy [≥15 mm] and 32 relative ApHCM) were compared with 50 patients with asymmetrical septal hypertrophy hypertrophic cardiomyopathy and 40 healthy volunteer controls. Perfusion was assessed visually and quantitatively as myocardial blood flow and myocardial perfusion reserve. RESULTS: Apical perfusion defects were present in all overt ApHCM patients (100%), all relative ApHCM patients (100%), 36% of asymmetrical septal hypertrophy hypertrophic cardiomyopathy, and 0% of healthy volunteers (P<0.001). In 10% of patients with ApHCM, perfusion defects were sufficiently apical that conventional short-axis views missed them. In 29%, stress myocardial blood flow fell below rest values. Stress myocardial blood flow was most impaired subendocardially, with greater hypertrophy or scar, and with apical aneurysms. Impaired apical myocardial blood flow was most strongly predicted by thicker apical segments (ß-coefficient, -0.031 mL/g per min [CI, -0.06 to -0.01]; P=0.013), higher ejection fraction (-0.025 mL/g per min [CI, -0.04 to -0.01]; P<0.005), and ECG maximum R-wave height (-0.023 mL/g per min [CI, -0.04 to -0.01]; P<0.005). CONCLUSIONS: Apical perfusion defects are universally present in ApHCM at all stages. Its ubiquitous presence along with characteristic ECG suggests ischemia may play a disease-defining role in ApHCM.

The atrial and ventricular myocardial proteome of end-stage lamin heart disease.

Lamins A/C (encoded by LMNA gene) can lead to dilated cardiomyopathy (DCM). This pilot study sought to explore the postgenomic phenotype of end-stage lamin heart disease. Consecutive patients with end-stage lamin heart disease (LMNA-group, n = 7) and ischaemic DCM (ICM-group, n = 7) undergoing heart transplantation were prospectively enrolled. Samples were obtained from left atrium (LA), left ventricle (LV), right atrium (RA), right ventricle (RV) and interventricular septum (IVS), avoiding the infarcted myocardial segments in the ICM-group. Samples were analysed using a discovery 'shotgun' proteomics approach. We found that 990 proteins were differentially abundant between LMNA and ICM samples with the LA being most perturbed (16-fold more than the LV). Abundance of lamin A/C protein was reduced, but lamin B increased in LMNA LA/RA tissue compared to ICM, but not in LV/RV. Carbonic anhydrase 3 (CA3) was over-abundant across all LMNA tissue samples (LA, LV, RA, RV, and IVS) when compared to ICM. Transthyretin was more abundant in the LV/RV of LMNA compared to ICM, while sarcomeric proteins such as titin and cardiac alpha-cardiac myosin heavy chain were generally less abundant in RA/LA of LMNA. Protein expression profiling and enrichment analysis pointed towards sarcopenia, extracellular matrix remodeling, deficient myocardial energetics, redox imbalances, and abnormal calcium handling in LMNA samples. Compared to ICM, end-stage lamin heart disease is a biventricular but especially a biatrial disease appearing to have an abundance of lamin B, CA3 and transthyretin, potentially hinting to compensatory responses.

Improved Diagnostic Criteria for Apical Hypertrophic Cardiomyopathy.

BACKGROUND: There is no acceptable maximum wall thickness (MWT) threshold for diagnosing apical hypertrophic cardiomyopathy (ApHCM), with guidelines referring to ≥15 mm MWT for all hypertrophic cardiomyopathy subtypes. A normal myocardium naturally tapers apically; a fixed diagnostic threshold fails to account for this. Using cardiac magnetic resonance, "relative" ApHCM has been described with typical electrocardiographic features, loss of apical tapering, and cavity obliteration but also with MWT <15 mm. OBJECTIVES: The authors aimed to define normal apical wall thickness thresholds in healthy subjects and use these to accurately identify ApHCM. METHODS: The following healthy subjects were recruited: healthy UK Biobank imaging substudy subjects (n = 4,112) and an independent healthy volunteer group (n = 489). A clinically defined disease population of 104 ApHCM subjects was enrolled, with 72 overt (MWT ≥15 mm) and 32 relative (MWT <15 mm but typical electrocardiographic/imaging findings) ApHCM subjects. Cardiac magnetic resonance-derived MWT was measured in 16 segments using a published clinically validated machine learning algorithm. Segmental normal reference ranges were created and indexed (for age, sex, and body surface area), and diagnostic performance was assessed. RESULTS: In healthy cohorts, there was no clinically significant age-related difference for apical wall thickness. There were sex-related differences, but these were not clinically significant after indexing to body surface area. Therefore, segmental reference ranges for apical hypertrophy required indexing to body surface area only (not age or sex). The upper limit of normal (the largest of the 4 apical segments measured) corresponded to a maximum apical MWT in healthy subjects of 5.2 to 5.6 mm/m2 with an accuracy of 0.94 (the unindexed equivalent being 11 mm). This threshold was categorized as abnormal in 99% (71/72) of overt ApHCM patients, 78% (25/32) of relative ApHCM patients, 3% (122/4,112) of UK Biobank subjects, and 3% (13/489) of healthy volunteers. CONCLUSIONS: Per-segment indexed apical wall thickness thresholds are highly accurate for detecting apical hypertrophy, providing confidence to the reader to diagnose ApHCM in those not reaching current internationally recognized criteria.

Almanac 2011: cardiomyopathies. The national society journals present selected research that has driven recent advances in clinical cardiology.

As we approach the end of 2011 it is clear that the next few years are going to be dominated by the application of new high throughput genetic screening techniques, capable of screening the entire exome or indeed genome. Understanding the data generated by these techniques will require new and equally sophisticated analysis of large and complex datasets, using a systems biology approach with deeper phenotyping and advanced modelling techniques that have the flexibility for continuous update, refinement with discovery of new knowledge. Exciting new developments that may also transform cardiomyopathy research include those of infrastructure and organisation (multi-centre collaborations) and spin-offs from the field of regenerative medicine research. For clinical researchers that translate this information to the clinic the focus will however remain the same; namely improvement of quality and quantity of life.

Almanac 2011: cardiomyopathies. The national society journals present selected research that has driven recent advances in clinical cardiology.

As we approach the end of 2011 it is clear that the next few years are going to be dominated by the application of new high throughput genetic screening techniques, capable of screening the entire exome or indeed genome. Understanding the data generated by these techniques will require new and equally sophisticated analysis of large and complex datasets, using a systems biology approach with deeper phenotyping and advanced modelling techniques that have the flexibility for continuous update, refinement with discovery of new knowledge. Exciting new developments that may also transform cardiomyopathy research include those of infrastructure and organisation (multi-centre collaborations) and spin-offs from the field of regenerative medicine research. For clinical researchers that translate this information to the clinic the focus will however remain the same; namely improvement of quality and quantity of life.