Characteristics of ventricular tachycardia and long-term treatment outcome in patients with dilated cardiomyopathy complicated by lamin A/C gene mutations.

BACKGROUND: Dilated cardiomyopathy caused by lamin A/C gene (LMNA) mutation is complicated with atrioventricular (AV) conduction disturbances, malignant ventricular arrhythmias, and progressive severe heart failure. Radiofrequency catheter ablation (RFCA) of ventricular tachycardia (VT) has been reported to be challenging due to the high recurrence rate in patients with LMNA-related cardiomyopathy. However, electrophysiological and histopathological characteristics of VT substrate remain to be fully elucidated. METHODS AND RESULTS: We experienced 6 familial patients with LMNA-related cardiomyopathy in 3 pedigrees (6 males, 43.7±4.5 [SD] years). All patients had first VT attack at 50±6.6 [SD] years of age, and 4 underwent RFCA for incessant VT. Their electrocardiograms during VT showed similar QRS morphologies, characterized by an inferior axis, SR pattern in aVR, and QS pattern in aVL, suggesting the origin of the basal anterior ventricle. Indeed, the VTs had multiple exits around the basal anterior ventricular septum in all RFCA cases. Although we performed multiple RFCA procedures including epicardial ablation and surgical cryoablation, all cases experienced VT recurrences in 4.5±6.4 [SD] months after last procedure. All patients developed end-stage heart failure with frequent VT events, and died at 59.5±3.6 years of age (severe heart failure in 5 and lung disease in 1). In three autopsy cases with RFCA, fibrofatty degeneration was noted in the AV node. In addition, in the deep basal ventricular septum, inhomogenous fibrotic degenerated tissue was noted beyond the reach of RF lesions. CONCLUSIONS: These results demonstrate that patients with LMNA-related cardiomyopathy are characterized by VTs refractory to RFCA probably because of the deep intramural focus at the basal ventricular septum, resulting in poor prognosis with progressive severe heart failure despite all available optimized therapies. Thus, we should consider heart transplantation in their early 50s when several VT events begin to occur.

Lamin A/C gene mutations in familial cardiomyopathy with advanced atrioventricular block and arrhythmia.

Lamin A and C proteins, encoded by the lamin A/C gene (LMNA), are inner nuclear membrane proteins predominantly expressed in terminally differentiated cells. Mutations in LMNA can cause various forms of cardiomyopathy with arrhythmia in an autosomal dominant manner. We collected and evaluated the clinical characteristics of unclassified familial cardiomyopathy with advanced AV block and sporadic cases with advanced AV block. Mutation in LMNA was directly screened using the cycle sequencing method in 5 probands of the familial cardiomyopathy and 60 sporadic cases with advanced AV block. In four of the five familial cases (80%), we identified four distinct mutations: two protein-truncation mutations, R225X and 815_818delinsCCAGAC, and two missense mutations, Y259H and R166P. No sporadic cases carried LMNA mutation. Left ventricular end-diastolic diameter (LVEDD) was slightly enlarged in LMNA mutant carriers (123.5 +/- 9.5%) as well as in non-carriers (125.1 +/- 13.3%), while left ventricular fractional shortening (LVFS) was preserved in LMNA mutant carriers (32.3 +/- 4.8%) and non-carriers (37.6 +/- 6.8%). In LMNA mutation carriers, the average age at onset of advanced AV block is significantly lower than that in non-carriers (43.7 +/- 9.5 vs. 65.3 +/- 13 yr., p < 0.01). Ventricular tachycardia, sudden death, and poor prognosis were observed in LMNA mutation carriers. LMNA mutation could cause familial cardiomyopathy with insignificant LV remodeling, early-age onset of advanced AV block, and lethal ventricular arrhythmia. Screening of LMNA mutation might be beneficial for risk stratification and clinical management of this type of unclassified familial cardiomyopathy.

Statin ameliorates hypoxia-induced pulmonary hypertension associated with down-regulated stromal cell-derived factor-1.

AIMS: Mobilization of stem cells/progenitors is regulated by the interaction between stromal cell-derived factor-1 (SDF-1) and its ligand, CXC chemokine receptor 4 (CXCR4). Statins have been suggested to ameliorate pulmonary arterial hypertension (PAH); however, the mechanisms involved, especially their effects on progenitors, are largely unknown. Therefore, we examined whether pravastatin ameliorates hypoxia-induced PAH in mice, and if so, which type of progenitors and what mechanism(s) are involved. METHODS AND RESULTS: Chronic hypoxia (10% O(2) for 5 weeks) increased the plasma levels of SDF-1 and mobilization of CXCR4(+)/vascular endothelial growth factor receptor (VEGFR)2(+)/c-kit(+) cells from bone marrow (BM) to pulmonary artery adventitia in Balb/c mice in vivo, both of which were significantly suppressed by simultaneous oral treatment with pravastatin (2 mg/kg/day). Furthermore, in vitro experiments demonstrated that hypoxia enhances differentiation of VEGFR2(+)/c-kit(+) cells into alpha-smooth muscle actin(+) cells. Importantly, pravastatin ameliorated hypoxia-induced PAH associated with a decrease in the number of BM-derived progenitors accumulating in the pulmonary artery adventitia. The expression of intercellular adhesion molecule-1 (ICAM-1) and its ligand, CD18 (beta2-integrin), were enhanced by hypoxia and were again suppressed by pravastatin. CONCLUSIONS: These results suggest that pravastatin ameliorates hypoxia-induced PAH through suppression of SDF-1/CXCR4 and ICAM-1/CD18 pathways with a resultant reduction in the mobilization and homing of BM-derived progenitor cells.

