Fabry Disease in Families With Hypertrophic Cardiomyopathy: Clinical Manifestations in the Classic and Later-Onset Phenotypes.

BACKGROUND: The screening of Icelandic patients clinically diagnosed with hypertrophic cardiomyopathy resulted in identification of 8 individuals from 2 families with X-linked Fabry disease (FD) caused by GLA(α-galactosidase A gene) mutations encoding p.D322E (family A) or p.I232T (family B). METHODS AND RESULTS: Familial screening of at-risk relatives identified mutations in 16 family A members (8 men and 8 heterozygotes) and 25 family B members (10 men and 15 heterozygotes). Clinical assessments, α-galactosidase A (α-GalA) activities, glycosphingolipid substrate levels, and in vitro mutation expression were used to categorize p.D322E as a classic FD mutation and p.I232T as a later-onset FD mutation. In vitro expression revealed that p.D322E and p.I232T had α-GalA activities of 1.4% and 14.9% of the mean wild-type activity, respectively. Family A men had markedly decreased α-GalA activity and childhood-onset classic manifestations, except for angiokeratoma and cornea verticillata. Family B men had residual α-GalA activity and developed FD manifestations in adulthood. Despite these differences, all family A and family B men >30 years of age had left ventricular hypertrophy, which was mainly asymmetrical, and had similar late gadolinium enhancement patterns. Ischemic stroke and severe white matter lesions were more frequent among family A men, but neither family A nor family B men had overt renal disease. Family A and family B heterozygotes had less severe or no clinical manifestations. CONCLUSIONS: Men with classic or later-onset FD caused by GLA missense mutations developed prominent and similar cardiovascular disease at similar ages, despite markedly different α-GalA activities.

Significance of false negative electrocardiograms in preparticipation screening of athletes for hypertrophic cardiomyopathy.

Preparticipation screening of athletes with 12-lead electrocardiography has been promoted for the detection of asymptomatic cardiovascular disease, particularly hypertrophic cardiomyopathy (HC). Although false-positive electrocardiographic (ECG) results for HC are well recognized in athlete screening, expected false-negative rates are unknown. The aim of this study was to characterize the rate of false-negative ECG findings in a cohort of young asymptomatic patients with phenotypically expressed HC, defined by cardiovascular magnetic resonance, using the 2010 European Society of Cardiology recommended ECG criteria for the identification of suspected heart disease in trained athletes. Cardiac magnetic resonance studies and 12-lead electrocardiography were performed in 114 consecutive asymptomatic patients with HC aged ≤35 years (mean age 22 ± 8 years; 77% male patients). Electrocardiograms were analyzed to distinguish pathologic ECG patterns from alterations considered nonpathologic and physiologic consequences of athletic training. Among the 114 patients with HC, 103 (90%) demonstrated ≥1 pathologic ECG abnormality, while the remaining 11 patients (10%) had normal or nonpathologic ECG patterns and therefore defined a subgroup in whom ECG screening would not be expected to raise suspicion of heart disease (i.e., false-negative results). In this false-negative ECG results group, maximal left ventricular wall thickness was 17 ± 2 mm (range 15 to 21), compared to patients with pathologic ECG patterns, in whom maximal left ventricular wall thickness was 22 ± 5 mm (p = 0.003). In conclusion, a substantial minority of young asymptomatic patients with HC with phenotypically expressed left ventricular hypertrophy have nonpathologic ECG findings on the basis of the 2010 European Society of Cardiology guidelines. In principle, this high false-negative rate of 10% represents an important limitation in applying 12-lead electrocardiography to large, apparently healthy athletic populations for the detection of HC.

Mitral valve abnormalities identified by cardiovascular magnetic resonance represent a primary phenotypic expression of hypertrophic cardiomyopathy.

