View Full Version : Jan. 2003 publications-general interest to the HCM community
01-12-2003, 01:01 PM
Genetic causes of inherited cardiac hypertrophy: Robert L. Frye Lecture.
Howard Hughes Medical Institute and Cardiovascular Division, Brigham & Women's Hospital, Boston, Mass, USA.
Cardiac hypertrophy is well recognized as a cardiac manifestation of systemic disorders such as hypertension or intrinsic myocardial disease, but it can also reflect an underlying genetic defect. Molecular studies of inherited forms of cardiac hypertrophy have defined 2 novel pathways that lead to cardiac remodeling in adults, discoveries that increasingly provide insights relevant for both diagnosis and management. This article reviews the genetic studies that led to the current molecular understanding of hypertrophic cardiomyopathy and discusses more recently discovered causes of inherited cardiac hypertrophy.
PMID: 12479519 [PubMed - indexed for MEDLINE]
01-12-2003, 01:01 PM
J Am Coll Cardiol 2002 Dec 18;40(12):2156-64 Related Articles, Links
Myocardial scarring in asymptomatic or mildly symptomatic patients with hypertrophic cardiomyopathy.
Choudhury L, Mahrholdt H, Wagner A, Choi KM, Elliott MD, Klocke FJ, Bonow RO, Judd RM, Kim RJ.
Feinberg Cardiovascular Research Institute, Department of Medicine, Northwestern University, Chicago, Illinois, USA
We sought to ascertain whether myocardial scarring occurs in living unselected patients with hypertrophic cardiomyopathy (HCM).Myocardial scarring is known to occur in select HCM patients, who were highly symptomatic prior to death or who died suddenly. The majority of HCM patients, however, are minimally symptomatic and have not suffered sudden death.Cine and gadolinium-enhanced magnetic resonance imaging was performed in 21 HCM patients who were predominantly asymptomatic. Gadolinium hyperenhancement was assumed to represent myocardial scar, and the extent of scar was compared to left ventricular (LV) morphology and function.Scarring was present in 17 patients (81%). Scarring occurred only in hypertrophied regions (>/=10 mm), was patchy with multiple foci, and predominantly involved the middle third of the ventricular wall. All 17 patients had scarring at the junction of the interventricular septum and the right ventricular (RV) free wall. On a regional basis, the extent of scarring correlated positively with wall thickness (r = 0.36, p < 0.0001), and inversely with wall thickening (r = -0.21, p < 0.0001). On a per patient basis, the extent of scarring (mean, 8 +/- 9% of LV mass) was minimally related to maximum wall thickness (r = 0.40, p = 0.07) and LV mass (r = 0.33, p = 0.15), and correlated inversely with ejection fraction (r = -0.46, p = 0.04).Myocardial scarring is common in asymptomatic or mildly symptomatic HCM patients who have not suffered sudden death. When present, scarring occurs in hypertrophied regions, is consistently localized to the junctions of the septum and RV free wall, and correlates positively with regional hypertrophy and inversely with regional contraction.
PMID: 12505229 [PubMed - in process]
01-12-2003, 01:02 PM
Circulation 2002 Dec 10;106(24):3085-90 Related Articles, Links
Prevalence and severity of "benign" mutations in the beta-myosin heavy chain, cardiac troponin T, and alpha-tropomyosin genes in hypertrophic cardiomyopathy.
Van Driest SL, Ackerman MJ, Ommen SR, Shakur R, Will ML, Nishimura RA, Tajik AJ, Gersh BJ.
Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minn 55905, USA.
