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HCM, the most common inherited cardiac disease, is mainly caused by mutations in sarcomeric genes. More than a third of the patients are heterozygous for mutations in the MYH7 gene encoding for the β-myosin heavy chain. In HCM-patients, expression of the mutant and the wildtype allele can be unequal, thus leading to fractions of mutant and wildtype mRNA and protein which deviate from 1:1. This so-called allelic imbalance was detected in whole tissue samples but also in individual cells. There is evidence that the severity of HCM not only depends on the functional effect of the mutation itself, but also on the fraction of mutant protein in the myocardial tissue. Allelic imbalance has been shown to occur in a broad range of genes. Therefore, we aimed to examine whether the MYH7-alleles are intrinsically expressed imbalanced or whether the allelic imbalance is solely associated with the disease. We compared the expression of MYH7-alleles in non-HCM donors and in HCM-patients with different MYH7-missense mutations. In the HCM-patients, we identified imbalanced as well as equal expression of both alleles. Also at the protein level, allelic imbalance was determined. Most interestingly, we also discovered allelic imbalance and balance in non-HCM donors. Our findings therefore strongly indicate that apart from mutation-specific mechanisms, also non-HCM associated allelic-mRNA expression regulation may account for the allelic imbalance of the MYH7 gene in HCM-patients. Since the relative amount of mutant mRNA and protein or the extent of allelic imbalance has been associated with the severity of HCM, individual analysis of the MYH7-allelic expression may provide valuable information for the prognosis of each patient.

Familial Hypertrophic Cardiomyopathy (FHC) is frequently caused by mutations in the β-cardiac myosin heavy chain (β-MyHC). To identify changes in sarcomeric function triggered by such mutations, distinguishing mutation effects from other functional alterations of the myocardium is essential. We previously identified a direct effect of mutation R723G (MyHC723) on myosin function in slow Musculus soleus fibers. Here we investigate contractile features of left ventricular cardiomyocytes of FHC-patients with the same MyHC723-mutation and compare these to the soleus data. In mechanically isolated, triton-permeabilized MyHC723-cardiomyocytes, maximum force was significantly lower but calcium-sensitivity was unchanged compared to donor. Conversely, MyHC723-soleus fibers showed significantly higher maximum force and reduced calcium-sensitivity compared to controls. Protein phosphorylation, a potential myocardium specific modifying mechanism, might account for differences compared to soleus fibers. Analysis revealed reduced phosphorylation of troponin I and T, myosin-binding-protein C, and myosin-light-chain 2 in MyHC723-myocardium compared to donor. Saturation of protein-kinaseA phospho-sites led to comparable, i.e., reduced MyHC723-calcium-sensitivity in cardiomyocytes as in M. soleus fibers, while maximum force remained reduced. Myofibrillar disarray and lower density of myofibrils, however, largely account for reduced maximum force in MyHC723-cardiomyocytes. The changes seen when phosphorylation of sarcomeric proteins in myocardium of affected patients is matched to control tissue suggest that the R723G mutation causes reduced Ca(++)-sensitivity in both cardiomyocytes and M. soleus fibers. In MyHC723-myocardium, however, hypophosphorylation can compensate for the reduced calcium-sensitivity, while maximum force generation, lowered by myofibrillar deficiency and disarray, remains impaired, and may only be compensated by hypertrophy., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Familial hypertrophic cardiomyopathy (FHC) is an autosomal dominant disease, which in about 30% of the patients is caused by missense mutations in one allele of the β-myosin heavy chain (β-MHC) gene (MYH7). To address potential molecular mechanisms underlying the family-specific prognosis, we determined the relative expression of mutant versus wild-type MYH7-mRNA. We found a hitherto unknown mutation-dependent unequal expression of mutant to wild-type MYH7-mRNA, which is paralleled by similar unequal expression of β-MHC at the protein level. Relative abundance of mutated versus wild-type MYH7-mRNA was determined by a specific restriction digest approach and by real-time PCR (RT-qPCR). Fourteen samples from M. soleus and myocardium of 12 genotyped and clinically well-characterized FHC patients were analyzed. The fraction of mutated MYH7-mRNA in five patients with mutation R723G averaged to 66 and 68% of total MYH7-mRNA in soleus and myocardium, respectively. For mutations I736T, R719W and V606M, fractions of mutated MYH7-mRNA in M. soleus were 39, 57 and 29%, respectively. For all mutations, unequal abundance was similar at the protein level. Importantly, fractions of mutated transcripts were comparable among siblings, in younger relatives and unrelated carriers of the same mutation. Hence, the extent of unequal expression of mutated versus wild-type transcript and protein is characteristic for each mutation, implying cis-acting regulatory mechanisms. Bioinformatics suggest mRNA stability or splicing effectors to be affected by certain mutations. Intriguingly, we observed a correlation between disease expression and fraction of mutated mRNA and protein. This strongly suggests that mutation-specific allelic imbalance represents a new pathogenic factor for FHC.

