Missense mutations in the beta-myosin heavy-chain gene cause central core disease in hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is an important cause of sudden death in apparently healthy young individuals. In less than half of kindreds with HCM, the disease is linked to the beta-myosin heavy-chain gene locus (MYH7). We have recently described two missense MYH7 gene mutations [Arg-403 to Gln (R403Q) and Leu-908 to Val (L908V)] and found that the mutant message is present in skeletal muscle soleus) and that the mutant beta-myosin obtained from soleus muscle has abnormal in vitro motility activity. Having identified a second kindred with the R403Q mutation, and 3 other kindreds with two additional mutations (G741R and G256E), we performed histochemical analysis of soleus muscle biopsies from 25 HCM patients with one of these four mutations. Light microscopic examination of the NADH-stained biopsies revealed the presence of central core disease (CCD) of skeletal muscle, a rare autosomal dominant nonprogressive myopathy characterized by a predominance of type I "slow" fibers and an absence of mitochondria in the center of many type I fibers. CCD was present in 10 of 13 patients with the L908V mutation, 5 of 8 patients with the R403Q mutation, 1 of 3 patients with the G741R mutation, and 1 patient with the G256E mutation. Mild-to-moderate myopathic changes with muscle fiber hypertrophy were present in 16 patients. Notably, CCD was present in 2 adults and 3 children with the L908V mutation who did not have cardiac hypertrophy. In contrast, soleus muscle samples from 5 patients from 4 kindreds in which HCM was not linked to the MYH7 locus showed no myopathy or CCD. Soleus muscle biopsies from 5 control subjects also showed normal histology. This work demonstrates that (i) MYH7-associated HCM is often a disease of striated muscle but with predominant cardiac involvement and (ii) a subset of HCM patients with MYH7 gene missense mutations have CCD.     

Altered cardiac hemodynamic and electrical state in normal sinus rhythm after chronic dual-chamber pacing for relief of left ventricular outflow obstruction in hypertrophic cardiomyopathy.

Dual-chamber (DDD) pacing relieves left ventricular (LV) outflow tract obstruction in patients with hypertrophic cardiomyopathy. The reduction in LV outflow gradient persists in some patients after cessation of pacing. Twelve-lead and signal-averaged electrocardiograms were obtained before and after 12 weeks of DDD pacing in 18 patients with obstructive hypertrophic cardiomyopathy to determine whether the altered hemodynamic state after chronic pacing is accompanied by electrical changes. Hemodynamic studies were performed at baseline and at follow-up. Signal-averaged electro-cardiograms were obtained using a Corazonix Predictor and bidirectional filters at 25 Hz to a noise level of less than 0.5 microV. At follow-up, LV outflow tract gradients were reduced significantly during DDD pacing and with cessation of pacing in sinus rhythm by 56 +/- 10 and 47 +/- 10 mm Hg, respectively (p less than 0.001). There was no simple relation between changes in LV outflow tract gradient and in the electrocardiogram. For example, amplitude of the R wave in V5,6 was reduced by greater than or equal to 0.5 mv in 4 patients, unchanged in 12 and increased in 2. Similarly, the S wave in leads V1,2 was reduced in 7 patients, unchanged in 7 and increased in 4. The T wave became more negative (greater than or equal to 0.1 mv) in leads II, III, aVF and V5,6 in 13 patients and more positive in leads I and aVL in 12.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacology of N-desmethylclozapine

Currently available treatments for schizophrenia have limited efficacy and are generally poorly tolerated. However, among these antipsychotic agents, clozapine stands apart in having generally superior motoric tolerability and efficacy. One intriguing possibility, based on clinical correlations, receptor activity profiles and studies with animal models predictive of antipsychotic or cognitive action is that the activity of N-desmethylclozapine (NDMC), a major metabolite of clozapine, may, at least in part, underlie the unique efficacy of clozapine. In this review we compare the pharmacological properties of NDMC to those of clozapine and consider how they may contribute to the overall clinical properties of clozapine. We also consider whether NDMC, in its own right, might be a superior antipsychotic drug.     