BACKGROUND: Whether morphological abnormalities of the mitral valve represent part of the hypertrophic cardiomyopathy (HCM) disease process is unresolved. Therefore, we applied cardiovascular magnetic resonance to characterize mitral valve morphology in a large HCM cohort. METHODS AND RESULTS: Cine cardiac magnetic resonance images were obtained in 172 HCM patients (age, 42±18 years; 62% men) and 172 control subjects. In addition, 15 HCM gene-positive/phenotype-negative relatives were studied. Anterior mitral leaflet (AML) and posterior mitral leaflet lengths were greater in HCM patients than in control subjects (26±5 versus 19±5 mm, P<0.001; and 14±4 versus 10±3 mm, P<0.001, respectively), including 59 patients (34%) in whom AML length alone, posterior mitral leaflet length alone, or both were particularly substantial (>2 SDs above controls). Leaflet length was increased compared with controls in virtually all HCM age groups, including young patients 15 to 20 years of age (AML, 26±5 versus 21±4 mm; P=0.0002) and those ≥60 years of age (AML, 26±4 versus 19±2 mm; P<0.001). No relation was evident between mitral leaflet length and LV thickness or mass index (P=0.09 and P=0.16, respectively). A ratio of AML length to LV outflow tract diameter of >2.0 was associated with subaortic obstruction (P=0.001). In addition, AML length in 15 genotype-positive relatives without LV hypertrophy exceeded that of matched control subjects (21±3 versus 18±3 mm; P<0.01). CONCLUSIONS: In HCM, mitral valve leaflets are elongated independently of other disease variables, likely constituting a primary phenotypic expression of this heterogeneous disease, and are an important morphological abnormality responsible for LV outflow obstruction in combination with small outflow tract dimension. These findings suggest a novel role for cardiac magnetic resonance in the assessment of HCM.

Noncardiac pathology on clinical cardiac magnetic resonance imaging.

OBJECTIVES: We sought to determine the prevalence of noncardiac pathology in a large consecutive series of patients referred for clinical cardiac magnetic resonance (CMR) studies. BACKGROUND: The imaging field for many CMR sequences extends outside of the heart border. As a result, noncardiac pathology may be identified. These noncardiac findings have clinical significance because they often lead to subsequent imaging/testing and intervention. The prevalence of noncardiac findings on clinical CMR studies has not been well described. METHODS: The reports of all 1,534 (62% male, age 50 +/- 15 years) clinical CMR studies performed at an academic medical center during calendar years 2002 to 2006 were reviewed. All studies had been interpreted by both a staff cardiologist (level III trained in CMR) and a board-certified radiologist (with fellowship training in CMR). For each study, sex, age, indication for CMR study, and reported noncardiac pathology were extracted. Follow-up for each major noncardiac pathology was evaluated by reviewing the patient's medical center electronic medical record. These noncardiac pathologies were then categorized as significant if an intervention or change in the patient's management ensued. RESULTS: A total of 116 (7.6%) studies had at least one noncardiac finding. These findings included 55 major findings (e.g., lymphadenopathy, lung abnormalities, mediastinal masses) in 48 distinct reports (prevalence of 3.1%) and 74 minor findings (e.g., small pleural effusions, liver cysts, renal cysts) in 70 distinct reports (prevalence of 4.6%). The majority (62%) of major findings were previously known, with only 8 findings in 6 (0.4%) of 1,534 reports ultimately deemed to be new and clinically important/significant. The age of those with noncardiac pathology was greater (54 +/- 16 years vs. 49 +/- 16 years, p < 0.001). CONCLUSIONS: In this large series of consecutive clinical CMR studies interpreted by both staff cardiologists and radiologists, noncardiac pathology is uncommonly reported. When reported, the majority of major findings are previously known. New major findings were detected in <0.5% of reports.

Diagnostic and prognostic utility of cardiovascular magnetic resonance imaging in light-chain cardiac amyloidosis.

Although the presence of abnormal late gadolinium enhancement (LGE) in cardiac amyloidosis has been well established, its prognostic implication and utility to identify cardiac involvement in patients with systemic amyloidosis is unknown. The aim of this study was to assess the diagnostic and prognostic significance of cardiovascular magnetic resonance imaging in patients with amyloid light-chain amyloidosis but unknown cardiac involvement. Cardiovascular magnetic resonance imaging with LGE was performed in 28 patients with systemic amyloidosis. The presence of cardiac amyloidosis was determined by separate clinical evaluation. The performance of LGE for the prediction of cardiac amyloidosis and prognostic implications of LGE were determined. LGE was observed in 19 patients (68%). The sensitivity, specificity, positive predictive value, and negative predictive value of LGE for the identification of clinical cardiac involvement were 86%, 86%, 95%, and 67%, respectively. During a median follow-up period of 29 months, there were 5 deaths (82% survival). LGE itself did not predict survival (p = 0.62). LGE volume was positively correlated with serum level of B-type natriuretic peptide (BNP; R = 0.64, p < or =0.001), and in multivariate analysis, LGE volume proved the strongest independent predictor of BNP. BNP was correlated with New York Heart Association class (p = 0.03). Reduced right ventricular end-diastolic volume (p <0.01) and stroke volume (p = 0.02) were associated with mortality. In conclusion, in patients with systemic amyloidosis, LGE is highly sensitive and specific for the identification of cardiac involvement but does not predict survival. LGE is strongly correlated with heart failure severity as assessed by BNP.