BACKGROUND: Genotype-phenotype correlative studies have implicated 8 particular mutations that cause hypertrophic cardiomyopathy (HCM) as "benign defects," associated with near-normal survival: N232S, G256E, F513C, V606M, R719Q, and L908V of beta-myosin heavy chain (MYH7); S179F of troponin T (TNNT2); and D175N of alpha-tropomyosin (TPM1). Routine genetic screening of HCM patients for specific mutations is anticipated to provide important diagnostic and prognostic information. The frequency and associated phenotype of these mutations in a large, unselected cohort of HCM is unknown. METHODS AND RESULTS: A total of 293 unrelated HCM patients were genotyped for the presence of a benign mutation. DNA was obtained after informed consent; specific MHY7, TNNT2, and TPM1 fragments were amplified by polymerase chain reaction; and the mutations were detected by denaturing high-performance liquid chromatography and automated DNA sequencing. Only 5 (1.7%) of the 293 patients possessed a benign mutation. Moreover, all 5 subjects with an ascribed benign mutation had already manifested clinically severe expression of HCM, with all 5 requiring surgical myectomy, 3 of the 5 having a family history of sudden cardiac death, and 1 adolescent requiring an orthotopic heart transplant. CONCLUSIONS: These findings demonstrate the rarity of specific mutations in HCM and challenge the notion of mutation-specific clinical outcomes. Fewer than 2% of the subjects harbored a benign mutation, and those patients with a benign mutation experienced a very serious clinical course.
PMID: 12473556 [PubMed - indexed for MEDLINE]
01-12-2003, 01:10 PM
Am J Hum Genet 2003 Jan;72(1):101-14 Related Articles, Links
Mutations in COX15 Produce a Defect in the Mitochondrial Heme Biosynthetic Pathway, Causing Early-Onset Fatal Hypertrophic Cardiomyopathy.
Antonicka H, Mattman A, Carlson CG, Glerum DM, Hoffbuhr KC, Leary SC, Kennaway NG, Shoubridge EA.
Montreal Neurological Institute, Montreal, Quebec H3A 2B4, Canada.
Deficiencies in the activity of cytochrome c oxidase (COX), the terminal enzyme in the respiratory chain, are a frequent cause of autosomal recessive mitochondrial disease in infants. These patients are clinically and genetically heterogeneous, and all defects so far identified in this group have been found in genes coding for accessory proteins that play important roles in the assembly of the COX holoenzyme complex. Many patients, however, remain without a molecular diagnosis. We have used a panel of retroviral vectors expressing human COX assembly factors in these patients to identify the molecular basis for the COX deficiency by functional complementation. Here we show that overexpression of COX15, a protein involved in the synthesis of heme A, the heme prosthetic group for COX, can functionally complement the isolated COX deficiency in fibroblasts from a patient with fatal, infantile hypertrophic cardiomyopathy. Mutation analysis of COX15 in the patient identified a missense mutation (C700T) on one allele, changing a conserved arginine to tryptophan (R217W), and a splice-site mutation in intron 3 on the other allele (C447-3G), resulting in a deletion of exon 4. This splicing error introduces a frameshift and a premature stop codon, resulting in an unstable mRNA and, likely, a null allele. Mitochondrial heme A content was reduced in the patient's heart and fibroblast mitochondria, and levels of heme O were increased in the patient's heart. COX activity and the total amount of fully assembled enzyme were reduced by 50%-70% in patient fibroblasts. Expression of COX15 increased heme A content and rescued COX activity. These results suggest that reduced availability of heme A stalls the assembly of COX. This study establishes COX15 as an additional cause, along with SCO2, of fatal infantile, hypertrophic cardiomyopathy associated with isolated COX deficiency.
PMID: 12474143 [PubMed - in process]
01-12-2003, 01:11 PM
Ital Heart J 2002 Oct;3(10):615-9 Related Articles, Links
Noninvasive assessment of intramyocardial coronary flow in hypertrophic cardiomyopathy by high-resolution Doppler echocardiography.
de Gregorio C, Recupero A, Grimaldi P, Coglitore S.
Division of Cardiology and Cardiovascular Pathophysiology, Clinical and Experimental Department of Internal Medicine and Pharmacology, University of Messina, Messina, Italy
Dyspnea and angina have been described in patients with hypertrophic cardiomyopathy (HCM). Given the complexity of the coronary microcirculation, the pathophysiological mechanisms of angina are discussed. The last generation of echo devices allows the investigation of epicardial coronary flow by means of the standard transthoracic approach (TTE). In the present study we describe 5 patients affected by HCM (with outflow tract dynamic obstruction in 2 cases, intraventricular dynamic obstruction in the other 2, no obstruction in the last one) in whom both the epicardial and intramyocardial coronary flows were assessed at high-resolution TTE. Regular flow velocities were shown in epicardial coronary arteries, while in intramyocardial branches the diastolic peak velocity was > 75 cm/s in all patients. Besides, the systolic flow was found to be inverted. Similar to what suggested by the few data presently available in the literature, the main findings of this study confirm the appropriateness of investigating the intramyocardial coronary circulation in patients with HCM by means of high-resolution Doppler echocardiography. In order to explain this clinical finding, an interesting hypothesis of a diastolic "milking-like" phenomenon associated with systolic "blood squeezing" in the intramural coronary arteries was taken into consideration. The noninvasive study of the intramyocardial coronary flow may be clinically relevant even in the evaluation of the effectiveness of the adopted therapeutic strategy in reducing myocardial wall stress in severe ventricular hypertrophy.
