-
[show abstract]
[hide abstract]
ABSTRACT: Our aim was to identify prognostic factors for an arrhythmic event (AE) in children with hypertrophic cardiomyopathy (HCM) without a previous AE. One hundred thirty-one nonconsecutive patients (≤ 20 years) with HCM but no previous AE were evaluated at the NIH Clinical Center from 1980 to 2001. At a median follow-up of 6.4 years, 22 patients experienced an AE [sudden death (SD) (n = 12), resuscitated cardiac arrest (n = 3), clinical sustained ventricular tachycardia (VT) (n = 2), and implantable cardiac defibrillator discharge (n = 5)], resulting in a 2% annual AE rate. Baseline factors that were most predictive in univariate risk analysis included ventricular septal thickness (ST) (P = 0.01), VT induction by programmed ventricular stimulation (PVS) (P = 0.01), age (P = 0.05), and presyncope/syncope (P = 0.05). In multivariate analysis, ST, age, presyncope/syncope, and PVS were not independently predictive of risk for an AE. However, the 5-year event rates for AE was 15% (95% CI: 5-23%) if ST ≥ 20 mm, 19% (95% CI: 6-31%) when age ≥ 13 years and ST ≥ 20 mm were combined together, and 23% (95% CI: 3-39%) when PVS and ST ≥ 20 mm were combined together. Of the various risk factors that were considered in our pediatric HCM cohort, ST and inducible VT were the most significant univariate predictors of risk for an AE. More traditional risk factors identified in older patients (family history of SD, VT on Holter, and exercise-induced hypotension) were not predictive of an AE in patients age under 21 years.
Pediatric Cardiology 04/2011; 32(8):1096-105. · 1.30 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: In patients with systolic heart failure, the ability of cardiopulmonary exercise testing (CPX) variables to reflect pathophysiology is well established. The relationship between CPX and pathophysiology has, however, not been thoroughly investigated in patients with nonobstructive hypertrophic cardiomyopathy (NHCM). The objective of this study was to assess the ability of CPX variables to reflect resting hemodynamics in patients with nonobstructive hypertrophic cardiomyopathy NHCM.
We performed CPX and right heart catheterization on 83 subjects with NHCM (51 male/32 female, mean age = 38 +/- 10 yr, NYHA I-III mean = 1.7). Peak oxygen consumption ( O2) and minute ventilation/carbon dioxide ratio (V E/VCO2) at peak exercise were compared to resting hemodynamics including pulmonary artery systolic, diastolic and mean pressures (PASP, PADP and MPAP), and pulmonary capillary wedge pressure (PCWP).
Elevations in PCWP (> or = 15 mm Hg), PASP (> or =30 and > or = 40 mm Hg), PADP (> 15 mm Hg) and MPAP (> or = 20 mm Hg) were detected in 22, 33, 10, and 23% of subjects, respectively. Peak V E/VCO2 (positive correlation) and peak VO2 (negative correlation) correlated modestly with all pressure measurements (r = 0.33-0.51, P < 0.01 for all measurements). By receiver operating curve analysis, a V E/VCO2 >35.5 exhibited the best diagnostic accuracy with a curve areas of 0.81 for PAP > or = 30 mm Hg (sensitivity/specificity = 86%/67%), 0.87 for PAP > or = 40 mm Hg (77%/100%), 0.86 for MPAP > 20 mm Hg (83%/79%), and 0.84 for PCWP > or = 15 mm Hg (80%/76%).
CPX can accurately identify abnormal resting hemodynamics in patients with NHCM. Further testing of this modality in other forms of diastolic dysfunction may be warranted.
Medicine & Science in Sports & Exercise 06/2008; 40(5):799-805. · 4.43 Impact Factor
-
Alexander Lossos,
Carol Dobson-Stone,
Anthony P Monaco,
Dov Soffer,
Ezra Rahamim,
J P Newman,
Saidi Mohiddin, Lameh Fananapazir,
Israela Lerer,
Eduard Linetsky,
Avinoam Reches,
Zohar Argov,
Oded Abramsky,
Natan Gadoth,
Menachem Sadeh,
John M Gomori,
Moshe Boher,
Vardiella Meiner
[show abstract]
[hide abstract]
ABSTRACT: Choreoacanthocytosis (CHAC) is a slowly progressive multisystem disorder with involuntary movements, cognitive decline, behavioral changes, seizures, and polyneuropathy caused by mutations in the VPS13A gene.