Background: In familial hypertrophic cardiomyopathy (FHC), asymmetric left ventricular (LV) hypertrophy has been considered to be the predominant phenotypic expression, whereas right ventricular (RV) involvement is still ambiguous. In most cases, the right ventricle remains unaffected until secondary pulmonary hypertension develops. Several FHC-causing mutations of genes encoding sarcomere-related proteins have been identified which are transmitted in an autosomal-dominant manner., Methods: We report the case of a 61 year old member of a Catalan family with a Arg723Gly missense mutation of the β-myosin heavy chain (β-MHC), that is associated with a malignant phenotype characterized by sudden cardiac death and heart failure. Because of progressive systolic LV dysfunction, the patient received a heart transplant in 2003., Results: Molecular analysis of the myocardial tissue of the explanted heart, taken from the left and right ventricle, showed a similar deviation of the ratio of mutant vs wild type mRNA of the β-MHC of 71.8 ± 5% and 68.5 ± 3%, respectively. This finding was confirmed for LV biopsies of this patient on protein level, showing a similar proportion of mutated β-myosin. But since the patient is heterozygous for the β-MHC mutation and the mutation is located in a coding region, the relative increase of the expression of the mutant allele is unexpected. It has been demonstrated before by our group for several β-MHC mutations that the relative abundance of mutated mRNA/protein correlates with the clinical severity of the disease. But since the right ventricle shows no (or only minor) manifestation in terms of hypertrophy or dysfunction, the level of mRNA and protein expression is not the only factor responsible for the development of the phenotype of FHC., Conclusions: Several mechanisms through which cardiac stresses may incite maladaptive cardiac remodeling primarily of the left ventricle that result in myocardial hypertrophy and heart failure are proposed. One of those triggers could be the enhanced work load of the left ventricle, especially if a LV outflow tract gradient is present, in contrast to the lesser demands to the right ventricle which is adapted to the low pressure system of the pulmonary circulation. Further studies are needed to confirm the results of this case, as well as functional studies involving both ventricles.

In order to analyse the hormonal and erythrocyte ion transport systems in relation to left ventricular hypertrophy (LV) in essential hypertension, a prospective study of 50 consecutive hypertensive patients under 55 years of age and without prior antihypertensive therapy was performed. Twenty-seven normal subjects with no family history of hypertension served as controls. LV hypertrophy, as assessed by echocardiography, was present in 64% of the hypertensive patients. This showed an increase (P < 0.001) in intra-erythrocyte Na+ concentration (8.1 +/- 1.2 vs 6.9 +/- 1 mmol.l-1.cells-1) and Na+:H+ exchange activity (8.8 +/- 4 vs 5.5 +/- 1.3 mmol.[l.cells.h-1]). There was a significant association between plasma aldosterone levels (19.1 +/- 12 ng.dl-1) with intra-erythrocyte Na+ content (r = 0.370, P < 0.05) and Na+:H+ exchange activity (r = 0.385, P < 0.01) as well as with echocardiographic LV mass index (138 +/- 40 g.m-2, r = 0.393, P < 0.01). The results are consistent with the concept that increased entry of Na+ into cells via Na+:H+ exchange could be a determining factor in left ventricular hypertrophy, which might be influenced by aldosterone.