Endogenous erythropoietin system in non-hematopoietic lineage cells plays a protective role in myocardial ischemia/reperfusion.

OBJECTIVE: Recent studies suggested that erythropoietin (Epo) receptors (EpoR) are expressed not only in the hematopoietic lineage cells but also in the heart and that the administration of recombinant human Epo elicits protective effects in myocardial ischemia and reperfusion (I/R). We tested our hypothesis that endogenous Epo signals mediated by EpoR expressed in the non-hematopoietic lineage cells play a protective role against myocardial I/R injury. METHODS: Transgene-rescued EpoR null mutant mice (RES), which express EpoR exclusively in the hematopoietic lineage cells, were subjected to 30 min left coronary artery occlusion followed by reperfusion. RESULTS: Hematocrit, heart rate, blood pressure, heart weight, and echocardiographic parameters were comparable between wild-type mice (WT) and RES under the baseline condition. After 24 h of reperfusion, the infarct size in RES with I/R (RES/MI) was larger than that in WT/MI. Caspase-3 activity and number of TUNEL-positive cardiomyocytes in the ischemic area were increased in RES/MI compared with WT/MI. The extents of p38 and JNK phosphorylations in the ischemic area were significantly increased in WT/MI, but not in RES/MI as compared with corresponding sham-operated mice. Plasma Epo concentration in RES/MI did not differ from that in sham-operated RES, while that in WT/MI was peaked at 24 h post I/R. Additionally, left ventricular (LV) end-diastolic diameter was increased and LV fractional shortening tended to be reduced in the RES/MI compared with WT/MI at 21 days after I/R. CONCLUSIONS: These results suggest that the endogenous Epo-EpoR system in the non-hematopoietic lineage cells plays an important protective role against myocardial I/R injury.

Important role of endogenous erythropoietin system in recruitment of endothelial progenitor cells in hypoxia-induced pulmonary hypertension in mice.

BACKGROUND: Recent studies have suggested that endogenous erythropoietin (Epo) plays an important role in the mobilization of bone marrow-derived endothelial progenitor cells (EPCs). However, it remains to be elucidated whether the Epo system exerts protective effects on pulmonary hypertension (PH), a fatal disorder encountered in cardiovascular medicine. METHODS AND RESULTS: A mouse model of hypoxia-induced PH was used for study. We evaluated right ventricular systolic pressure, right ventricular hypertrophy, and pulmonary vascular remodeling in mice lacking the Epo receptor (EpoR) in nonerythroid lineages (EpoR(-/-) rescued mice) after 3 weeks of exposure to hypoxia. Those mice lack EpoR in the cardiovascular system but not in the hematopoietic system. The development of PH and pulmonary vascular remodeling were accelerated in EpoR(-/-) rescued mice compared with wild-type mice. The mobilization of EPCs and their recruitment to the pulmonary endothelium were significantly impaired in EpoR(-/-) rescued mice. By contrast, reconstitution of the bone marrow with wild-type bone marrow cells ameliorated PH in the EpoR(-/-) rescued mice. Hypoxia enhanced the expression of EpoR on pulmonary endothelial cells in wild-type but not EpoR(-/-) rescued mice. Finally, hypoxia activated endothelial nitric oxide synthase in the lungs in wild-type mice but not in EpoR(-/-) rescued mice. CONCLUSIONS: These results indicate that the endogenous Epo/EpoR system plays an important role in the recruitment of EPCs and prevents the development of PH during chronic hypoxia in mice in vivo, suggesting the therapeutic importance of the system for the treatment of PH.

Accumulation of risk markers predicts the incidence of sudden death in patients with chronic heart failure.