PMID: 12478823 [PubMed - in process]
01-12-2003, 01:12 PM
Basic Res Cardiol 2002;97 Suppl 1:I102-10 Related Articles, Links
Molecular mechanisms of cardiac myofilament activation: modulation by pH and a troponin T mutant R92Q.
Solaro RJ, Varghese J, Marian AJ, Chandra M.
Department of Physiology and Biophysics (M/C 901), College of Medicine, University of Illinois at Chicago, 835 South Wolcott Avenue, Chicago, IL 60612-7342, USA.
Activation of cardiac myofilaments is a complex process involving steric, allosteric, and cooperative mechanisms. The complexity of the protein-protein interactions that result in the rise and fall of tension in the heartbeat provide many points that may be modified by various control mechanisms. These include modulation by the sarcomere length, covalent modulation by protein phosphorylation and non-covalent modulation by the chemical environment surrounding the myofilaments. We focus here on effects of pH change in the context of one of the mutations in cardiac troponin T (R92Q) that causes familial hypertrophic cardiomyopathy (FHC). We tested whether this change in charge would manifest itself functionally by a difference in the pCa-force relations of skinned fiber bundles activated at pH values of 6.5, 7.0 and 7.5. Fiber bundles containing the cTnT-R92Q mutant demonstrated an increase in sensitivity to Ca2+ at all three pH values. However, the relative magnitude of the increase in Ca2+-sensitivity induced by the mutant cTnT increased as the pH was decreased from pH 7.5 to pH 7.0 and to pH 6.5. Maximum force generated by the myofilaments fell as pH was lowered over this range, but the percent fall in maximum force was the same for fiber bundles containing wild-type and mutant cTnT. Our results indicate that ischemia that may be associated with FHC may exacerbate the functional changes induced by the cTnT mutation.
PMID: 12479243 [PubMed - indexed for MEDLINE]
01-12-2003, 01:13 PM
Z Kardiol 2002 Dec;91(12):992-1002 Related Articles, Links
Fabry disease in patients with hypertrophic cardiomyopathy (HCM).
Beer G, Reinecke P, Gabbert HE, Hort W, Kuhn H.
Department of Cardiology and Internal Intensive Care The Bielefeld Klinikum Teutoburgerstr. 50 33604 Bielefeld, Germany.
Fabry disease is an X-linked recessive lysosomal storage disorder with variable phenotype characterized by the accumulation of glycosphingolipid in various tissues. Unlike patients with the classical systemic Fabry disease entity, who present with multiple organ involvement, patients with a cardiac variant of Fabry disease are characterized mainly by myocardial hypertrophy. Therefore, the cardiac variant of Fabry disease may be defined as a cardiomyocytic storage disorder, thus, mimicking the clinical features of hypertrophic obstructive and especially non-obstructive cardiomyopathy. In patients with unexplained left ventricular hypertrophy the diagnosis of a cardiac variant of Fabry disease is performed by light- and electron microscopic evaluation of endomyocardial catheter biopsy specimens and/or serologic investigations (decreased activity of alpha-galactosidase A in plasma or leucocytes). Several studies show that between 4% and 8% of unselected patients with the clinical features of hypertrophic non-obstructive cardiomyopathy have a cardiac variant of Fabry disease. In each patient with unexplained myocardial hypertrophy concealed myocardial storage disease, especially cardiac Fabry disease has to be considered and should be ruled out or confirmed by endomyocardial catheter biopsy. This is important because of the recently reported alpha-galactosidase A enzyme replacement therapy in Fabry disease. Randomized, multicenter studies are mandatory to test the hypothesis that enzyme replacement therapy leads to a beneficial clinical effect in the cardiac variant form of Fabry disease and may prevent the progression of the disease in asymptomatic patients.