Simplified models of re-entry may help in our understanding of the electrophysiologic effects of class III drugs. In a model of re-entrant ventricular tachycardia around a ring of epicardium in Langendorff-perfused rabbit hearts, the electrophysiologic effects of class III antiarrhythmic drugs were studied and compared to those of class I drugs. Class III drugs were effective in terminating fast re-entrant ventricular tachycardias. Prolongation of the refractory period without affecting conduction velocity resulted in a closure of the excitable gap and collision of the head of the propagating impulse against its own tail of refractoriness. In slow ventricular tachycardias, despite a similar increase in refractory period, the excitable gap remained large enough to allow perpetuation of the tachycardia.

Several pathophysiological substrates may be responsible for ventricular tachycardia (VT) occurring in the chronic phase of a myocardial infarction. Reentrant circuits can have anatomical or functional characteristics. Macroreentrant or microreentrant circuits have been described. Activation maps have shown that the circuit can be represented as a single loop or as a figure-of-eight reentrant pattern. All these different substrates have in common that they result in sustained monomorphic VT. The adequate treatment will probably be different for each one of them. In this article, some possible pathophysiological substrates of VT occurring in the chronic phase of a myocardial infarction are reviewed. Finally, we speculate on how catheter ablation may modify each one of the substrates.

To assess the diagnostic value of technetium-99m-MIBI (99mTc-MIBI) as a myocardial perfusion imaging agent, and if rest and exercise scans could be performed on the same day, 21 patients with coronary artery disease were studied. Qualitative planar 201-thallium (201Tl) scans, coronary angiography, or both were also performed (median between studies 11 days). In 10 patients an injection of 740 mBq of 99mTc-MIBI at stress was followed by a second injection of 740 mBq at rest 24 h later (long interal) (LI). In 11 patients injection of 370 mBq at rest was followed 3 h later by an injection of 740 mBq at stress (short interval) (SI). Exercise scans were performed to similar maximal work load (LI = 6.6 +/- 1.8 METs; SI = 6.3 +/- 1.7 METs; 201Tl = 6.8 +/- 1.2 METs; p = NS) and double product (LI = 19551 +/- 7370; SI = 19900 +/- 6797; 201Tl = 19965 +/- 5282; p = NS). Overall, 99mTc-MIBI and 201Tl agreed in 92% of the patients tested and in 165 of 180 (92%) left ventricular segments in both 99mTc-MIBI protocols using short and long intervals between injections. In 15 patients with significant stenosis, 99mTc-MIBI correctly identified 13 patients (sensitivity of 87%). Thus, 99mTc-MIBI is a useful imaging agent with similar diagnostic value as 201Tl. In spite of its lack of myocardial redistribution, 99mTc-MIBI rest and exercise scans performed on the same day seem to have a similar concordance rate with 201Tl as when performed on separate days.

A 47-year-old man presented with exertional angina. Selective coronary arteriography showed complete systolic segmental occlusion of the left anterior descending coronary artery producing milking effect. Permanent relief of symptoms was achieved by surgical excision of myocardial bridges. Postoperative angiography performed 11 months later was normal. Periarterial muscle resection should be considered in symptomatic patients with this rare anomaly.

The association of myocardial infarction with normal coronary arteries was analyzed prospectively. A series of 259 consecutive men aged 60 years or less underwent selective coronary angiography 30 days after a definite infarct. Coronary arterial lesions were documented in 251 patients, normal coronary arteries in the remaining 8. The latter patients had a significantly lower (p less than 0.001) mean age than the former; no patient older than 50 years had patent coronary arteries, whereas 5 of the 11 patients under age 35 had normal arteries. The prevalence of risk factors was similar in both groups of patients. Although there were no group differences in infarct size or location, patients with normal coronary arteries had a higher ejection fraction (p less than 0.01) and a lower left ventricular end-diastolic pressure (p less than 0.05). A previous history of angina or infarction and the occurrence of new coronary events were confined to patients with coronary arterial lesions. The clinical course of patients presenting with normal angiograms was uneventful. Transient coronary occlusion, the most likely mechanism of infarction in this group of patients, could not be ascribed to either spasm or platelet hyperactivity.