To describe the early clinical features and possible genotype-phenotype correlation in CHAC.
Case series in a tertiary care center. PATIENTS AND MAIN OUTCOME METHODS: Choreoacanthocytosis was diagnosed in 3 patients of Jewish origin from 3 unrelated families. We reviewed their medical histories and performed molecular analysis by screening all 73 exons of VPS13A.
Trichotillomania, hypertrophic cardiomyopathy, and idiopathic hyperCKemia, in 1 patient each, preceded the development of the full clinical spectrum of CHAC by 2 to 20 years. At diagnosis, 2 patients manifested signs of overt neuromuscular involvement and were homozygous for the 6059delC mutation, whereas 1 patient had only hyporeflexia and was homozygous for the EX23del mutation. Because only 1 of the 2 patients with 6059delC had cardiomyopathy, its relevance to CHAC is unclear.
These findings extend the knowledge of significant early clinical heterogeneity in CHAC and suggest a possible genotype-phenotype correlation. Awareness of the early manifestations may prevent misdiagnosis and enable appropriate genetic counseling.
Archives of Neurology 05/2005; 62(4):611-4. · 7.58 Impact Factor
-
Julie M Schultz,
Yandan Yang,
Ariel J Caride,
Adelaida G Filoteo,
Alan R Penheiter,
Ayala Lagziel,
Robert J Morell,
Saidi A Mohiddin, Lameh Fananapazir,
Anne C Madeo,
John T Penniston,
Andrew J Griffith
[show abstract]
[hide abstract]
ABSTRACT: Five adult siblings presented with autosomal recessive sensorineural hearing loss: two had high-frequency loss, whereas the other three had severe-to-profound loss affecting all frequencies. Genetic evaluation revealed that a homozygous mutation in CDH23 (which encodes cadherin 23) caused the hearing loss in all five siblings and that a heterozygous, hypofunctional variant (V586M) in plasma-membrane calcium pump PMCA2, which is encoded by ATP2B2, was associated with increased loss in the three severely affected siblings. V586M was detected in two unrelated persons with increased sensorineural hearing loss, in the other caused by a mutation in MYO6 (which encodes myosin VI) in one and by noise exposure, suggesting that this variant may modify the severity of sensorineural hearing loss caused by a variety of factors.
New England Journal of Medicine 05/2005; 352(15):1557-64. · 53.30 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The left atrium is afterload sensitive, responding to immediate changes in left ventricular (LV) diastolic pressure, and left atrial volumetric remodeling has been reported in conditions associated with abnormal diastolic function. We examined the relationship between left atrial volumetric remodeling and objective measures of exercise capacity in patients with nonobstructive hypertrophic cardiomyopathy (HCM).
We compared LA volume indices, other 2-dimensional and Doppler echocardiographic parameters, invasive hemodynamic measures, and magnetic resonance imaging (MRI)-derived LV mass with exercise duration, maximal oxygen uptake (MV* O2), anaerobic threshold (AT), and ventilatory efficiency (VE/V* CO2 slope) in 43 patients with nonobstructive HCM. Patients underwent cardiac catheterization within 48 hours and metabolic stress testing within 1 week of their echocardiogram and MRI examinations.
Left atrial volume at end-ventricular systole (LA max) and end-atrial emptying (LA min) correlated with MV* O2 (r = -0.39, P < .01 for both), AT (r = -0.42, r = -0.39, respectively, P < .01 for both), and VE/V* CO2 slope (r = 0.45, P = .003; r = 0.41, P = .008). Patients with an LA max > or =33 mL/m2 had significantly lower MV* O2 (P = .025) and AT levels (P = .017) and higher VE/V* CO2 slope levels (P = .004) as compared with patients with a smaller LA size. In multivariate analysis, MRI-determined LV mass, which was not a univariate correlate of exercise tolerance, provided additional effect when combined with LA volume index.
Left atrial volumetric remodeling predicts exercise capacity in nonobstructive HCM and may reflect chronic LV diastolic burden. This simple noninvasive measure of LA size may provide a long-term indication of the effects of chronically elevated filling pressures in patients with HCM and further studies testing its prognostic value are necessary.
