Pertti Jääskeläinen

Mutations in the cardiac myosin-binding protein C gene are the predominant cause of familial hypertrophic cardiomyopathy in eastern Finland

Hypertrophic cardiomyopathy (HCM) is a genetic disorder characterized by cardiac hypertrophy caused by mutations in genes encoding sarcomere proteins. This study screened all patients with HCM from the Kuopio University Hospital region in eastern Finland for variants in the cardiac myosin-binding protein C gene ( MYBPC3). All 35 exons of MYBPC3 were screened by the single-strand conformation polymorphism method in 37 unrelated patients with HCM. In MYBPC3 we identified seven novel (Gln1061X, IVS5-2A→C, IVS14-13G→A, Ex25ΔLys, Pro147Leu, Ser236Gly, and Arg1138His) and two previously reported (Arg326Gln, Val896Met) variants, all of which are predicted to affect the structure of the encoded protein. Four of the nine variants, a nonsense mutation Gln1061X, a splice acceptor mutation (IVS5-2A→C), a novel substitution in intron 14 (IVS14-13G→A), and a novel 3-bp deletion in exon 25 (Ex25ΔLys) were concluded to be disease-causing mutations because they cosegregated with the HCM phenotype or were absent in more than 200 normal chromosomes, or both. The mutation Gln1061X was found most frequently, being present in 6 families (23 subjects) while the other three mutations were found in single families each. Haplotype analysis indicated a likely founder effect among the families carrying the Gln1061X mutation. We found four novel mutations in MYBPC3, accounting for approx. 38% of familial and 24% of all cases of HCM. In our previous and unpublished studies no more frequent cause of HCM has been found in genetic analyses of other eight sarcomeric proteins. Consequently MYBPC3 is the predominant gene for HCM in eastern Finland. In addition, several amino acid substitutions in MYBPC3 suspected to be not associated with HCM were identified, indicating that some of the missense variants found in MYBPC3 are possibly not disease-causing mutations.

The cardiac β-myosin heavy chain gene is not the predominant gene for hypertrophic cardiomyopathy in the Finnish population

OBJECTIVES The aim of the study was to screen 36 unrelated patients with hypertrophic cardiomyopathy (HCM; 16 familial and 20 sporadic cases) from a genetically homogeneous area in eastern Finland for variants in the cardiac beta-myosin heavy chain (beta-MHC) and alpha-tropomyosin (alpha-TM) genes. BACKGROUND Mutations in the beta-MHC and alpha-TM genes have been reported to be responsible for 30% to 40% and less than 5% of familial HCM cases, respectively. However, most genetic studies have included patients from tertiary care centers and are subject to referral bias. METHODS Exons 3-26 and 40 of the beta-MHC gene and the nine exons of the alpha-TM gene were screened with the PCR-SSCP (polymerase chain reaction-single strand conformation polymorphism) method. Linkage analyses between familial HCM locus and two intragenic polymorphic markers (MYO I and MYO II) of the beta-MHC gene were performed in 16 familial HCM kindreds. RESULTS A previously reported Arg719Trp (arginine converted to tryptophan in codon 719) mutation of the beta-MHC gene was found in one proband and two relatives. In addition, a novel Asn696Ser (asparagine converted to serine in codon 696) substitution was found in one HCM patient. No linkage between familial HCM and the beta-MHC gene was observed in 16 familial kindreds. A previously reported Aspl75Asn (aspartic acid converted to asparagine in codon 175) mutation of the alpha-TM gene was found in four probands and 16 relatives. Mutations in the beta-MHC and alpha-TM genes accounted for 6% and 25% familial HCM cases and 3% and 11% of all cases, respectively. CONCLUSIONS Our results indicate that the beta-MHC gene is not the predominant gene for HCM in the Finnish population, whereas HCM caused by the Aspl75Asn mutation of the a-TM gene is more common than previously reported.

Genetics of hypertrophic cardiomyopathy in eastern Finland: few founder mutations with benign or intermediary phenotypes

Hypertrophic cardiomyopathy (HCM) is a genetically and clinically heterogeneous myocardial disease caused by mutations in genes encoding sarcomeric proteins. To assess the genetic background and phenotypic expression of HCM in eastern Finland, we screened 35 unrelated patients with HCM from the Kuopio University Hospital area for variants in 9 genes encoding sarcomeric proteins with the PCR‐SSCP method. We herewith describe our previous findings in five sarcomeric genes and also report hitherto unpublished data on four additional sarcomeric genes. Mutations in the cardiac myosin‐binding protein C gene (MYBPC3) were most frequent, accounting for 26% of cases. A novel mutation (Gln1061X) in this gene was the most common mutation, found in 6 of 35 families and accounting for 17% of all cases. Other novel mutations in MYBPC3 (IVS5‐2A → C, IVS14‐13G → A, and Ex25ΔLys) were found in one family each. A previously described α‐tropomyosin (TPM1) mutation (Asp175Asn) was found in 11% of cases. Haplotype analysis suggested that the two most common variants (MYBPC3‐Gln1061X and TPM1‐Asp175Asn) were founder mutations. Only one mutation (Arg719Trp) in the β‐myosin heavy chain gene (MYH7) was found in one family, and no disease‐causing mutations were found in the genes encoding α‐actin, cardiac troponin I, T, C, or myosin essential and regulatory light chains. Altogether, the aforementioned 6 mutations found in MYBPC3, TPM1, and MYH7 accounted for 61% of familial and 40% of all HCM cases. The mutations were associated mostly with benign or intermediary phenotypes with only few HCM‐related deaths. We conclude that the genetic profile of HCM in eastern Finland is unique, characterized by few founder mutations with benign or intermediary phenotypes.

