Lameh Fananapazir

Mutations in either the essential or regulatory light chains of myosin are associated with a rare myopathy in human heart and skeletal muscle

The muscle myosins are hexomeric proteins consisting of two heavy chains and two pairs of light chains, the latter called essential (ELC) and regulatory (RLC). The light chains stabilize the long alpha helical neck of the myosin head. Their function in striated muscle, however, is only partially understood. We report here the identification of distinct missense mutations in a skeletal/ventricular ELC and RLC, each of which are associated with a rare variant of cardiac hypertrophy as well as abnormal skeletal muscle.We show that myosin containing the mutant ELC has abnormal function, map the mutant residues on the three–dimensional structure of myosin and suggest that the mutations disrupt the stretch activation response of the cardiac papillary muscles.

Long-term results of dual-chamber (DDD) pacing in obstructive hypertrophic cardiomyopathy. Evidence for progressive symptomatic and hemodynamic improvement and reduction of left ventricular hypertrophy.

BackgroundWe previously reported that 6 to 12 weeks of dual-chamber (DDD) pacing results in clinical and hemodynamic improvement in obstructive hypertrophic cardiomyopathy (HCM). This study examines the long-term results of DDD pacing in obstructive HCM. Methods and ResultsDDD devices were implanted in 84 patients (mean age, 49 ± 16 years) with obstructive HCM and severe drug-refractory symptoms. At a mean follow-up of 2.3 ± 0.8 years (maximum, 3.5 years), the New York Heart Association (NYHA) functional class had improved significantly (1.6 ± 0.6 versus 3.2 ± 0.5, P < .00001). Symptoms were eliminated in 28 patients (33%), improved in 47 patients (56%), but remained unchanged in 7 patients (8%). Two patients died suddenly (97% cumulative 3-year survival rate). In 74 patients with significant left ventricular outflow tract (LVOT) obstruction at rest, the LVOT gradients were significantly reduced at follow-up (27 ± 31 versus 96 ± 41 mm Hg, P < .00001). Symptoms and provokable LVOT gradients were also reduced in all 10 patients without significant resting but with provokable LVOT obstruction. Persistence of the LVOT obstruction and symptoms was attributed to inability to pre-excite the interventricular septum (n = 8) and onset of atrial fibrillation (n = 7). Fifty patients had two cardiac catheterization evaluations, 3 ± 1 and 16 ± 4 months after implantation of a pacemaker. In this subgroup, the NYHA functional class improved from 3.2 ± 0.5 at baseline to 1.8 ± 0.7 at the initial evaluation (P < .00001), but with a further significant improvement at the second evaluation: 1.4 ± 0.6, P < .001. This symptomatic improvement was associated with progressive reduction of LVOT gradient at the two evaluations: baseline, 100 ± 47 mm Hg; first evaluation, 41 ± 36 mm Hg (P < .0001); and second evaluation, 29 ± 34 mm Hg (P < .01). Despite the presence of left bundle branch block, DDD pacing reduced LVOT obstruction significantly in 15 patients (LVOT gradient, baseline 89 ± 36 mm Hg versus 18 ± 26 mm Hg at follow-up, P < .0001). There was a weak but significant correlation between the reduction in LVOT gradients accomplished by AV pacing before implantation of DDD device and the eventual reduction in LVOT gradients recorded at the follow-up evaluation (r = .38, P = .0017). Echocardiography demonstrated significant thinning of the anterior septum and distal anterior LV wall in the absence of deterioration of LV systolic function. Conclusions(1) Although most of the improvement of symptoms and hemodynamic indexes occurs during the first few months of DDD pacing, further changes are often observed a year later; (2) DDD pacing is associated with an excellent prognosis in a subgroup of severely disabled patients, many of whom present with syncope or presyncope; (3) baseline pacing studies are not essential to identify patients who may benefit from pacing; (4) preexisting left bundle branch block is compatible with severe LVOT obstruction, and DDD pacing is also beneficial in this subgroup; (5) DDD pacing reduces both resting and provokable LVOT obstruction; (6) additional therapy, for example, radiofrequency ablation of the AV node, may be necessary in some patients either to preexcite the interventricular septum or to control atrial fibrillation; and (7) although LV hypertrophy has been considered a primary feature of HCM, pacing appears to reverse LV wall thickness in a significant subset of adult HCM patients.