PMID: 12490989 [PubMed - in process]
01-12-2003, 01:20 PM
J Cardiovasc Electrophysiol 2002 Dec;13(12):1300-2 Related Articles, Links
Pulmonary vein firing triggering atrial fibrillation after open heart surgery.
Saad EB, Saliba WI, Marrouche NF, Natale A.
The Center for Atrial Fibrillation, Department of Cardiovascular Medicine, Section of Cardiac Pacing and Electrophysiology, The Cleveland Clinic Foundation, Cleveland Ohio 44195, USA.
We report the case of a 44-year-old woman with obstructive hypertrophic cardiomyopathy without history of prior arrhythmias who underwent surgical myectomy. She developed symptomatic postoperative atrial fibrillation (AF) that was refractory to antiarrhythmic therapy and could not be adequately rate controlled. AF always was preceded by short and fast runs of atrial tachycardia. In the electrophysiology laboratory, this arrhythmia appeared to originate from the right superior pulmonary vein and conducted with variable degrees of exit block. Pulmonary vein isolation guided by circular mapping was performed, and no further episodes of either atrial tachycardia or AF were noted. This case highlights the potential role of the pulmonary veins in the pathophysiology of postoperative AF.
01-12-2003, 01:23 PM
J Intern Med 2002 Dec;252(6):529-36 Related Articles, Links
Sudden cardiac death in 15-35-year olds in Sweden during 1992-99.
Wisten A, Forsberg H, Krantz P, Messner T.
Department of Internal Medicine, Sunderby Hospital, Lulea, Sweden.
OBJECTIVES: To study the incidence, pathogenesis and symptoms preceding sudden cardiovascular death amongst 15-35-year olds without substance abuse in Sweden during 1992-99. DESIGN: This was a register study of a national database of forensic medicine, Rattsbase. Clinical details were obtained from forensic, police and medical records and from interviews with family members. SETTING: The whole nation of Sweden. SUBJECTS: Individuals having suffered a sudden cardiac death. RESULTS: We found 181 cases of sudden cardiovascular death in a nationwide database, Rattsbase, in 15-35-year olds, of which 132 (73%) were male and 49 (27%) were female, and a rather stable incidence of 0.93 per 100,000 per year. Preceding symptoms were seen in half of the cases. The most common forensic diagnoses were: no structural abnormality (21.0%), coronary atherosclerosis (17.7%), dilated cardiomyopathy (12.2%), hypertrophic cardiomyopathy (10.5%) and myocarditis (10.5%). CONCLUSION: Sudden cardiovascular death was uncommon in the young, but the incidence was not decreasing. Postmortem diagnoses were often difficult to establish. There was a high frequency of structurally normal hearts. Because premortal cardiac-related symptoms are relatively common and treatment methods are developing, we should learn to recognize early symptoms of heart disease. To identify individuals at risk, further studies of preceding symptoms, life-style factors and electrocardiogram (ECG) changes are needed.
PMID: 12472914 [PubMed - in process]
01-12-2003, 01:24 PM
Expert Rev Mol Diagn 2002 Nov;2(6):587-602 Related Articles, Links
Molecular diagnosis of myocardial disease.
Towbin JA, Bowles NE.
Department of Pediatrics Cardiology, Baylor College of Medicine, One Baylor Plaza, Room 333E, Houston, TX 77030, USA.
Myocardial disorders are major causes of morbidity and mortality, including heart failure, sudden death and the need for heart transplantation. The two most common forms of myocardial disorders, dilated cardiomyopathy and hypertrophic cardiomyopathy are paradigms of left ventricular systolic dysfunction and diastolic dysfunction. The genetics of these disorders are increasingly understood with the sarcomere playing a central role in the development of HCM and the link between sarcomere and sarcolemma being key to the development of DCM. In this review, the genetics of the myocardial diseases will be described.
PMID: 12465455 [PubMed - in process]
01-12-2003, 01:25 PM
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J Am Coll Cardiol 2002 Nov 20;40(10):1864-9 Related Articles, Links
Risk associated with pregnancy in hypertrophic cardiomyopathy.
