Serum free-carnitine levels were determined in 973 unrelated white collar workers in Akita, Japan. Fourteen of these participants consistently had serum free-carnitine levels below the fifth percentile (28 microM for females and 38 microM for males). The OCTN2 (organic cation transporter) gene was sequenced for these 14 subjects, for 22 subjects whose carnitine levels were below the fifth percentile in the first screening but were normal in the second measurement and in 69 individuals with normal carnitine levels for two separate measurements. Polymorphic sequences defined three major haplotypes with equal frequency. Mutations were identified in nine subjects with low carnitine levels: Trp132X (three individuals), Ser467Cys (four), Trp283Cys (one) and Met179Leu (one). In vitro expression studies in HEK cells indicated that Ser467Cys and Trp283Cys, but not Met179Leu, significantly reduced L-carnitine uptake relative to the normal control. Trp132X and Ser467Cys were associated with specific haplotypes, suggesting a founder effect. A conservative estimate of the overall prevalence of heterozygotes was 1.01% in the Akita prefecture, Japan, giving an estimated incidence of primary systemic carnitine deficiency (MIM 212140) as 1 in 40 000 births. An echocardiographic study of the families of patients with primary carnitine deficiency revealed that the heterozygotes for OCTN2 mutations were predisposed to late onset benign cardiac hypertrophy (odds ratio 15.1, 95% CI 1.39-164) compared with the wild-types. Sequencing of DNA isolated from three deceased siblings (1.5-8 years) in two families retrospectively confirmed that all three deceased subjects were homozygous for the OCTN2 mutations.

SUMMARY 1. The rat intermediate conductance calcium‐activated potassium channel (ImK) was cloned from a cDNA library of vascular smooth muscle cells (VSM) in rat pulmonary artery. The ImK distributes in a variety of tissue, including VSM, endothelial cells, leucocytes and fibroblasts. The ImK has a tyrosine phosphorylation consensus site in the proximal portion of the C‐terminus and motifs exist for the DNA‐binding protein AP‐1 in the promoter, suggesting this channel is upregulated and active in cell cycle functions. The aim of the present study was to examine the role of ImK in postischaemic cardiovascular remodelling in relation to the angiotensin AT1 receptor‐mediated AP‐1 signalling pathway. 2. Rats underwent left coronary artery ligation for periods between 1 day and 3 weeks. The temporal profile of expression of ImK mRNA was analysed by RNase protection assay. To test the effect of AT1 receptor blockade, candesartan (3 mg/kg per day) was administered via an osmotic mini‐pump implanted in the intraperitoneal space 3 days prior to coronary occlusion. 3. ImK expression in postischaemic hearts showed a significant increase with two distinct peaks; the first peak at day 3 (2.7‐fold compared with control levels; P < 0.001) and the second after 2 weeks (1.5‐fold; P < 0.01). Reperfusion following 30 min of ischaemia markedly accelerated and augmented the first peak at days 1–3 (4.8‐fold), but completely abolished the second peak after 1–2 weeks (0.8‐fold). In situ hybridization of ImK mRNA and immunostaining of ImK protein with specific antibody revealed that this was not only the result of the increase in ImK expression in vascular cells, but also related to infiltration of mononuclear leucocytes and fibroblasts into the ischaemic region. Candesartan inhibited cardiac hypertrophy and perivascular fibrosis of coronary arterioles in the non‐ischaemic region. Candesartan also abrogated both peaks in ImK expression. 4. These findings indicate that both the inflammatory reaction and the postischaemic cardiovascular remodelling promote increased expression of ImK in postischaemic hearts via the AT1 receptor‐mediated AP‐1 signalling pathway.

We have reported that intermediate conductance Ca²⁺-activated K⁺ channels (ImK) showed augmented expression in angiotensin II (AII) type 1 receptor-dependent manner in post-ischemic rat heart. ImK has tyrosine phosphorylation sequence in the C-terminus and motifs for NFĸB and AP1 in the promoter. While statin inhibits AII-mediated vascular remodeling via anti-inflammatory effect independent of cholesterol lowering. To test the possible effect of statin on expression of ImK, Wistar-Kyoto rats received L-nitro-arginine methyl ester (LNAME: 1 mg/ml in drinking water) for 4 weeks in group L. While in L+P group, rats received both LNAME and pitavastatin (PTV: 1 mg/kg/day in drinking water). Temporal profile of ImK mRNA was examined by RT-PCR using specific primers for ImK. Results: Long-term LNAME administration produced significant hypertension and resulted in marked microvascular remodeling characterized by medial thickening and perivascular fibrosis of coronary arterioles (100–200 µm in diameter). RT-PCR revealed significant up-regulation of ImK mRNA with two distinct peaks in L group in the early phase (days 3–7) and the late phase (4 weeks). PTV partially inhibited a rise in systolic blood pressure, but completely abolished the first peak of ImK upregulation (0.76 ± 0.04 vs. 3.96 ± 1.43 folds at day 7, p < 0.001). Co-treatments with PTV also significantly inhibited medial thickening and perivascular fibrosis. These findings indicate that statin inhibits microvascular remodeling induced by chronic inhibition of NO synthesis through the action independent of cholesterol lowering.

t has been well established that dual-chamber pacing reduces the pressure gradients in the left ventricular outflow tract (LVOT) and improves the symptoms of hypertrophic obstructive cardiomyopathy. [1][2][3][4][5] However, the effect of pacing therapy on a hypertrophic mid-ventricular obstruction (MVO) with an apical aneurysm has rarely been described 6 and we report such a case that was dramatically improved by dual-chamber pacing.This report is of special interest from 2 points of view. We demonstrate, on the basis of this case, that the pacing therapy was effective in not only reducing intraventricular pressure gradient, but also in preventing sustained ventricular tachycardia (VT). Secondly, we are the first to attempt to evaluate the intraventricular flow dynamics during pacing in such a case. Case ReportA 63-year-old woman suffered chest discomfort with a syncope attack and was admitted to hospital. Her past history and familial history were unremarkable. The 12-lead electrocardiogram (ECG) on admission showed sustained monomorphic VT (170 beats/min) with a right bundle branch block pattern in V1 and a QS pattern in leads I, II, III, aVF and V2-6, and an axis of -140°. These findings were Circulation Journal Vol.66, October 2002 similar to those seen with VT originating from the septoapical area of the left ventricle (Fig 1). 7 After spontaneous recovery to sinus rhythm 40 s later, the ECG showed negative T waves in leads I, II, III, aVF and V1-6 with slight ST elevation in III, aVF and V4 (Fig 1). Holter monitoring showed 2 episodes of sustained monomorphic VT (30-40 s), 1,220 episodes of nonsustained monomorphic VT and 355 episodes of couplet ventricular extrasystoles per day. Although a -blocking agent is the drug of choice, it did not completely suppress the VT. The 2-dimensional echocardiographic examination revealed left mid-ventricular hypertrophy at the papillary muscle level and a discrete Invasive assessment of intraventricular pressure showed a peak-to-peak gradient greater than 100 mmHg. Treatment with antiarrhythmic agents could not prevent the VT, but dual-chamber pacing reduced the intraventricular pressure gradient and suppressed the VT completely. Continuous wave Doppler showed that the early systolic ejection flow from the apex had disappeared, that there was isovolumetric relaxation flow toward the apex and that there was attenuation of the diastolic paradoxical jet flow toward the basal chamber. Such findings by continuous wave Doppler can be useful in pacing therapy for evaluating changes in the severity of mid-ventricular obstruction. (Circ J 2002; 66: 981 -984)