Impact of dual-chamber permanent pacing in patients with obstructive hypertrophic cardiomyopathy with symptoms refractory to verapamil and beta-adrenergic blocker therapy.

BackgroundPatients with obstructive hypertrophic cardiomyopathy (HCM) with symptoms refractory to drugs (β-blockers or verapamil) are candidates for cardiac surgery (left ventricular septal myectomy or mitral valve replacement). The present study examines prospectively the ability of dual-chamber (DDD) pacing to improve symptoms and relieve left ventricular outflow obstruction in such patients. Methods and ResultsForty-four consecutive patients with obstructive HCM who had failed to benefit from pharmacotherapy underwent treadmill exercise tests, echocardiography, and cardiac catheterization before and 1.5-3 months after implantation of a DDD pacemaker. Symptoms (angina, dyspnea, palpitations, presyncope, and syncope), New York Heart Association functional class status (1.7±0.7 versus 3.4±0.5, p<0.00001), and exercise durations were improved at follow-up evaluation. This was associated with significant reduction in left ventricular outflow tract gradient (38±38 versus 87±43 mm Hg, p<0.0001) and significant increases in cardiac output and systemic arterial pressures. Notably, when pacing was discontinued and comparisons were made in sinus rhythm, treadmill exercise durations were greater and left ventricular outflow tract gradients were less at the follow-up evaluation compared with the baseline study. ConclusionsDDD pacing is an effective alternative to surgery in most patients with obstructive HCM with drug-refractory symptoms. The beneficial effects of pacing continue to be evident when pacing is acutely discontinued.

Myocardial ischemia detected by thallium scintigraphy is frequently related to cardiac arrest and syncope in young patients with hypertrophic cardiomyopathy

OBJECTIVES The purpose of this study was to determine the frequency of myocardial ischemia as a potential mechanism for cardiac arrest and syncope in young patients with hypertrophic cardiomyopathy who experienced such complications. BACKGROUND Sudden cardiac death and syncope occur frequently in patients with hypertrophic cardiomyopathy. Although ventricular arrhythmias account for most of these events in adult patients, the mechanism responsible for cardiac arrest and syncope in young patients has not been established. METHODS Twenty-three patients with hypertrophic cardiomyopathy, aged 6 to 23 years, with previous cardiac arrest (n = 8), syncope (n = 7) or a family history of sudden cardiac death (n = 8) were evaluated to determine the prevalence of spontaneous ambulatory ventricular tachycardia (24- to 72-h electrocardiographic [ECG] monitoring), exercise-induced myocardial ischemia (thallium scintigraphy) and inducibility of ventricular tachycardia (electrophysiologic studies). RESULTS Three of 15 patients with a history of cardiac arrest or syncope had ventricular tachycardia on ambulatory ECG monitoring. However, all 15 patients, had inducible ischemia by thallium scintigraphy compared with only 3 (37%) of 8 patients with no such history (p < 0.01). In contrast, ventricular tachycardia induction was uncommon in all of the young patients (27% in those with cardiac arrest or syncope; 0% in the others). During therapy for ischemia with verapamil alone or in combination with beta-adrenergic blocking agents, only 4 of the 15 patients with cardiac arrest or syncope had further episodes. In three of the four patients, these events were temporally related to discontinuation of verapamil. Among eight patients who had a repeat exercise thallium study while receiving anti-ischemic therapy, seven (88%) had improved regional thallium uptake, of whom three had normal thallium studies. CONCLUSIONS These data suggest that in young patients with hypertrophic cardiomyopathy, sudden cardiac arrest or syncope is frequently related to ischemia rather than to a primary arrhythmogenic ventricular substrate.

Prognostic determinants in hypertrophic cardiomyopathy. Prospective evaluation of a therapeutic strategy based on clinical, Holter, hemodynamic, and electrophysiological findings.

