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Hypertrophic cardiomyopathy in Northern Sweden: with special emphasis on molecular genetics
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine. (Kardiologi)
2004 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Hypertrophic cardiomyopathy (HCM) is a heterogeneous, often familial disease, characterized by cardiac hypertrophy, predominantly affecting the interventricular septum. To date, no study has systematically analysed the genetic and phenotypic aspects of the disease in a Swedish population. The aim of this thesis was to identify the genotypes causing HCM in northern Sweden, to characterize the disease phenotypes and correlate these findings.

Forty-six patients were recruited for the genetic studies (21 women), 11 familial and 35 sporadic cases. Eight sarcomeric protein genes were screened for mutations. A total of 11 different disease causing mutations were found in four genes. Six of the mutations were previously not described. A novel mutation (a 33 base pair deletion) in the troponin I gene was found in one HCM family. Despite the severe genetic defect, the associated phenotype displayed only mild cardiac hypertrophy and few symptoms. Most mutations (64%) were identified in the myosin binding protein C gene, a gene considered to have a low penetrance. Mutations were identified in 10 of 11 familial HCM cases, but only in three of the 35 sporadic cases.

It was found that cardiac amyloidosis can sometimes present itself as HCM. Three HCM patients (7%) carried the ATTR Val30Met mutation, also found in Swedish patients with familial amyloid polyneuropathy (FAP). The patients had no symptoms of polyneuropathy, but cardiac amyloidosis as the cause of hypertrophy was verified by myocardial biopsy in an index case. Amyloid heart disease should therefore be considered as a differential diagnosis in patients with HCM.

By studying heart rate variability (HRV), it was found that young patients with HCM had signs of autonomic dysfunction, expressed as a reduced HRV. Treatment with beta-blockade attenuated these effects. Abnormal autonomic function might be a substrate for lethal arrhythmias, most often encountered in younger patients with HCM. The results suggest a possible protective effect of beta-blockade, remaining to be studied further.

Ventricular function is frequently abnormal in HCM. In particular, diastolic dysfunction has been demonstrated. The recently described myocardial performance index allows the assessment of cardiac function by combining systolic and diastolic performance. We found that patients with hypertrophic cardiomyopathy had evidence of global and regional right ventricular dysfunction, besides left ventricular dysfunction. Hypertrophic cardiomyopathy is traditionally considered to be a disease of the left ventricle. The results show that hypertrophic cardiomyopathy should more be regarded as a biventricular disease.

In conclusion, the myosin binding protein C gene is the most common gene causing familial HCM in northern Sweden. This disease gene is considered to be associated with a mild, late-onset disease with ≈50% penetrance at 30 years of age. The low disease penetrance emphasizes the importance of adequate family screening when evaluating patients with HCM, since the familial nature of the disease might easily be overlooked. These particular disease features in northern Sweden contrast to most previous reports, which indicate another disease gene as the most frequent in HCM, associated with a much higher penetrance. Amyloid heart disease, requiring different treatment than HCM, should be kept in mind as a differential diagnosis in the management of patients with HCM.

Key words: Hypertrophic cardiomyopathy, genetics, autonomic nervous system, familial amyloid polyneuropathy, echocardiography.

Place, publisher, year, edition, pages
2004.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 894
Keyword [en]
Hypertrophic cardiomyopathy, genetics, autonomic nervous system, familial amyloid polyneuropathy, echocardiography
Research subject
Epidemiology
Identifiers
URN: urn:nbn:se:umu:diva-274ISBN: 91-7305-660-X (print)OAI: oai:DiVA.org:umu-274DiVA: diva2:142914
Public defence
2004-05-28, Sal E04, Byggnad 6E, Norrlands Universitetssjukhus, Umeå, 09:00 (English)
Opponent
Available from: 2004-05-10 Created: 2004-05-10 Last updated: 2010-08-10Bibliographically approved
List of papers
1. Deletion in the cardiac troponin I gene in a family from Northern Sweden with hypertrophic cardiomyopathy
Open this publication in new window or tab >>Deletion in the cardiac troponin I gene in a family from Northern Sweden with hypertrophic cardiomyopathy
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2000 (English)In: Journal of Molecular and Cellular Cardiology, ISSN 0022-2828, E-ISSN 1095-8584, Vol. 32, no 3, 521-525 p.Article in journal (Refereed) Published
Abstract [en]