Skin-derived microorgan autotransplantation as a novel approach for therapeutic angiogenesis.

Despite promising preclinical results, transient single-factor-based therapeutic angiogenesis has shown no definitive benefits in clinical trials. The use of skin-derived microorgans (SMOs), capable of sustained expression of angiogenic factors and sustained viability with their cellular and extracellular elements, constitutes an attractive alternative. We sought to evaluate the efficacy of SMO implantation in a porcine model of chronic myocardial ischemia. Eighteen pigs underwent placement of an ameroid constrictor on the proximal circumflex artery. Three weeks later, split-thickness skin biopsies were harvested and pigs were randomized to lateral wall implantation of either 8 or 16 SMOs or blank injections. The procedure was safe and resulted in no adverse events. Three weeks after treatment, SMO implantation resulted in significant improvement of lateral wall perfusion during pacing, assessed by isotope-labeled microspheres [post- vs. pretreatment ratios of lateral/anterior wall blood flow were 1.31 +/- 0.09 (SMOs) and 1.04 +/- 0.06 (controls); P = 0.03]. No significant difference in angiographic scores was observed. Microvascular relaxation in response to VEGF was impaired in the ischemic territory of the control group but returned to normal after SMO implantation, indicating restoration of endothelial function. Molecular studies showed significant increases in VEGF and CD31 expression in the ischemic area of treated animals. Morphometric analysis showed increased neovascularization with SMO treatment. Autotransplantation of SMOs constitutes a novel approach for safe and effective therapeutic angiogenesis with improvement in perfusion, normalization of microvascular reactivity, and increased expression of VEGF and CD31.

Coronary magnetic resonance imaging.

This article highlights the technical challenges and general imaging strategies for coronary MRI. This is followed by a review of the clinical results for the assessment of anomalous CAD, coronary artery aneurysms, native vessel integrity, and coronary artery bypass graft disease using the more commonly applied MRI methods. It concludes with a brief discussion of the advantages/disadvantages and clinical results comparing coronary MRI with multidetector CT (MDCT) coronary angiography.

Coronary magnetic resonance imaging: current state-of-the-art.

Over the past decade, coronary magnetic resonance imaging has been transformed from a scientific curiosity to a clinically useful imaging tool for patients with known or suspected anomalous coronary arteries or coronary artery aneurysms and for assessment of coronary artery bypass graft patency. Coronary magnetic resonance imaging also appears to be of clinical value for assessment of native vessel integrity in selected patients, especially those patients with suspected left main/multivessel disease. Among patients referred for X-ray angiography, a normal coronary magnetic resonance imaging strongly suggests the absence of severe multivessel disease. Technical and methodological advances in motion suppression, along with increasing clinical experience will no doubt facilitate improved visualization of the distal and branch vessel.

The incremental value of troponin-I testing in patients with intermediate risk unstable angina.

BACKGROUND: Classification of patients with unstable angina (UA) by Agency for Health Care Policy and Research (AHCPR) guidelines in the emergency department reliably stratifies risk of death or myocardial infarction (MI) for triage to outpatient evaluation (low-risk), hospitalization (high-risk), or additional testing (intermediate-risk). Cardiac troponin-I elevation may identify patients at higher risk, but the incremental value may vary with AHCPR clinical risk. HYPOTHESIS: The objective of this study was to determine whether cardiac troponin-I had any additional value beyond triage based upon history, physical examination, and electrocardiogram, in the evaluation of patients with UA. METHODS: In all, 212 consecutive patients with UA and normal serum creatine kinase (CK)-MB levels and elevated troponin-I were risk stratified by AHCPR guidelines to evaluate the incremental value of adding routine troponin-I measurements to our current model for risk stratification. RESULTS: Primary events (death/nonfatal MI) occurred in 35% of high-risk, 15% of intermediate-risk, and 0% of low-risk patients (p < 0.001 by chi-square for trend). High troponin-I (> or =2.0 ng/dl) occurred in 48% of high-risk, 21% of intermediate-risk, and 19% of low-risk patients. The remaining patients in each risk group had indeterminate troponin-I levels (> or =0.4 < 2 ng/dl). Of those with high troponin-I, a primary event occurred in 36, 42, and 0% in the respective high-, intermediate-, and low-risk groups (p < 0.001). High troponin-I levels corresponded with a statistically significant increased rate of primary events only in patients at AHCPR intermediate risk: 42.4 vs. 7.3%, p < 0.001. CONCLUSION: The AHCPR guidelines risk stratify patients with UA. High troponin-I adds significant (p < 0.001) prognostic value in the patients at AHCPR intermediate risk and should be evaluated further in larger trials of such patients.