Late gadolinium enhanced cardiovascular magnetic resonance of lamin A/C gene mutation related dilated cardiomyopathy.

BACKGROUND: The purpose of this study was to identify early features of lamin A/C gene mutation related dilated cardiomyopathy (DCM) with cardiovascular magnetic resonance (CMR). We characterise myocardial and functional findings in carriers of lamin A/C mutation to facilitate the recognition of these patients using this method. We also investigated the connection between myocardial fibrosis and conduction abnormalities. METHODS: Seventeen lamin A/C mutation carriers underwent CMR. Late gadolinium enhancement (LGE) and cine images were performed to evaluate myocardial fibrosis, regional wall motion, longitudinal myocardial function, global function and volumetry of both ventricles. The location, pattern and extent of enhancement in the left ventricle (LV) myocardium were visually estimated. RESULTS: Patients had LV myocardial fibrosis in 88% of cases. Segmental wall motion abnormalities correlated strongly with the degree of enhancement. Myocardial enhancement was associated with conduction abnormalities. Sixty-nine percent of our asymptomatic or mildly symptomatic patients showed mild ventricular dilatation, systolic failure or both in global ventricular analysis. Decreased longitudinal systolic LV function was observed in 53% of patients. CONCLUSIONS: Cardiac conduction abnormalities, mildly dilated LV and depressed systolic dysfunction are common in DCM caused by a lamin A/C gene mutation. However, other cardiac diseases may produce similar symptoms. CMR is an accurate tool to determine the typical cardiac involvement in lamin A/C cardiomyopathy and may help to initiate early treatment in this malignant familiar form of DCM.

Population-prevalent desmosomal mutations predisposing to arrhythmogenic right ventricular cardiomyopathy.

BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a progressive myocardial disorder caused by mutations of desmosomal cell adhesion proteins. The prevalence of these variants in the general population is unknown. OBJECTIVE: This study examined the spectrum and population prevalence of desmosomal mutations predisposing to ARVC in Finland. METHODS: We screened 29 Finnish ARVC probands for mutations in the DSP, DSG2, and DSC2 genes. All Finnish-type ARVC-associated mutations, including those 3 previously identified in PKP2 in the same patient group, were analyzed in the population-based Health 2000 cohort of 6,334 individuals and tested for association with electrocardiographic variables. RESULTS: We detected 2 novel mutations: DSG2 3059_3062delAGAG and DSP T1373A. DSG2 3059_3062delAGAG was present in a family with 5 mutation carriers. The endomyocardial samples of the DSG2 deletion carrier showed reduced immunoreactive signal for desmoglein-2, plakophilin-2, plakoglobin, and desmoplakin. DSP T1373A was found in 1 proband with typical right ventricular disease and exercise-related ventricular tachycardia. In the population sample, the collective prevalence of all 5 mutations identified in the 29 ARVC patients (PKP2 Q62K, Q59L, N613K, DSG2 3059_3062delAGAG, and DSP T1373A) was 31 of 6,334 individuals, or 0.5%. The apparent founder mutation PKP2 Q59L is present in 0.3% of Finns and was previously shown to have an approximately 20% disease penetrance. CONCLUSION: One of 200 Finns carries a desmosomal mutation that may predispose to ARVC and its clinical sequelae. ARVC-associated mutations may thus be more prevalent in the population than expected based on the published ARVC prevalence data.

Outcome of aortic valve replacement with bioprostheses in the elderly.

BACKGROUND AND AIM OF THE STUDY: Today, the elderly population continues to increase worldwide, and rates of aortic stenosis (AS) climb with age. Since aortic valve replacement (AVR) is the current treatment for elderly patients with symptomatic AS, the number of patients undergoing AVR is expected to grow. METHODS: Among patients operated on at Helsinki University Hospital between 1992 and 1997, a cohort (n = 145) was followed after AVR with a bioprosthesis. The patients were allocated to three groups, based on their age at the time of surgery: > or = 80 years (n = 30), < 80 to > or = 70 years (n = 94), and < or = 70 years (n = 21). All data relating to preoperative risk factors were collected. A control examination, which included echocardiography, was performed at least five years after surgery, and the follow up was continued until July 2006. The number of deaths and causes of death, as well as valve-related complications, were noted. RESULTS: The 30-day mortality rates were 3.3% in the oldest (> or = 80-year) group, 6.4% in the middle (< 80 to > or = 70-year) group, and zero in the youngest (< or = 70-year) group. The mean age at death was 88 and 81 years in the oldest and middle groups, respectively. In the oldest and youngest groups, there were no reoperations, but five valve-related reoperations were performed during follow up in the middle group. At the control visit, the left ventricular ejection fraction was > 60% in all groups. In the oldest and middle groups the aortic valve gradient was lower than the preoperative level, while the left ventricular diameters and wall dimensions were smaller (p < 0.05). Valve calcification was observed in one patient in the youngest group. CONCLUSION: Elderly patients who had undergone AVR with a bioprosthesis had a good outcome after more than 10 years of follow up, with an improved cardiac function being preserved for at least seven years after surgery. Despite a severely impaired preoperative aortic valve function, octogenarians especially had a good life expectancy, possibly due to their low comorbidity rates. Hence, AVR with a bioprosthesis proved to be an excellent treatment in this patient group.

Electrocardiographic ventricular repolarization during cardiovascular autonomic function testing in patients with arrhythmogenic right ventricular cardiomyopathy.