BackgroundPatients with hypertrophic cardiomyopathy (HCM) frequently have arrhythmias and hemodynamic abnormalities and are prone to sudden death and syncope. An important need exists for improved risk stratification and definition of appropriate investigation and therapy. Methods and ResultsThe relation of 31 clinical, Holter, cardiac catheterization, and electrophysiological (EP) variables to subsequent cardiac events in 230 HCM patients was examined by multivariate analysis. Studies were for cardiac arrest (n=32), syncope (n=80), presyncope (n=52), ventricular tachycardia (VT) on Holter (n=36), a strong family history of sudden death (n=9), and palpitations (n=21). Nonsustained VT on Holter was present in 115 patients (50%). Sustained ventricular arrhythmia was induced in 82 patients (36%). Seventeen cardiac events (eight sudden deaths, one cardiac arrest, and eight syncope with defibrillator discharges) occurred during a follow-up of 28±19 months. The 1-year and 5-year event-free rates were 99%, and 79%, respectively. Two variables were significant independent predictors of subsequent events: sustained ventricular arrhythmia induced at EP study (β, 3.5; p=0.002) and a history of cardiac arrest or syncope (β 2.9; p<0.05). Only two of 66 patients without symptoms of impaired consciousness had a cardiac event (3-year event-free rate, 97%). In contrast, nonsustained VT on Holter was associated with a worse prognosis only in patients with symptoms of impaired consciousness: 11 of 79 symptomatic patients with VT on Holter (14%) had events versus only four of 85 symptomatic patients without VT on Bolter (5%) (p=0.057). Notably, none of 51 patients without symptoms of impaired consciousness in whom VT was not induced at EP study had a cardiac event. ConclusionsIn HCM, VT on Holter is of benign prognostic significance in the absence of symptoms of impaired consciousness and inducible VT, and sustained VT induced at EP study, especially when associated with cardiac arrest or syncope, identifies a subgroup at high risk for subsequent cardiac events.

Abnormal cardiac sensitivity in patients with chest pain and normal coronary arteries

The causes of chest pain in patients found to have angiographically normal coronary arteries during cardiac catheterization remain controversial. Cardiac sensitivity to catheter manipulation, pacing at various stimulus intensities and intracoronary injection of contrast medium was examined in several groups of patients who underwent cardiac catheterization. Right heart (especially right ventricular) catheter manipulation and pacing and intracoronary contrast medium provoked chest pain typical of that previously experienced in 29 (81%) of 36 patients with chest pain and angiographically normal coronary arteries and 15 (46%) of 33 symptomatic patients with hypertrophic cardiomyopathy. In contrast, only 2 (6%) of 33 symptomatic patients with coronary artery disease experienced their typical chest pain with these sensitivity tests (p less than 0.001). None of 10 patients with valvular heart disease but without a chest pain syndrome experienced any sensation with these tests. Cutaneous pain threshold testing demonstrated that patients with chest pain and normal coronary arteries had a higher pain threshold to thermal stimulation compared with patients who had coronary artery disease or hypertrophic cardiomyopathy. No relation existed between cardiac sensitivity and cutaneous sensitivity testing. Thus, patients who have chest pain despite angiographically normal coronary arteries may have abnormal cardiac sensitivity to a variety of stimuli. This increased sensitivity may be of causal importance to their chest pain syndrome or may contribute to their perception of ischemia-induced pain. The same phenomenon was also commonly seen in symptomatic patients with hypertrophic cardiomyopathy. Whether this phenomenon represents abnormal activation of pain receptors within the heart or abnormal processing of visceral afferent neural impulses in the peripheral or central nervous system is unknown.

Differences in clinical expression of hypertrophic cardiomyopathy associated with two distinct mutations in the beta-myosin heavy chain gene. A 908Leu----Val mutation and a 403Arg----Gln mutation.