American heart journal 04/2005; 149(4):730-6. · 4.65 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Autosomal dominant familial hypertrophic cardiomyopathy (FHC) has variable penetrance and phenotype. Heterozygous mutations in MYH7 encoding beta-myosin heavy chain are the most common causes of FHC, and we proposed that "enhanced" mutant actin-myosin function is the causative molecular abnormality. We have studied individuals from families in which members have two, one, or no mutant MYH7 alleles to examine for dose effects. In one family, a member homozygous for Lys207Gln had cardiomyopathy complicated by left ventricular dilatation, systolic impairment, atrial fibrillation, and defibrillator interventions. Only one of five heterozygous relatives had FHC. Leu908Val and Asp906Gly mutations were detected in a second family in which penetrance for Leu908Val heterozygotes was 46% (21/46) and 25% (3/12) for Asp906Gly. Despite the low penetrance, hypertrophy was severe in several heterozygotes. Two individuals with both mutations developed severe FHC. The velocities of actin translocation (V(actin)) by mutant and wild-type (WT) myosins were compared in the in vitro motility assay. Compared with WT/WT, V(actin) was 34% faster for WT/D906G and 21% for WT/L908V. Surprisingly V(actin) for Leu908Val/Asp906Gly and Lys207Gln/Lys207Gln mutants were similar to WT. The apparent enhancement of mechanical performance with mutant/WT myosin was not observed for mutant/mutant myosin. This suggests that V(actin) may be a poor predictor of disease penetrance or severity and that power production may be more appropriate, or that the limited availability of double mutant patients prohibits any definitive conclusions. Finally, severe FHC in heterozygous individuals can occur despite very low penetrance, suggesting these mutations alone are insufficient to cause FHC and that uncharacterized modifying mechanisms exert powerful influences.
AJP Heart and Circulatory Physiology 04/2005; 288(3):H1097-102. · 3.71 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The profound and progressive neurological features largely dominate the clinical course of neuroacanthocytosis. However, the
development of a cardiomyopathy is reported in up to two thirds of cases, and sudden death from cardiac arrest is not infrequent.
This review summarizes current understanding of familial hypertrophic and dilated cardiomyopathies and the cardiac findings
in the neuroacanthocytosis syndromes. Unraveling the molecular basis of neuroacanthocytosis may provide us with a novel cardiomyopathic
mechanism.
12/2004: pages 139-152;
-
Sergey V Ivanov,
Jerrold M Ward,
Lino Tessarollo,
Dorothea McAreavey,
Vandana Sachdev, Lameh Fananapazir,
Melissa K Banks,
Nicole Morris,
Draginja Djurickovic,
Deborah E Devor-Henneman,
Ming-Hui Wei,
Gregory W Alvord,
Boning Gao,
James A Richardson,
John D Minna,
Michael A Rogawski,
Michael I Lerman
[show abstract]
[hide abstract]
ABSTRACT: CACNA2D2 is a putative tumor suppressor gene located in the human chromosome 3p21.3 region that shows frequent allelic imbalances in lung, breast, and other cancers. The alpha2delta-2 protein encoded by the gene is a regulatory subunit of voltage-dependent calcium channels and is expressed in brain, heart, and other tissues. Here we report that mice homozygous for targeted disruption of the Cacna2d2 gene exhibit growth retardation, reduced life span, ataxic gait with apoptosis of cerebellar granule cells followed by Purkinje cell depletion, enhanced susceptibility to seizures, and cardiac abnormalities. The Cacna2d2(tm1NCIF) null phenotype has much in common with that of Cacna1a mutants, such as cerebellar neuro-degeneration associated with ataxia, seizures, and premature death. A tendency to bradycardia and limited response of null mutants to isoflurane implicate alpha2delta-2 in sympathetic regulation of cardiac function. In summary, our findings provide genetic evidence that the alpha2delta-2 subunit serves in vivo as a component of P/Q-type calcium channels, is indispensable for the central nervous system function, and may be involved in hereditary cerebellar ataxias and epileptic disorders in humans.
American Journal Of Pathology 10/2004; 165(3):1007-18. · 4.89 Impact Factor
-
Carol Dobson-Stone,
Antonio Velayos-Baeza,
Lea A Filippone,
Sarah Westbury,
Alexander Storch,
Torsten Erdmann,
Stephen J Wroe,
Klaus L Leenders,
Anthony E Lang,
Maria Teresa Dotti,
Antonio Federico,
Saidi A Mohiddin, Lameh Fananapazir,
Geoff Daniels,
Adrian Danek,
Anthony P Monaco
[show abstract]
[hide abstract]
ABSTRACT: Chorea-acanthocytosis (ChAc) is a severe, neurodegenerative disorder that shares clinical features with Huntington's disease and McLeod syndrome. It is caused by mutations in VPS13A, which encodes a large protein called chorein. Using antichorein antisera, we found expression of chorein in all human cells analyzed. However, chorein expression was absent or noticeably reduced in ChAc patient cells, but not McLeod syndrome and Huntington's disease cells. This suggests that loss of chorein expression is a diagnostic feature of ChAc.