The cardiac troponin I gene has been described to be associated with hypertrophic cardiomyopathy. Until now, mutations in this gene have been found only in the Japanese population. We now present the first non-Japanese family, from northern Sweden, with a mutation in the cardiac troponin I gene. Clinical diagnose was based on echocardiography, with a maximum left ventricular wall thickness of >13 mm, or major electrocardiographic abnormalities, excluding subjects with other known causes of cardiac hypertrophy. Mutation screening was performed with a single-strand conformation polymorphism analysis and identification of mutation by direct DNA sequencing. We have identified a 33-bp deletion in exon 8 encompassing the stop codon. Nine individuals in three generations were tested, and four were carriers of this deletion. The mother was genetically affected and died of heart failure aged 90. Echocardiography at 71 years of age revealed no hypertrophy, but the electrocardiogram showed signs of left ventricular hypertrophy. Her two sons, also genetically affected, had left ventricular hypertrophy, with maximum wall thickness of 15 and 16 mm, respectively. One daughter and four grandchildren were clinically unaffected, but one of them, a 27-year-old woman with maximum wall thickness of 8 mm and normal electrocardiogram, was found to be genetically affected. In conclusion, we describe a non-Japanese family in which hypertrophic cardiomyopathy is due to a genetic defect in the cardiac troponin I gene. This mutation is a deletion of 33 bp in the last exon, whereas the previously described mutations in this gene are single nucleotide changes and a single codon deletion. The deletion of the C-terminal part of the cardiac troponin I protein, seems in this particular family to be associated with a mild phenotypic expression of familial hypertrophic cardiomyopathy.

Keyword
Cardiac troponin I, Familial hypertrophic cardiomyopathy, Genetics, Mutation
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:umu:diva-3982 (URN)10.1006/jmcc.1999.1099 (DOI)10731450 (PubMedID)
Available from: 2004-05-10 Created: 2004-05-10 Last updated: 2017-12-14Bibliographically approved
2. Identification of the genotypes causing hypertrophic cardiomyopathy in northern Sweden
Open this publication in new window or tab >>Identification of the genotypes causing hypertrophic cardiomyopathy in northern Sweden
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2003 (English)In: Journal of Molecular and Cellular Cardiology, ISSN 0022-2828, E-ISSN 1095-8584, Vol. 35, no 7, 841-849 p.Article in journal (Refereed) Published
Abstract [en]

Hypertrophic cardiomyopathy (HCM) is a heterogenous disease, with variable genotypic and phenotypic expressions, often caused by mutations in sarcomeric protein genes. The aim of this study was to identify the genotypes and associated phenotypes related to HCM in northern Sweden. In 46 unrelated individuals with familial or sporadic HCM, mutation analysis of eight sarcomeric protein genes was performed; the cardiac beta-myosin heavy chain, cardiac myosin-binding protein C, cardiac troponin T, alpha-tropomyosin, cardiac essential and regulatory myosin light chains, cardiac troponin I and cardiac alpha-actin. A total of 11 mutations, of which six were novel ones, were found in 13 individuals. Seven mutations were located in the myosin-binding protein C gene, two in the beta-myosin heavy chain gene and one in the regulatory myosin light chain and troponin I genes, respectively. This is the first Swedish study, where a population with HCM has been genotyped. Mutations in the cardiac myosin-binding protein C gene were the most common ones found in northern Sweden, whereas mutations in the beta-myosin heavy chain gene were less frequent than previously described. There are differences in the phenotypes mediated by these genes characterised by a more late-onset disease for the myosin-binding protein C gene mutations. This should be taken into consideration, when evaluating clinical findings in the diagnosis of the disease, especially in young adults in families with HCM, where penetrance can be expected to be incomplete in the presence of a myosin-binding protein C gene mutation.

Keyword
Sarcomeric proteins, Hypertrophic cardiomyopathy, Genetics, Mutation
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:umu:diva-3983 (URN)10.1016/S0022-2828(03)00146-9 (DOI)12818575 (PubMedID)
Available from: 2004-05-10 Created: 2004-05-10 Last updated: 2017-12-14Bibliographically approved
3. Parasympathetic dysfunction in hypertrophic cardiomyopathy assessed by heart rate variability: comparison between short-term and 24-h measurements
Open this publication in new window or tab >>Parasympathetic dysfunction in hypertrophic cardiomyopathy assessed by heart rate variability: comparison between short-term and 24-h measurements
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2005 (English)In: Clinical Physiology and Functional Imaging, ISSN 1475-0961, E-ISSN 1475-097X, Vol. 25, no 2, 90-99 p.Article in journal (Other academic) Published
Abstract [en]

In this study, we evaluate cardiac autonomic function in hypertrophic cardiomyopathy (HCM) by assessing heart rate variability (HRV), comparing a short-term laboratory method with an ambulatory (24-h) method, in patients with and without beta-blockade. Reduced HRV is a risk factor for adverse events in some cardiac diseases, but is not a proven risk indicator in HCM. Analysis of HRV has been based on either short- or long-term electrocardiographic recordings and previous studies in HCM have shown conflicting results. There is no consensus on which method to prefer, and we evaluate, for the first time, both short- and long-term analyses in patients with HCM. Long- and short-term HRV analyses were performed in 43 patients with HCM. They were divided in two groups, 22 patients on beta-blockade and 21 non-treated patients. As controls, 121 healthy subjects were used. Young patients without beta-blockade showed a reduction in HRV parameters reflecting parasympathetic function, both in the short- and long-term registrations, which was attenuated by beta-blockade. Parasympathetic autonomic regulation was found to be impaired in young patients with HCM. This may be of clinical relevance as abnormal autonomic function might be a substrate for malignant dysrhythmias. The impairment was attenuated by beta-blockade, which might indicate a clinically useful effect. We also show that short- and long-term methods yield similar results, suggesting that a short-term registration might be sufficient to assess HRV in patients with HCM.