To determine the prevalence of alcoholic myopathy and cardiomyopathy, we studied a group of 50 asymptomatic alcoholic men (mean age, 38.5 years) entering an outpatient treatment program. Studies performed included an assessment of muscle strength by electronic myometer, muscle biopsy, echocardiography, and radionuclide cardiac scanning, with comparison to healthy control subjects of similar age. The patients' mean (+/- SEM) daily alcohol consumption was 243 +/- 13 g over an average of 16 years. These patients had no clinical or laboratory signs of malnutrition or electrolyte imbalance. Forty-two percent of the patients, as compared with none of the controls, had strength of less than 20 kg as measured in the deltoid muscle. Muscle-biopsy specimens from 23 patients (46 percent) had histologic evidence of myopathy. In the cardiac studies, when the alcoholic patients were compared with 20 healthy controls, the patients had a significantly lower mean ejection fraction (59 vs. 67 percent), a lower mean shortening fraction (33 vs. 38 percent), a greater mean end-diastolic diameter (51 vs. 49 mm), and a greater mean left ventricular mass (123 vs. 106 g per square meter of body-surface area). One third of the alcoholics had an ejection fraction of 55 percent or less, as compared with none of the controls. Endomyocardial biopsy specimens from six patients with ejection fractions below 50 percent showed histologic changes of cardiomyopathy. The estimated total lifetime dose of ethanol correlated inversely with muscular strength (r = -0.65; P less than 0.001). In an analysis that also included six patients with symptomatic alcoholic cardiomyopathy, the estimated total lifetime dose of ethanol correlated inversely with the ejection fraction (r = -0.58; P less than 0.001) and directly with the left ventricular mass (r = 0.59; P less than 0.001). We conclude that myopathy of skeletal muscle and cardiomyopathy are common among persons with chronic alcoholism and that alcohol is toxic to striated muscle in a dose-dependent manner.

Prevalence, prognosis, and coronary anatomy associated with nontransmural myocardial infarction (MI) were prospectively assessed in 458 consecutive men admitted to our coronary care unit with a first MI. Cardiac catheterization was performed in 402 of the 436 survivors within 1 month of the acute event. Mean follow-up was 33 months (range 5 to 72). Nontransmural MI was diagnosed in 28 patients (6%). These patients were younger (46 +/- 10 versus 51 +/- 7 years, p less than 0.001) and had lower peak creatine kinase values (601 +/- 319 versus 1,141 +/- 923 U, p less than 0.01) and better ejection fraction (63 +/- 8 versus 46 +/- 14, p less than 0.001) than did their counterparts. Survivors of nontransmural MI also had fewer affected arteries (p less than 0.001) and a lower prevalence of total or subtotal occlusion (greater than 90%) in the involved artery (p less than 0.01). Mortality in the acute phase and long-term survival at 4 years (Kaplan-Meier) in patients with nontransmural MI (94%) were similar to those in patients with transmural MI (90%). The occurrence of new nonfatal coronary events was also similar in both groups of MI survivors. Thus, in the absence of symptoms, more aggressive management to improve survival does not seem warranted after nontransmural MI.

Isolated T wave alternans (TWA) could be consistently induced in 13 dogs by infusion of an acid dextrose solution (ACD) and in nine with a 2% EDTA disodium solution. To study the factors concerned in evoking TWA, serial determinations of total and ionized serum calcium (ICa), Mg, K, pH, pCO2 and pO2 were performed. Arterial or LV pressures and LV dp/dt as well as a standard electrocardiographic lead were monitored. TWA appeared after the QT interval was significantly prolonged and was associated with a fall in LV pressure and with mechanical alternans. QT alternans could also be detected in 50% of the cases. ICa levels were significantly reduced at the moment of appearance of the TWA. Data obtained support the conclusion that TWA was the result of a reduction in the level of the ICa, probably interfering with the calcium transport mechanisms of the myocardial cell, although the possibility that the alternans may be due to other effects of the two agents employed unrelated to calcium lowering cannot be excluded.