Annals of Neurology 09/2004; 56(2):299-302. · 11.09 Impact Factor
-
Journal of the American College of Cardiology 04/2004; 43(6):1133; author reply 1133. · 14.16 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Hypertrophic cardiomyopathy (HCM) is a primary disease of cardiac muscle characterized by a thickening of the left ventricular wall and often predominantly affecting the interventricular septum. This paper presents a case study of a 53-year-old female with a dynamic and obstructive form of HCM. The study includes a case presentation, clinical findings, investigations, and management. Patient findings were obtained before and after alcohol septal ablation, a novel interventional therapy. The article reviews the various forms of HCM and describes the currently available treatment modalities for obstructive HCM. Further research will be necessary to determine the comparative efficacy between past, present, and future therapies.
Progress in Cardiovascular Nursing 01/2004; 19(4):133-40.
-
[show abstract]
[hide abstract]
ABSTRACT: 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.
Magnetic Resonance in Medicine 09/2003; 50(3):638-42. · 2.96 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Risk stratification and effectiveness of implantable cardioverter-defibrillator (ICD) therapy are unresolved issues in hypertrophic cardiomyopathy (HCM), a cardiac disease that is associated with arrhythmias and sudden death. We assessed ICD therapy in 132 patients with HCM: age at implantation was 34 +/- 17 years, and 44 (33%) patients were aged </= 20 years. Indications were sustained ventricular tachycardia (VT) or cardiac arrest (secondary prevention) in 47 (36%) patients, and clinical features associated with increased risk for sudden death (primary prevention) in 85 (64%) patients. There were 6 deaths and 55 appropriate interventions in 27 (20%) patients during a mean follow-up period of 4.8 +/- 4.2 years: 5-year survival and event-free rates were 96%+/- 2%and 75%+/- 5%, respectively. ICD intervention-free rates were significantly less for secondary than for primary prevention:64%+/- 7%versus 84%+/- 6%at 5 years,P = 0.02. Notably, 59 of 67 events (cardiac arrest and therapeutic ICD interventions), or 88%, occurred during sedentary or noncompetitive activity. Incidence of therapeutic shocks was related to age but not to other reported risk factors, including severity of cardiac hypertrophy, nonsustained VT during Holter monitoring, and abnormal blood pressure response to exercise. ICD related complications occurred in 38 (29%) patients, including 60 inappropriate ICD interventions in 30 (23%) patients. However, 8 (27%) of the patients with inappropriate shocks also had therapeutic interventions. ICD is effective for secondary prevention of sudden death in HCM. However, selection of patients for primary prevention of sudden death, and prevention of device related complications require further refinement.
Pacing and Clinical Electrophysiology 09/2003; 26(9):1887-96. · 1.35 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Linkage analysis identifies 10q24-26 as a disease locus for dilated cardiomyopathy (DCM), a region including the N-RAP gene. N-RAP is a nebulin-like LIM protein that may mediate force transmission and myofibril assembly in cardiomyocytes. We describe the sequence, genomic structure, and expression of human N-RAP, as well as an initial screen to determine whether N-RAP mutations cause cardiomyopathy. Human expressed sequence tag databases were searched with the published 3,528-bp mouse N-RAP open reading frame (ORF). Putative cDNA sequences were interrogated by direct sequencing from cardiac and skeletal muscle RNA. We identified two human N-RAP isoforms with ORFs of 5,085 bp (isoform C) and 5,190 bp (isoform S), encoding products of 193-197 kDa. Genomic database searches localize N-RAP to human chromosome 10q25.3 and match isoforms C and S to 41 and 42 exons. Only isoform C is detected in human cardiac RNA; in skeletal muscle, approximately 10% is isoform C and approximately 90% is isoform S. We investigated apparent differences between human N-RAP cDNA and mouse sequences. Two mouse N-RAP isoforms with ORFs of 5,079 and 5,184 bp were identified with approximately 85% similarity to human isoforms; published mouse sequences include cloning artifacts truncating the ORF. Murine and human isoforms have similar gene structure, tissue specificity, and size. N-RAP is especially conserved within its nebulin-like and LIM domains. We expressed both N-RAP isoforms and the previously described truncated N-RAP in embryonic chick cardiomyocytes. All constructs targeted to myofibril precursors and the cell periphery, and inhibited myofibril assembly. Several human N-RAP polymorphisms were detected, but none were unique to cardiomyopathy patients. N-RAP is highly conserved and exclusively expressed in cardiac and skeletal muscle. Genetic abnormalities remain excellent candidate causes for cardiac and skeletal myopathies.