Keyword
Autonomic nervous system, cross-sectional study, heart rate variability, hypertrophic cardiomyopathy
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:umu:diva-14178 (URN)10.1111/j.1475-097X.2004.00595.x (DOI)15725307 (PubMedID)
Available from: 2007-04-20 Created: 2007-04-20 Last updated: 2017-12-14Bibliographically approved
4. Amyloid heart disease mimicking hypertrophic cardiomyopathy.
Open this publication in new window or tab >>Amyloid heart disease mimicking hypertrophic cardiomyopathy.
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2005 (English)In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 258, no 3, 225-230 p.Article in journal (Refereed) Published
Abstract [en]

OBJECTIVE: To investigate the importance of transthyretin (TTR) gene mutations in explaining the phenotypic expression in patients diagnosed with hypertrophic cardiomyopathy (HCM) in northern Sweden. BACKGROUND: Hypertrophic cardiomyopathy is relatively common and often caused by mutations in sarcomeric protein genes. Mutations in the TTR gene are also common, one of which causes familial amyloid polyneuropathy (FAP), with peripheral polyneuropathy and frequently, cardiac hypertrophy. These circumstances were highlighted by the finding of an index case with amyloidosis, presenting itself as HCM. Initial rectal and fat biopsies did not show amyloid deposits. Later on, the patient was shown to carry a TTR gene mutation, and cardiac amyloidosis was confirmed by myocardial biopsy. Only then was a repeated fat biopsy positive for amyloid deposits. DESIGN: Cross-sectional study. SETTING: Cardiology tertiary referral centre. SUBJECTS: Forty-six unrelated individuals with HCM and the index case were included. Common diagnostic criteria for HCM were used. The 46 patients with HCM were previously analysed for mutations in eight sarcomeric protein genes and the TTR gene was now analysed by denaturing high-performance liquid chromatography and direct sequencing. RESULTS: One mutation in the TTR gene (Val30Met) was found in three individuals and the index case. CONCLUSIONS: Three of the 46 cases with HCM carried the Val30Met mutation, and were considered likely to have cardiac amyloidosis, like the index case. As a correct diagnosis of cardiac amyloidosis is mandatory for a potentially life-saving treatment, TTR mutation analysis should be considered in cases of HCM not explained by mutations in sarcomeric protein genes.

Keyword
Adult, Aged, Aged, 80 and over, Amyloid Neuropathies, Familial/diagnosis/*genetics, Cardiology Service, Hospital, Cardiomyopathy, Hypertrophic/diagnosis/*genetics, Cross-Sectional Studies, DNA Mutational Analysis, Diagnosis, Differential, Humans, Male, Middle Aged, Point Mutation, Prealbumin/*genetics
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:umu:diva-14815 (URN)10.1111/j.1365-2796.2005.01522.x (DOI)16115295 (PubMedID)
Available from: 2007-06-18 Created: 2007-06-18 Last updated: 2017-12-14Bibliographically approved
5. Right ventricular dysfunction in hypertrophic cardiomyopathy as evidenced by the myocardial performance index
Open this publication in new window or tab >>Right ventricular dysfunction in hypertrophic cardiomyopathy as evidenced by the myocardial performance index
2007 (English)In: International Journal of Cardiology, ISSN 0167-5273, E-ISSN 1874-1754, Vol. 124, no 1, 57-63 p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Left ventricular function in hypertrophic cardiomyopathy (HCM) has been extensively studied, whereas right ventricular function is much less explored. The myocardial performance index (MPI) has been shown to be useful in functional assessment of both ventricles. Furthermore, right ventricular MPI was found to be of predictive value in heart failure due to dilated cardiomyopathy and ischemic heart disease. The aim of this study was, therefore, to evaluate the right ventricular MPI in patients with HCM. METHODS: Fifty patients with HCM and 250 healthy controls were studied by conventional Doppler echocardiography and Doppler tissue imaging. RESULTS: Patients showed increased global, 0.48 (0.15) vs. 0.21 (0.14), and regional, 0.71 (0.23) vs. 0.55 (0.17), right ventricular MPI, as compared to controls, p<0.001. Tricuspid annular plane systolic excursion and peak myocardial systolic velocities were also reduced. Patients with dyspnoea had increased global right ventricular MPI (0.53 vs. 0.36, p<0.05) as compared to those without dyspnoea. CONCLUSION: In the present study, patients with HCM showed evidence of both global and regional right ventricular dysfunction. Previous studies of the right ventricle in HCM have only shown evidence of diastolic dysfunction, contrary to our results, showing impairment of both systolic and diastolic function. This study suggests that HCM should not only be regarded as an isolated disease of the left ventricle, but rather as a biventricular disease. The predictive value of our findings in HCM needs to be assessed in a separate study with special reference to those with and without dyspnoea.

Keyword
Hypertrophic cardiomyopathy, Echocardiography, Myocardial performance index, Doppler tissue imaging
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:umu:diva-16346 (URN)10.1016/j.ijcard.2006.12.022 (DOI)17383757 (PubMedID)
Available from: 2009-01-16 Created: 2009-01-16 Last updated: 2017-12-14Bibliographically approved

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