Henning Bundgaard

Nationwide study of sudden cardiac death in persons aged 1–35 years

AIMS The aim of this investigation was to study the incidence of sudden cardiac death (SCD) in persons aged 1-35 years in a nationwide setting (5.38 million people) by systematic evaluation of all deaths. METHODS AND RESULTS All deaths in persons aged 1-35 years in Denmark in 2000-06 were included. Death certificates were read independently by two physicians. The National Patient Registry was used to retrieve information on prior medical history. All autopsy reports were read and the cause of death was revised based on autopsy findings. We identified 625 cases of sudden unexpected death (10% of all deaths), of which 156 (25%) were not autopsied. Of the 469 autopsied cases, 314 (67%) were SCD. The most common cardiac cause of death was ischaemic heart disease (13%); 29% of autopsied sudden unexpected death cases were unexplained. In 45% of SCD cases, the death was witnessed; 34% died during sleep; 89% were out-of-hospital deaths. Highest possible incidence rate of SCD in the young was 2.8 per 100 000 person-years including non-autopsied cases of sudden unexpected death. Excluding those, the incidence rate declined to 1.9 per 100 000 person-years. CONCLUSIONS A total of 7% of all deaths in the young can be attributed to SCD, when including non-autopsied cases (autopsy ratio 75%). The incidence rate of SCD in the young of 2.8 per 100 000 person-years is higher than previously reported.

The Na, K-ATPase in the failing human heart

The Na, K-ATPase consists of alpha- and beta-subunits and actively transports Na out and K into the myocyte. It is the receptor for cardiac glycosides exerting its positive inotropic effect by inhibiting enzyme activity, decreasing the driving force for the Na/Ca-exchange and increasing cellular content and release of Ca during depolarization. The specific binding capacity for cardiac glycosides is utilized as a tool for Na, K-ATPase quantification with high accuracy and precision. In treatment of patients with heart failure cardiac glycosides improve symptoms and reduce the need for hospitalization without affecting mortality. In endomyocardial biopsies from patients with compromised cardiac function total Na, K-ATPase concentration is decreased by approximately 40% and a correlation between decrease in heart function and decrease in Na, K-ATPase concentration exists. At the subunit level, the alpha1-, alpha3- and beta1-proteins are reduced in human heart failure. During digitalization approximately 30% of remaining Na, K-pumps are occupied by digoxin. Thus, a total of not less than half the Na, K-pumps may be out of function in the myocardium of digitalised heart failure patients. It is still a matter of debate whether a digitalis-like factor exists. There is a pressing need for the identification of its precise chemical structure, properties and quantitative relation to the Na, K-ATPase. It is recommended that cardiac glycosides are prescribed to heart failure patients who are still having heart failure symptoms after institution of mortality reducing therapy. Cardiac glycoside treatment is still the only safe inotropic drug for oral use that improves hemodynamics in patients with compromised cardiac function.

Diagnostic yield, interpretation, and clinical utility of mutation screening of sarcomere encoding genes in Danish hypertrophic cardiomyopathy patients and relatives.

The American Heart Association (AHA) recommends family screening for hypertrophic cardiomyopathy (HCM). We assessed the outcome of family screening combining clinical evaluation and screening for sarcomere gene mutations in a cohort of 90 Danish HCM patients and their close relatives, in all 451 persons. Index patients were screened for mutations in all coding regions of 10 sarcomere genes (MYH7, MYL3, MYBPC3, TNNI3, TNNT2, TPM1, ACTC, CSRP3, TCAP, and TNNC1) and five exons of TTN. Relatives were screened for presence of minor or major diagnostic criteria for HCM and tracking of DNA variants was performed. In total, 297 adult relatives (>18 years) (51.2%) fulfilled one or more criteria for HCM. A total of 38 HCM‐causing mutations were detected in 32 index patients. Six patients carried two disease‐associated mutations. Twenty‐two mutations have only been identified in the present cohort. The genetic diagnostic yield was almost twice as high in familial HCM (53%) vs. HCM of sporadic or unclear inheritance (19%). The yield was highest in families with an additional history of HCM‐related clinical events. In relatives, 29.9% of mutation carriers did not fulfil any clinical diagnostic criterion, and in 37.5% of relatives without a mutation, one or more criteria was fulfilled. A total of 60% of family members had no mutation and could be reassured and further follow‐up ceased. Genetic diagnosis may be established in approximately 40% of families with the highest yield in familial HCM with clinical events. Mutation‐screening was superior to clinical investigation in identification of individuals not at increased risk, where follow‐up is redundant, but should be offered in all families with relatives at risk for developing HCM. Hum Mutat 0,1–8, 2008.