Cell Motility and the Cytoskeleton 08/2003; 55(3):200-12. · 4.19 Impact Factor
-
Zubair M Ahmed,
Robert J Morell,
Saima Riazuddin,
Andrea Gropman,
Shahzad Shaukat,
Mussaber M Ahmad,
Saidi A Mohiddin, Lameh Fananapazir,
Rafael C Caruso,
Tayyab Husnain,
Shaheen N Khan,
Sheikh Riazuddin,
Andrew J Griffith,
Thomas B Friedman,
Edward R Wilcox
[show abstract]
[hide abstract]
ABSTRACT: Cosegregation of profound, congenital deafness with markers on chromosome 6q13 in three Pakistani families defines a new recessive deafness locus, DFNB37. Haplotype analyses reveal a 6-cM linkage region, flanked by markers D6S1282 and D6S1031, that includes the gene encoding unconventional myosin VI. In families with recessively inherited deafness, DFNB37, our sequence analyses of MYO6 reveal a frameshift mutation (36-37insT), a nonsense mutation (R1166X), and a missense mutation (E216V). These mutations, along with a previously published missense allele linked to autosomal dominant progressive hearing loss (DFNA22), provide an allelic spectrum that probes the relationship between myosin VI dysfunction and the resulting phenotype.
The American Journal of Human Genetics 06/2003; 72(5):1315-22. · 10.60 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Genetic screening of the beta-myosin heavy chain gene (MYH7) was evaluated in 100 consecutive unrelated patients with hypertrophic cardiomyopathy (HCM) and 200 normal unrelated subjects. Seventeen beta-myosin mutations were identified in 19 patients. Notably, 13, or 76%, were novel. Mutations were detected in both alleles in two patients: homozygous for Lys207Gln in one, and heterozygous for Pro211 Leu and Arg663His in another. No mutation was detected in the controls. MYH7-associated HCM was associated with more marked left atrial enlargement and syncope than non-MYH7-related HCM. Our findings indicate that: (1) screening methods should allow identification of novel mutations; and (2) more than one sarcomeric mutation may be present in a patient more commonly than is appreciated. Further studies are necessary to ascertain the clinical consequences of the novel and compound gene abnormalities, and to determine whether correlating functional domain to phenotype provides more useful information about the clinical significance of the molecular defects.
Genetic Testing 02/2003; 7(1):21-7. · 1.17 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: It has been suggested that systolic compression of epicardial coronary arteries is an important cause of myocardial ischemia and sudden death in children with hypertrophic cardiomyopathy. We examined the associations between sudden death, systolic coronary compression of intra- and epicardial arteries, myocardial perfusion abnormalities, and severity of hypertrophy in children with hypertrophic cardiomyopathy. We reviewed the angiograms from 57 children with hypertrophic cardiomyopathy for the presence of coronary and septal artery compression; coronary compression was present in 23 (40%). The left anterior descending artery was most often affected, and multiple sites were found in 4 children. Myocardial perfusion abnormalities were more frequently present in children with coronary compression than in those without (94% vs 47%, P = 0.002). Coronary compression was also associated with more severe septal hypertrophy and greater left ventricular outflow gradient. Septal branch compression was present in 65% of the children and was significantly associated with coronary compression, severity of septal hypertrophy, and outflow obstruction. Multivariate analysis showed that septal thickness and septal branch compression, but not coronary compression, were independent predictors of perfusion abnormalities. Coronary compression was not associated with symptom severity, ventricular tachycardia, or a worse prognosis. We conclude that compression of coronary arteries and their septal branches is common in children with hypertrophic cardiomyopathy and is related to the magnitude of left ventricular hypertrophy. Our findings suggest that coronary compression does not make an important contribution to myocardial ischemia in hypertrophic cardiomyopathy; however, left ventricular hypertrophy and compression of intramural arteries may contribute significantly.