BackgroundThe disease gene for hypertrophic cardiomyopathy (HCM) has been identified as the β-myosin heavy chain (β-MHC) gene in some HCM families. We describe extensive clinical evaluations in two kindreds with two distinct point mutations in the β-MHC gene. Methods and ResultWe used single-strand confirmation polymorphism (SSCP) gel analysis of polymerase chain reaction-amplified products capturing each of the 40 β-MHC gene exons to identify distinct missense mutations in two HCM kindreds. Clinical, ECG, and echocardiographic studies were performed in the two kindreds: kindred 2755 with amino acid 908Leu→Val mutation and kindred 2002 with amino acid 403Arg→Gln mutation. The morphological appearances of HCM were similar in these two kindreds. However, the two kindreds differed with respect to disease penetrance, age of onset of disease, and incidence of premature sudden death. Twelve of 31 adults (≥ 17 years) with the disease gene in kindred 2755 did not have left ventricular hypertrophy (LVH), and only five of these had ECG abnormalities. Thus, the disease penetrance in adults with this mutation was only 61%. None of 11 children aged < 16 years had LVH. The 908 mutation was associated with a low incidence of cardiac events: Only two sudden deaths and one syncope occurred in 46 individuals with the mutant allele. In contrast, LVH was present in all 11 adults in kindred 2002 with the 403 mutation (100% disease penetrance). In addition, three of four affected children were symptomatic and had clinical evidence of HCM. The disease in this kindred was severe and resulted in six premature sudden deaths. Seven additional patients had syncope or presyncope. ConclusionsIn some kindreds, the HCM disease gene is more prevalent than indicated by echocardiography and ECG. Some point mutations may be associated with a more malignant prognosis. Preclinical identification of children with mutations associated with a high incidence of sudden death and syncope provides the opportunity to evaluate efficacy of early therapeutic interventions.

Electrophysiologic abnormalities in patients with hypertrophic cardiomyopathy. A consecutive analysis in 155 patients.

Electrophysiologic studies (EPS) were performed in 155 patients with hypertrophic cardiomyopathy (HCM). Indications for EPS were cardiac arrest in 22 patients, syncope in 55 patients, presyncope in 37 patients, asymptomatic ventricular tachycardia (VT) in 24 patients, palpitations in 10 patients, and a strong family history of sudden cardiac death in seven patients. Thirty-five (23%) patients had significant resting left ventricular outflow tract obstruction. Electrophysiologic abnormalities were present in 126 (81%) patients. A high prevalence of abnormal sinus-node function (66%) and His-Purkinje (HV) conduction (30%) was noted. The most commonly induced supraventricular arrhythmias were atrial reentrant tachycardia and atrial fibrillation (10% and 11% of patients, respectively). Accessory atrioventricular pathways were present in seven (5%) patients. Programmed ventricular stimulation (PVS) induced nonsustained ventricular tachycardia in 22 (14%) patients and sustained ventricular arrhythmia in 66 (43%) patients. Sustained ventricular arrhythmia was polymorphic VT in 48 (73%) patients, monomorphic VT in 16 (24%) patients, and ventricular fibrillation in two (3%) patients. Induction was with two premature stimuli in 19 (29%) patients and three premature stimuli in 47 (71%) patients. Of 17 cardiac arrest survivors with sustained ventricular arrhythmia, 16 (94%) patients required three premature stimuli for arrhythmia induction. Sustained ventricular arrhythmia was induced at a right ventricular site in 51 (77%) patients and at a left ventricular site in 15 (23%) patients. Univariate analysis showed a significant (p less than 0.05) association between inducibility of sustained ventricular arrhythmia and VT on Holter in patients with a history of cardiac arrest or syncope but not in patients with presyncope or asymptomatic patients. Multivariate logistic regression analysis revealed that the following were significantly associated with inducibility of sustained ventricular arrhythmia: clinical presentation (cardiac arrest more than syncope more than presyncope more than asymptomatic patients, p = 0.0002; chronic or inducible atrial fibrillation, p = 0.002; and male gender, p = 0.04). In contrast, there was no clinical correlate of induced nonsustained VT.(ABSTRACT TRUNCATED AT 400 WORDS)