Repetitive use of levosimendan for treatment of chronic advanced heart failure: Clinical evidence, practical considerations, and perspectives: An expert panel consensus

BACKGROUND The intravenous inodilator levosimendan was developed for the treatment of patients with acutely decompensated heart failure. In the last decade scientific and clinical interest has arisen for its repetitive or intermittent use in patients with advanced chronic, but not necessarily acutely decompensated, heart failure. Recent studies have suggested long-lasting favourable effects of levosimendan when administered repetitively, in terms of haemodynamic parameters, neurohormonal and inflammatory markers, and clinical outcomes. The existing data, however, requires further exploration to allow for definitive conclusions on the safety and clinical efficacy of repetitive use of levosimendan. METHODS AND RESULTS A panel of 30 experts from 15 countries convened to review and discuss the existing data, and agreed on the patient groups that can be considered to potentially benefit from intermittent treatment with levosimendan. The panel gave recommendations regarding patient dosing and monitoring, derived from the available evidence and from clinical experience. CONCLUSIONS The current data suggest that in selected patients and support out-of-hospital care, intermittent/repetitive levosimendan can be used in advanced heart failure to maintain patient stability. Further studies are needed to focus on morbidity and mortality outcomes, dosing intervals, and patient monitoring. Recommendations for the design of further clinical studies are made.

Two novel mutations in the β-myosin heavy chain gene associated with dilated cardiomyopathy

Dilated cardiomyopathy (DCM) is familial in approximately 20–35% of cases of idiopathic DCM. Several mutations in the different sarcomere protein genes have been reported to cause DCM.

Two founder mutations in the alpha-tropomyosin and the cardiac myosin-binding protein C genes are common causes of hypertrophic cardiomyopathy in the Finnish population

Background. Hypertrophic cardiomyopathy (HCM) is predominantly caused by a large number of various mutations in the genes encoding sarcomeric proteins. However, two prevalent founder mutations for HCM in the alpha-tropomyosin (TPM1-D175N) and myosin-binding protein C (MYBPC3-Q1061X) genes have previously been identified in eastern Finland. Objective. To assess the prevalence of these founder mutations in a large population of patients with HCM from all over Finland. Patients and methods. We screened for two founder mutations (TPM1-D175N and MYBPC3-Q1061X) in 306 unrelated Finnish patients with HCM from the regions covering a population of ∼4,000,000. Results. The TPM1-D175N mutation was found in 20 patients (6.5%) and the MYBPC3-Q1061X in 35 patients (11.4%). Altogether, the two mutations accounted for 17.9% of the HCM cases. In addition, 61 and 59 relatives of the probands were found to be carriers of TPM1-D175N and MYBPC3-Q1061X, respectively. The mutations showed regional clustering. TPM1-D175N was prevalent in central and western Finland, and MYBPC3-Q1061X in central and eastern Finland. Conclusion. The TPM1-D175N and MYBPC3-Q1061X mutations account for a substantial part of all HCM cases in the Finnish population, indicating that routine genetic screening of these mutations is warranted in Finnish patients with HCM.

Significance of Plasma Levels of N-Terminal Pro-B-Type Natriuretic Peptide on Left Ventricular Remodeling in Non-Obstructive Hypertrophic Cardiomyopathy Attributable to the Asp175Asn Mutation in the α-Tropomyosin Gene