Two patients with isolated T wave alternans are reported, with their vectocardiograms, their response to carotid sinus stimulation, and the response to calcium infusion in one of them with documented severe hypocalcemia. Eleven cases of the literature are briefly reviewed. The alternans of the T wave appears with severe QT prolongation, QT alternans, and an increased tendency to ventricular fibrillation. The findings are consistent with the hypothesis that T wave alternans may be the electrocardiographic manifestation of the transmembrane action potential alternans and could be related in some cases to hypocalcemia.

Reports of patients undergoing long-term hemodialysis presenting with angina pectoris have usually shown severe coronary atherosclerosis. We studied a series of nine patients undergoing regular maintenance dialysis referred for incapacitating angina. Of them, four had strictly normal coronary angiograms. The patients with normal angiograms were all females who were significantly younger (p less than 0.05) and had more severe hypertension and higher left ventricular wall stress than patients showing coronary artery lesions. Anemia and increased myocardial oxygen consumption due to high blood pressure may explain the syndrome of angina pectoris in the presence of long-term dialysis in patients with normal coronary arteries. The prevalence of this association cannot be ascertained unless prospective studies are conducted. However, our data suggest that it might not be an uncommon finding.

A unique case of severe and diffuse endocardial fibroelastosis covering the entire left ventricle and associated with pseudoxanthoma elasticum is presented. The clinical picture was that of an apparently primary restrictive cardiomyopathy. Specific histologic lesions could be recognized in the endocardium.

Coronary anatomy as it relates to left ventricular function was assessed prospectively in patients who survived acute myocardial infarction. The study population included 259 consecutive male patients age 60 years or younger who underwent catheterization 30 days after the acute event. Coronary artery obstructive lesions (greater than 50% reduction in luminal diameter) were found in 241 patients (93%), 118 (45%) of whom had total and 76 (29%) subtotal (greater than 90%) stenosis) occlusion of at least one coronary artery. Normal coronary vessels were seen in eight patients (3%) and nonobstructive lesions in 10 (4%). One-, two- and three-vessel disease were present in 89, 86 and 66 patients, respectively. Patients with normal coronary arteries or nonobstructive lesions had higher ejection fractions than those with obstructive lesions in one, two or three vessels (p less than 0.05). Ejection fraction was lower (p less than .001) and the percentage of akinetic segments higher (p less than 0.001) in patients with total or subtotal lesions and no collaterals. Adequate collaterals, seen in 29 patients (11%), significantly improved regional wall motion (p less than 0.05) and decreased the percentage of akinetic segments (p less than 0.001). Thus, in a substantial number of patients (32% in our series), the infarcted area is spontaneously reperfused by collaterals or through the involved artery. Both mechanisms ameliorate wall motion in corresponding areas.

To determine the prevalence and significance of the systolic compression of the anterior descending coronary artery in hypertrophic cardiomyopathy, we studied 54 consecutive patients out of a catheterization laboratory population of 1619. This angiographic finding was found to be more prevalent (P less than 0.001) and severe in myopathic than in secondary hypertrophy. Complete systolic occlusion occurred in 5 of the 6 patients with nonobstructive cardiomyopathy showing the systolic narrowing. Severe septal squeezing was also present in these cases and the diastolic time lag to refill the distal branches reached 20-33% of the diastolic period. This subset of patients showed the least dynamic anterior wall contraction (P less than 0.001) and the highest incidence of thallium-201 perfusion defects (P less than 0.05) and of recurrent cardiac arrest (P less than 0.05). We conclude that severe systolic compression of the descending coronary artery in hypertrophic cardiomyopathy may be an angiographic marker of the myopathic hypertrophy extending to the anterior wall and might contribute to ischemia when the time to restore the distal perfusion is greatly delayed.