Utility of continuous wave doppler echocardiography in the noninvasive assessment of left ventricular outflow tract pressure gradient in patients with hypertrophic cardiomyopathy

Subaortic obstruction is an important determinant of the clinical presentation of and therapeutic approach to patients with hypertrophic cardiomyopathy. Therefore, assessment of the presence and magnitude of the intraventricular pressure gradient is paramount in the clinical evaluation of these patients. To establish the utility of continuous wave Doppler echocardiography in assessing the pressure gradient in hypertrophic cardiomyopathy, 28 patients representing the wide hemodynamic spectrum of this disease underwent simultaneous determination of the subaortic gradient by continuous wave Doppler ultrasound and cardiac catheterization. With use of the modified Bernoulli equation, the Doppler-estimated gradient showed a strong correlation with the maximal instantaneous pressure difference measured at catheterization, both under basal conditions (r = 0.93; p less than 0.0001) and during provocative maneuvers (r = 0.89; p less than 0.0001). In 26 of the 28 patients, all assessments of the subaortic gradient were in agreement within 15 mm Hg (average difference 5 +/- 3 mm Hg). In the other two patients there were substantial differences between these measurements (under basal conditions in one patient and after provocation in another), although the Doppler technique predicted the presence of marked subaortic obstruction in each. In both patients the erroneous interpretation was due to superimposition of the mitral regurgitation signal on that of left ventricular outflow. Doppler waveforms from the left ventricular outflow tract showed variability in contour among different patients and in individual patients. Hence, continuous wave Doppler echocardiography is a useful noninvasive method for estimating the subaortic gradient in patients with hypertrophic cardiomyopathy. However, technical factors such as contamination of the outflow tract jet with that of mitral regurgitation and variability in waveform configuration may importantly influence such assessments of the subaortic gradient.

Myocardial metabolic, hemodynamic, and electrocardiographic significance of reversible thallium-201 abnormalities in hypertrophic cardiomyopathy.

BackgroundExercise-induced abnormalities during thallium-201 scintigraphy that normalize at rest frequently occur in patients with hypertrophic cardiomyopathy. However, it is not known whether these abnormalities are indicative of myocardial ischemia. Methods and ResultsFifty patients with hypertrophic cardiomyopathy underwent exercise 20UT1 scintigraphy and, during the same week, measurement of myocardial lactate metabolism and hemodynamics during pacing stress. Thirty-seven patients (74%) had one or more 201TI abnormalities that completely normalized after 3 hours of rest; 26 had regional myocardial 201T1 defects, and 26 had apparent left ventricular cavity dilatation with exercise, with 15 having coexistence of these abnormal findings. Of the 37 patients with reversible 201T1 abnormalities, 27 (73%) had metabolic evidence of myocardial ischemia during rapid atrial pacing (myocardial lactate extraction of 0 mmol/l or less) compared with four of 13 patients (31%) with normal 201T1 scans (p < 0.01). Eleven patients had apparent cavity dilatation as their only 201T1 abnormality; their mean postpacing left ventricular end-diastolic pressure was significantly higher than that of the 13 patients with normal 2OtTl studies (33±5 versus 21±10 mm Hg, p < 0.001). There was no correlation between the angiographic presence of systolic septal or epicardial coronary arterial compression and the presence or distribution of 201TI abnormalities. Patients with ischemic ST segment responses to exercise had an 80% prevalence rate of reversible 20MT1 abnormalities and a 70% prevalence rate of pacing-induced ischemia. However, 69% of patients with nonischemic ST segment responses had reversible 20MT1 abnormalities, and 55% had pacing-inducedischemia. ConclusionsReversible 2OtTl abnormalities during exercise stress are markers of myocardial ischemia in hypertrophic cardiomyopathy and most likely identify relatively underperfused myocardium. In contrast, ST segment changes with exercise and systolic compression of coronary arteries on angiography are unreliable markers of inducible myocardial ischemia in hypertrophic cardiomyopathy. Apparent cavity dilatation during 20tTI scintigraphy may indicate ischemia-related changes in left ventricular filling, with elevation in diastolic pressures and endocardial compression.