Texas Heart Institute journal / from the Texas Heart Institute of St. Luke's Episcopal Hospital, Texas Children's Hospital 02/2002; 29(4):290-8. · 0.65 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: BEGLEY, D., et al.: Dual Chamber Pacemaker Therapy for Mid-Cavity Obstructive Hypertrophic Cardiomyopathy. Intracavitary LV obstruction is an important determinant of clinical outcome in hypertrophic cardiomyopathy (HCM). In a minority of patients the obstruction is at the level of the papillary muscles. Mid-cavity obstructive HCM may be associated with a distal LV aneurysm and a worse prognosis. It is often not amenable to standard cardiac surgery for LV outflow obstruction. The long-term effects (mean follow-up 4.8 ± 2.9 years) of dual chamber (DDD) pacemaker therapy in 14 patients with mid-cavity obstructive HCM (mean age 34 ± 16 years, range 15–65 years) were studied. Patients were evaluated by cardiac catheterization at baseline and 6 months to 1 year after receiving DDD pacemakers off all drug therapy. Symptoms were improved in all patients and NYHA functional class reduced from 2.8 ± 0.1 to 1.9 ± 0.4 (P < 0.0005). Intracavitary LV pressure gradients was reduced significantly (43 ± 36 vs 84 ± 31 mmHg at baseline, P < 0.0005). There was a significant associated reduction in apical LV systolic pressure (152 ± 37 vs 188 ± 34 mmHg, P < 0.001). In addition, there was a trend towards increased exercise tolerance (445 ± 123 vs 396 ± 165). Cardiac output and LV filling pressures were unchanged. In conclusion, chronic DDD pacing results in significant symptomatic and hemodynamic improvement in this uncommon but important subset of patients with obstructive HCM in whom the role of cardiac surgery is less well defined compared with the more typical outflow tract location of LV obstruction.
Pacing and Clinical Electrophysiology 10/2001; 24(11):1639 - 1644. · 1.35 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Familial hypertrophic cardiomyopathy (FHC) is a disease of the sarcomere. In the -myosin heavy chain gene, which codes for the mechanical enzyme myosin, greater than 40 point mutations have been found that are causal for this disease. We have studied the effect of two mutations, the R403Q and L908V, on myosin molecular mechanics. In the in vitro motility assay, the mutant myosins produced a 30% greater velocity of actin filament movement (actin). At the single molecule level, actin d/t
on, where d is the myosin unitary step displacement and t
on is the step duration. Laser trap studies were performed at 10 M MgATP to estimate d and t
on for the normal and mutant myosin molecules. The increase in actin can be explained by a significant decrease in the average t
on''s in both the R403Q and L908V mutants (30 ms) compared to controls (40 ms), while d was not different for all myosins tested (7 nm). Thus the mutations affect the kinetics of the cross-bridge cycle without any effect on myosin''s inherent motion and force generating capacity. Based on these studies, the primary signal for the hypertrophic response appears to be an apparent gain in function of the individual mutant myosin molecules.
Journal of Muscle Research and Cell Motility 09/2000; 21(7):609-620. · 1.98 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Several mutations in the β-myosin heavy chain gene cause hypertrophic cardiomyopathy. This study investigates (1) the in vitro
velocities of translocation of fluorescently-labelled actin by β-myosin purified from soleus muscle of 30 hypertrophic cardiomyopathy
patients with seven distinct β-myosin heavy chain gene mutations: Thr124Ile, Tyr162Cys, Gly256Glu, Arg403Gln, Val606Met, Arg870His,
and Leu908Val mutations; and (2) motility activity of β-myosin purified from cardiac and soleus muscle biopsies in the same
patients. The velocity of translocation of actin by β-myosin purified from soleus or cardiac muscle of 22 normal controls
was 0.48 ± 0.09 μm s−1. By comparison, the motility activity was reduced in all 30 patients with β-myosin heavy chain gene
mutations (range, 0.112 ± 0.041 to 0.292 ± 0.066 μm s−1). Notably, the Tyr162Cys and Arg403Gln mutations demonstrated significantly
lower actin sliding velocities: 0.123 ± 0.044, and 0.112 ± 0.041 μm s−1, respectively. β-myosin purified from soleus muscle
from four patients with the Arg403Gln mutation had a similar actomyosin motility activity compared to β-myosin purified from
their cardiac biopsies (0.127 ± 0.045 μm s−1 versus 0.119 ± 0.068 μm s−1, respectively). Since these seven mutations lie in
several distinct functional domains, it is likely that the mechanisms of their inhibitions of motility are different
Journal of Muscle Research and Cell Motility 04/1997; 18(3):275-283. · 1.98 Impact Factor