BACKGROUND: Sudden death is common in chronic heart failure (CHF). Risk stratification is the first step for primary prevention. AIM: To evaluate the use of risk markers for estimating sudden death risk. METHODS AND RESULTS: We prospectively examined 680 stable patients with CHF. Risk markers were evaluated using the Cox's proportional hazard model in a stepwise manner. Ejection fraction <30%, left ventricular end-diastolic diameter >60 mm, brain natriuretic peptide >200 pg/ml, non-sustained ventricular tachycardia, and diabetes were significantly associated with increased risk of sudden death. When the number of risk markers were included as co-variables, only "number of risk markers >or=3'' entered the model (hazard ratio 8.95, 95% confidence interval 4.57-17.52), while the effects of individual markers did not enter the model. The annual mortality from sudden death was 11% in patients with 3 or more risk markers and 1.4% in patients with 2 or less. CONCLUSIONS: Rather than particular risk markers, the number of accumulated risk markers was a more powerful predictor for sudden death in patients with CHF. The number of risk markers could be useful for risk stratification of sudden death.

Prognostic value of plasma brain natriuretic peptide combined with left ventricular dimensions in predicting sudden death of patients with chronic heart failure.

BACKGROUND: We evaluated a combined assessment of brain natriuretic peptide (BNP) with left ventricular dimensions as a prognostic marker for sudden death in patients with chronic heart failure (CHF). Ventricular dimensions and BNP are separately recognized as prognostic markers for sudden death in patients with CHF. METHODS AND RESULTS: CHF patients at Stage C and B were registered for a prospective study. From the database, we analyzed 417 patients with coronary arterial disease (CAD) or primary/secondary dilated cardiomyopathy (DCM). Main effects of BNP, left ventricular ejection fraction (EF), LV diastolic dimension (LVDD), and interaction of BNP with the EF and LVDD were tested with Cox's proportional hazard model. BNP in sudden death patients was significantly higher than that in event-free patients. Although multivariate analysis revealed that BNP by itself was not an independent risk factor for sudden death after adjustments, it was revealed that BNP entered the model via interaction with EF as a risk factor associating with sudden death. On the other hand, BNP was an independent risk factor associating with heart failure events (death and hospitalization), and BNP did not enter the model via an interaction with EF. CONCLUSION: BNP by itself was an independent risk factor for the heart failure events, but not for sudden death in CHF patients of the present study. However, BNP should be important in predicting sudden death when measured with EF.

Electrophysiological and histopathological characteristics of progressive atrioventricular block accompanied by familial dilated cardiomyopathy caused by a novel mutation of lamin A/C gene.

UNLABELLED: Conduction defect caused by lamin A/C gene mutation. INTRODUCTION: Mutations of lamin A/C gene (LMNA) cause dilated cardiomyopathy (DCM) with atrioventricular (AV) conduction defect, although the electrophysiological and histological profiles are not fully understood. METHODS AND RESULTS: We analyzed a large Japanese family (21 affected and 203 unaffected members) of DCM with AV block. The responsible LMNA mutation of IVS3-10A>G was novel and caused an aberrant splicing. The first clinical manifestation was low-grade AV block or atrial fibrillation (AF), which developed in affected members aged >or=30 years. We observed that the AV block progressed to third-degree within several years. The electrophysiological study of the four affected members revealed an impairment of intra-AV nodal conduction. Because of advanced AV block, pacemakers were implanted in 14 out of 21 affected members at the mean age of 44 years. Three affected members died suddenly and two affected members died of heart failure and/or ventricular tachycardia (VT) even after the pacemaker implantation. Postmortem examination showed conspicuous fibrofatty degeneration of the AV node. Endomyocardial biopsies showed remarkably deformed nuclei and substantial glycogen deposits in the subsarcolemma. CONCLUSION: The clinical phenotype in this family was characterized by (1) the first manifestation of the prolonged PQ interval or AF in adolescence, (2) progressive intra-AV nodal block to the third degree in several years, and (3) progressive heart failure after pacemaker implantation. Histological study revealed preferential degeneration at the AV node area and novel cellular damages in the working myocardium.

Characteristics and 1-year prognosis of medically treated patients with chronic heart failure in Japan.

The study was designed to characterize patients with chronic heart failure (CHF) in Japan in terms of the etiologies and prognosis. CHF was defined by ejection fraction (EF >or=50%), left ventricular diastolic dimension (LVDD >or=55 mm) or a past history of congestive heart failure. Among the 721 recruited patients, the most frequent etiology for CHF was dilated cardiomyopathy (DCM) in patients aged less than 59 years, and valvular heart disease (VHD) in those aged 70 years or more. The 1-year crude mortality was 8% overall and 12% in patients with myocardial infarction (MI). Sudden death accounted for 40% of the total deaths among all patients, and 60% in patients with MI. Multivariate logistic regression analysis showed that brain natriuretic peptide (BNP) was a consistent prognostic marker in CHF patients with a variety of etiologies. Total death and hospitalization because of heart failure were significantly less frequent in patients with BNP less than 100 pg/ml. In conclusion, the etiologies of Japanese CHF appear to be more diverse than those of other Western countries, but BNP is an excellent prognostic marker despite the etiological diversity. Sudden, unexpected death in CHF patients is also a serious problem in Japan. A nation-wide epidemiologic study should be done to characterize Japanese CHF.