Autore C, Conte MR, Piccininno M, Bernabo P, Bonfiglio G, Bruzzi P, Spirito P.
Dipartimento di Scienze Cardiovascolari e Respiratorie, Universita La Sapienza, Viale del Policlinico 155, 00161 Rome, Italy.
OBJECTIVES: We sought to assess mortality and morbidity in pregnant women with hypertrophic cardiomyopathy (HCM). BACKGROUND: The risk associated with pregnancy in women with HCM is an important and increasingly frequent clinical issue for which systematic data are not available and a large measure of uncertainty persists. METHODS: Maternal mortality in 91 consecutively evaluated families with HCM was compared with that reported in the general population. The study cohort included 100 women with HCM with one or more live births, for a total of 199 live births. Morbidity related to HCM during pregnancy was investigated in 40 women evaluated within five years of their pregnancy. RESULTS: Two pregnancy-related deaths occurred, both in patients at a particularly high risk. The maternal mortality rate was 10 per 1,000 live births (95% confidence interval [CI] 1.1 to 36.2/1,000) and was in excess of the expected mortality in the general Italian population (relative risk 17.1, 95% CI 2.0 to 61.8). In the 40 patients evaluated within close proximity of their pregnancy, 1 (4%) of the 28 who were previously asymptomatic and 5 (42%) of the 12 with symptoms progressed to functional class III or IV during pregnancy (p < 0.01). One patient had atrial fibrillation and one had syncope, both of whom had already experienced similar and recurrent events before their pregnancy. CONCLUSIONS: Maternal mortality is increased in patients with HCM compared with the general population. However, absolute maternal mortality is low and appears to be principally confined to women at a particularly high risk. In the presence of a favorable clinical profile, the progression of symptoms, atrial fibrillation, and syncope are also uncommon during pregnancy.
PMID: 12446072 [PubMed - indexed for MEDLINE]
01-12-2003, 01:26 PM
J Nucl Cardiol 2002 Nov-Dec;9(6):594-600 Related Articles, Links
Gated SPECT in patients with hypertrophic obstructive cardiomyopathy undergoing transcoronary ethanol septal ablation.
Keng FY, Chang SM, Cwajg E, He ZX, Lakkis NM, Nagueh SF, Spencer WH 3rd, Verani MS.
Section of Cardiology, Baylor College of Medicine and The Methodist Hospital, Houston, Tex.
Background. Transcoronary ethanol septal ablation (TESA) is a novel treatment for obstructive hypertrophic cardiomyopathy (HOCM). Our objective was to evaluate the use of gated single photon emission computed tomography (SPECT) in patients with HOCM and the effects of TESA on myocardial perfusion. Methods and Results. We performed gated SPECT and Doppler echocardiography before and 6 weeks after TESA in 30 patients with severe HOCM. The lung-to-heart and septal-to-lateral wall count-activity ratios were calculated. Before ablation, SPECT showed perfusion abnormalities in only 6 patients. Asymmetric septal hypertrophy was noted in 21 patients (70%). In patients with a lung-to-heart ratio greater than 0.50 before ablation, the ratio decreased from 0.56 +/- 0.04 to 0.45 +/- 0.08 after ablation (P <.01). The septal-to-lateral wall ratio also decreased significantly after ablation. Mean Doppler pressure gradient across the left ventricular outflow tract decreased from 52 +/- 39 mm Hg to 13 +/- 13 mm Hg (P <.01) immediately after ablation and to 10 +/- 21 mm Hg 6 weeks later (P <.01). There were no significant changes in left ventricular ejection fraction by gated SPECT after the procedure. SPECT studies done after ablation showed fixed septal defects in 29 of 30 patients (96.7%). The defects involved the basal and mid septum in 100% and 38% of patients, respectively, and ranged in size from 2% to 30% of the left ventricle (mean, 8.8% +/- 7.0%). Conclusions. TESA is an effective technique for relieving left ventricular outflow obstruction in patients with HOCM. Myocardial gated SPECT can identify the presence and location of infarction after TESA.
PMID: 12466783 [PubMed - in process]
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