Assessment of regional systolic and diastolic dysfunction in familial hypertrophic cardiomyopathy using MR tagging.

Diastolic and systolic left ventricular (LV) dysfunction often significantly contribute to disabling symptoms in familial hypertrophic cardiomyopathy (FHC). This study compares regional LV function (midwall circumferential strain) during systole and diastole in eight FHC patients and six normal volunteers (NVs) using MR tagging. A prospectively-gated fast gradient-echo sequence with an echo-train readout was modified to support complementary spatial modulation of magnetization (CSPAMM) tagging and full cardiac cycle data acquisition using the cardiac phase to order reconstruction (CAPTOR), thus providing tag persistence and data acquisition during the entire cardiac cycle. Total systolic strains in FHC patients were significantly reduced in septal and inferior regions (both P < 0.01). Early-diastolic strain rates were reduced in all regions of the FHC group (all P < 0.03). The combination of CSPAMM and CAPTOR allows regional indices of myocardial function to be quantified throughout the cardiac cycle. This technique reveals regional differences in systolic and diastolic impairment in FHC patients.     

Practical dose reduction tips for abdominal interventional procedures using CT-guidance

Reducing the radiation dose should be an endeavor not only for diagnostic CT exams but also for interventional procedures using CT-guidance. Given that interventional procedures vary in scope and complexity, there is greater variability in radiation doses delivered during CT procedures. The goal in an interventional procedure is simply to advance the interventional instruments into the target lesions, and as such diagnostic level doses are not required and only narrow scan range scans need to be acquired. Adherence to the principles outlined in this article will allow such procedures to be performed with reduced radiation doses.     

Differential regulation of muscarinic M1 receptors by orthosteric and allosteric ligands

Allosteric modulation of membrane receptors is a widespread mechanism by which endogenous and exogenous agents regulate receptor function. For example, several members of the nicotinic receptor family are modulated by physiological concentrations of extracellular calcium ions. In this paper, we examined conformational changes underlying this modulation and compare these with changes evoked by ACh. Two sets of residues in the α7 acetylcholine receptor extracellular domain were mutated to cysteine and analyzed by measuring the rates of modification by the thiol-specific reagent 2-aminoethylmethane thiosulfonate. Using Ba²⁺ as a surrogate for Ca²⁺, we found a divalent-dependent decrease the modification rates of cysteine substitutions at M³⁷ and M⁴⁰, residues at which rates were also slowed by ACh. In contrast, Ba²⁺ had no significant effect at N⁵²C, a residue where ACh increased the rate of modification. Thus divalent modulators cause some but not all of the conformational effects elicited by agonist. Cysteine substitution of either of two glutamates (E⁴⁴ or E¹⁷²), thought to participate in the divalent cation binding site, caused a loss of allosteric modulation, yet Ba²⁺ still had a significant effect on modification rates of these residues. In addition, the effect of Ba²⁺ at these residues did not appear to be due to direct occlusion. Our data demonstrate that modulation by divalent cations involves substantial conformational changes in the receptor extracellular domain. Our evidence also suggests the modulation occurs via a binding site distinct from one which includes either (or both) of the conserved glutamates at E⁴⁴ or E¹⁷².     

Skeletal muscle expression and abnormal function of beta-myosin in hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy is an important inherited disease. The phenotype has been linked, in some kindreds, to the beta-myosin heavy chain (beta-MHC) gene. Missense and silent mutations in the beta-MHC gene were used as markers to demonstrate the expression of mutant and normal cardiac beta-MHC gene message in skeletal muscle of hypertrophic cardiomyopathy patients. Mutant beta-myosin, also shown to be present in skeletal muscle by Western blot analysis, translocated actin filaments slower than normal controls in an in vitro motility assay. Thus, single amino acid changes in beta-myosin result in abnormal actomyosin interactions, confirming the primary role of missense mutations in beta-MHC gene in the etiology of hypertrophic cardiomyopathy.