Hypertrophic cardiomyopathy (HC) is an inherited heart disease characterized by left ventricular (LV) remodeling. The present study was conducted to investigate the association of N-terminal pro-B-type natriuretic peptide (NT-pro-BNP) levels with LV remodeling on magnetic resonance imaging and procollagen formation in 17 healthy controls and 24 patients with nonobstructive HC attributable to an identical Asp175Asn (aspartic acid to asparagine at codon 175) mutation in the alpha-tropomyosin gene. None of the patients had history of decompensated heart failure, and all patients had normal LV ejection fraction. Patients with HC had higher NT-pro-BNP levels compared with controls (median 60 pmol/L, range <40 to 359, vs <40 pmol/L; p <0.001), but 9 patients with HC had normal NT-pro-BNP levels (<40 pmol/L). In patients with HC, levels of NT-pro-BNP were correlated significantly with LV end-systolic volume index (r = 0.50, p <0.05), LV mass index (r = 0.47, p <0.05), proportion of hypokinetic segments (r = 0.50, p <0.05), and levels of serum aminoterminal propeptide of type III procollagen (r = 0.52, p <0.01). When patients with HC were divided into 3 groups on the basis of their NT-pro-BNP levels, there were statistically significant linear associations of LV end-systolic volume (test for linearity p = 0.034), LV mass index (p = 0.009), proportion of hypokinetic segments (p = 0.016), and levels of serum aminoterminal propeptide of type III procollagen (p = 0.020) with NT-pro-BNP levels over the 3 groups, suggesting a tight relation between LV remodeling and levels of NT-pro-BNP. In conclusion, in patients with nonobstructive HC attributable to an Asp175Asn mutation in the alpha-tropomyosin gene, elevated NT-pro-BNP levels are associated with incipient LV remodeling, suggesting that NT-pro-BNP could be used to diagnose insidious unfavorable LV remodeling in HC.

A new common mutation in the cardiac beta-myosin heavy chain gene in Finnish patients with hypertrophic cardiomyopathy

Abstract Background. In the nationwide FinHCM Study including 306 Finnish patients with hypertrophic cardiomyopathy (HCM), we have previously identified two founder mutations in the alpha-tropomyosin (TPM1-D175N) and myosin-binding protein C (MYBPC3-Q1061X) genes, accounting for 18% of all cases. Objective. To screen additional mutations, previously identified in eastern Finnish cohorts with HCM, in the FinHCM Study population. Patients and methods. Ten mutations in the beta-myosin heavy chain gene (MYH7), TPM1, and MYBPC3 were screened. Results. MYH7-R1053Q was found in 17 of 306 patients (5.6%). No carriers of MYH7-R719W or N696S were found. A novel TPM1-D175G mutation was found in a single patient. MYBPC3 mutations were found in 14 patients: IVS5-2A-C in two, IVS14-13G-A in two, K811del in six, and A851insT in four patients. Altogether, a HCM-causing mutation was identified in 32 patients, accounting for 10.5% of all cases. In addition, two MYBPC3 variants R326Q and V896M with uncertain pathogenicity were found in eight and in 10 patients, respectively. Conclusion. Combining the present findings with our previous results, a causative mutation was identified in 28% of the FinHCM cohort. MYH7-R1053Q was the third most common mutation, and should be screened in all new cases of HCM in Finland.

Simultaneous hypertrophic cardiomyopathy and ventricular septal defect in children.

Our findings are based on clinical observations and not on a designed study. However, in our University Hospital area, all children with suspected or verified HC are sent to the same pediatric cardiologist (TT). Therefore, our patients are probably representative of children with HC, at least in East Finland. Although the number of patients was small, the prevalence of VSD in children with HC was so high, that it is improbable that the association between the 2 diseases is due to chance alone. Larger studies are needed to confirm our results and to show if muscular VSDs are typical of all HC cases or of specific subgroups only. We suggest that children with HC should undergo a thorough echocardiographic examination to detect possible muscular VSDs, which are usually readily detected by modern color flow mapping techniques. Importantly, in children with a muscular VSD, the possibility of HC as an underlying pathology should be kept in mind.

Left ventricular mechanical dispersion is associated with nonsustained ventricular tachycardia in hypertrophic cardiomyopathy

Abstract Objective: We assessed the value of speckle tracking two-dimensional (2D) strain echocardiography (2DSE) measured mechanical dispersion (MD) with other imaging and electrocardiographic parameters in differentiating hypertrophic cardiomyopathy (HCM) patients with and without nonsustained ventricular tachycardia (NSVT) on 24-h ambulatory ECG monitoring. Methods and results: We studied 31 patients with HCM caused by the Finnish founder mutation MYBPC3-Q1061X and 20 control subjects with comprehensive 2DSE echocardiography and cardiac magnetic resonance imaging (CMRI). The presence of NSVT was assessed from ambulatory 24-h ECG monitoring. NSVT episodes were recorded in 11 (35%) patients with HCM. MD was significantly higher in HCM patients with NSVT (93 ± 41 ms) compared to HCM patients without NSVT (50 ± 18 ms, p = 0.012) and control subjects (41 ± 16 ms, p < 0.001). MD was the only variable independently associated with the presence of NSVT (OR: 1.60, 95% CI: 1.05–2.45, p = 0.030). Assessed by ROC curves, MD performed best in differentiating between HCM patients with and without NSVT (AUC = 0.81). Conclusions: Increased mechanical dispersion was associated with NSVT in HCM patients on 24-h ambulatory ECG monitoring. Key messages The prediction of sudden cardiac death in hypertrophic cardiomyopathy remains a challenge and novel imaging methods are required to identify individuals at risk of malignant ventricular arrhythmias. Mechanical dispersion by speckle tracking echocardiography is associated with NSVT on 24-h ambulatory ECG monitoring in patients with hypertrophic cardiomyopathy