OBJECTIVES: Patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) experience exercise-related malignant arrhythmias possibly based on delayed repolarization in the diseased right ventricle (RV). Autonomic interventions might unveil repolarization abnormalities in RV. DESIGN: We recorded 25-lead electrocardiograms from nine symptomatic ARVC patients and nine controls during rest, Valsalva maneuver, mental stress, handgrip and supine exercise. Interventricular repolarization gradient was defined as difference of QT intervals between left ventricular (LV) and RV type leads. T-wave peak to T-wave end interval (TPE) was defined as the electrocardiographic (ECG) equivalent of transmural dispersion of repolarization. RESULTS: ARVC patients showed longer QT and TPE intervals in RV than in LV whereas control subjects showed the opposite. Valsalva strain reversed the interventricular repolarization gradient from -5+/-13 to 4+/-20 ms (p<0.02) and induced fluctuation of TPE in ARVC patients. CONCLUSIONS: ARVC patients show ECG interventricular repolarization gradient from RV to LV and increased ECG transmural dispersion of repolarization in RV. Valsalva strain induces fluctuation of interventricular repolarization gradient and of transmural dispersion of repolarization in RV possibly modifying the substrate for arrhythmias.

Plakophilin-2 missense mutations in arrhythmogenic right ventricular cardiomyopathy.

BACKGROUND: Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is an inherited cardiac disorder characterized by life-threatening ventricular arrhythmias and fibrofatty replacement of myocardial tissue. Recent data suggest a dominant mode of inheritance in ARVD due to mutations in desmosomal proteins, plakophilin-2 (PKP2) in particular. We carried out a search for PKP2 mutations in the Finnish population representing a genetic isolate. METHODS: Mutations were detected by direct sequencing of PKP2 exons in 29 unrelated ARVD patients. Subcellular changes in ARVD associated with PKP2 mutations were searched for using immunohistochemistry and electron microscopy. RESULTS: We identified three PKP2 amino acid substitutions, absent in controls, in three (10%) cases. Two of them (Q62K and N613K) co-occurred in a patient with arrhythmia and structural changes of the heart. Visualized with plakophilin-2 antibodies, the intercalated disks in this compound heterozygous ARVD sample appeared wavier than in non-ARVD controls. Partial irregularities were occasionally seen in the organization and distribution of the cell-cell junctions. Relatives carrying one of these mutant alleles were phenotypically normal or showed only limited electrocardiographic (ECG) changes. The third substitution (Q59L) was detected in two ARVD probands with ventricular tachycardias, ECG abnormalities and right ventricular structural alterations. CONCLUSIONS: We identified two novel plakophilin-2 missense mutations associated with 10% of ARVD, and a previously reported Q62K variant with a possible disease modifying role. The low prevalence of predominantly missense mutations may present population-specific differences in the pathogenesis of ARVD. Our preliminary data also suggest that ultrastructural cell junction abnormalities may associate with plakophilin-2 mutations.

Characterization of familial and sporadic arrhythmogenic right ventricular cardiomyopathy in Finland.

BACKGROUND: Autosomal dominant inheritance is reported in arrhythmogenic right ventricular cardiomyopathy (ARVC) but the prevalence of the familial and sporadic forms in the general population is unknown. AIM: To evaluate the familial occurrence and clinical features of ARVC in the genetically homogenous Finnish population. METHODS: The study included 29 Finnish ARVC index patients and 135 relatives from 21 families evaluated. They underwent echocardiography, 24-hour electrocardiographic monitoring, signal-averaged electrocardiography, and exercise stress test. RESULTS: Twenty-two index patients had ventricular arrhythmias as first manifestation, and three developed arrhythmias later. The right ventricle (RV) was mildly affected in 22 and strongly dilated in 7 index patients. Patients with dilated RV manifested first symptoms at younger age (mean 28 years) than those without RV dilatation (mean 38 years). Of the 135 relatives, ARVC was present in 12 (9%) patients belonging to 5 of the 21 families studied, resulting in 24% familial involvement. In addition, 46 relatives (34%) had subtle cardiac abnormalities, suggesting subclinical presentation. CONCLUSIONS: The ARVC in Finland presents with distinct arrhythmic and RV dilative subtypes. The sporadic disease is similar to the familial one which may reflect low penetration in relatives. The proportion of familial manifestation of ARVC in Finland seems comparable to that elsewhere in Europe.

Prognostic usefulness of plasma monocyte/macrophage and T-lymphocyte activation markers in patients with acute coronary syndromes.

Macrophages and T lymphocytes accumulate and are activated in atherosclerotic plaques. We tested the hypothesis that plasma levels of the monocyte/macrophage and T-lymphocyte activation markers, monocyte chemoattractant protein-1 (MCP-1) and soluble interleukin-2 receptor (sIL-2r), respectively, can be used in acute coronary syndrome classification and risk prediction. Blood samples were collected at hospital admissions of 183 patients who had ischemic chest pain. Of these, 59 had acute myocardial infarction, 60 had unstable angina, and 64 had angina pectoris. No significant differences in the levels or proportions of subjects with increased levels of MCP-1 or sIL-2r were found across groups. During a mean follow-up of 13 months, 117 patients (64%) had a study end point (i.e., cardiac death, recurrent myocardial infarction, unstable angina, or revascularization). Increased levels (above median) of MCP-1 and sIL-2r were associated with increased risk, with odds ratios of 1.85 (95% confidence interval 0.92 to 3.73, p = 0.08) and 2.34 (95% confidence interval 1.16 to 4.71, p <0.02), respectively. In summary, in this unselected patient population with a very high rate of coronary events during follow-up, increased plasma levels of MCP-1 and sIL-2r were helpful for predicting new coronary events.