Echocardiographic Strain Imaging to Assess Early and Late Consequences of Sarcomere Mutations in Hypertrophic Cardiomyopathy

Background—Genetic testing identifies sarcomere mutation carriers (G+) before clinical diagnosis of hypertrophic cardiomyopathy (HCM), allowing characterization of initial disease manifestations. Previous studies demonstrated that impaired relaxation develops before left ventricular hypertrophy (LVH). The precise impact of sarcomere mutations on systolic function in early and late disease is unclear. Methods and Results—Comprehensive echocardiography with strain imaging was performed on 146 genotyped individuals with mutations in 5 sarcomere genes. Contractile parameters were compared in 68 preclinical (G+/LVH−), 40 overt (G+/LVH+) subjects with HCM, and 38 mutation (−) normal control relatives. All subjects had normal left ventricular ejection fraction. In preclinical HCM, global and regional peak systolic strain (ϵsys) and longitudinal systolic strain rate were not significantly different from controls, but early diastolic mitral annular velocity (Ea) was reduced by 13%. In overt HCM, there was a significant 27% and 14% decrease in global longitudinal ϵsys and systolic strain rate, respectively, compared with both preclinical HCM and controls (P<0.013 for all comparisons), and a 33% reduction in Ea. Conclusions—Sarcomere mutations have disparate initial effects on diastolic and systolic functions. Preclinical HCM is characterized by impaired relaxation but preserved systolic strain. In contrast, both diastolic and longitudinal systolic abnormalities are present in overt disease despite normal ejection fraction. We propose that diastolic dysfunction is an early consequence of sarcomere mutations, whereas systolic dysfunction results from mutations combined with subsequent pathological remodeling. Identifying mechanistic pathways triggered by these mutations may begin to reshape the clinical paradigm for treatment, based on early diagnosis and disease prevention.

Simvastatin Effects on Skeletal Muscle: Relation to Decreased Mitochondrial Function and Glucose Intolerance

OBJECTIVES Glucose tolerance and skeletal muscle coenzyme Q(10) (Q(10)) content, mitochondrial density, and mitochondrial oxidative phosphorylation (OXPHOS) capacity were measured in simvastatin-treated patients (n = 10) and in well-matched control subjects (n = 9). BACKGROUND A prevalent side effect of statin therapy is muscle pain, and yet the basic mechanism behind it remains unknown. We hypothesize that a statin-induced reduction in muscle Q(10) may attenuate mitochondrial OXPHOS capacity, which may be an underlying mechanism. METHODS Plasma glucose and insulin concentrations were measured during an oral glucose tolerance test. Mitochondrial OXPHOS capacity was measured in permeabilized muscle fibers by high-resolution respirometry in a cross-sectional design. Mitochondrial content (estimated by citrate synthase [CS] activity, cardiolipin content, and voltage-dependent anion channel [VDAC] content) as well as Q(10) content was determined. RESULTS Simvastatin-treated patients had an impaired glucose tolerance and displayed a decreased insulin sensitivity index. Regarding mitochondrial studies, Q(10) content was reduced (p = 0.05), whereas mitochondrial content was similar between the groups. OXPHOS capacity was comparable between groups when complex I- and complex II-linked substrates were used alone, but when complex I + II-linked substrates were used (eliciting convergent electron input into the Q intersection [maximal ex vivo OXPHOS capacity]), a decreased (p < 0.01) capacity was observed in the patients compared with the control subjects. CONCLUSIONS These simvastatin-treated patients were glucose intolerant. A decreased Q(10) content was accompanied by a decreased maximal OXPHOS capacity in the simvastatin-treated patients. It is plausible that this finding partly explains the muscle pain and exercise intolerance that many patients experience with their statin treatment.

Myosin light chain mutations in familial hypertrophic cardiomyopathy: phenotypic presentation and frequency in Danish and South African populations

Editor—Familial hypertrophic cardiomyopathy (FHC) is an autosomal dominant disease, which may afflict as many as 1 in 500 subjects.1 The disease is characterised by an unexplained local or general myocardial hypertrophy and by myocyte disarray.2 Molecular genetic studies have so far identified nine disease associated genes, all of which encode sarcomeric proteins. The two genes in which most mutations have been described are the β-myosin heavy chain ( MYH7 )3 and the myosin binding protein C ( MYBPC3 ) genes,4 each of which may account for up to 30% of all familial cases. Mutations in α-tropomyosin ( TPM1 ),5troponin T ( TNNT2 ),5 6troponin I ( TNNI3 ),6 cardiac α-actin ( ACTC ),7 titin ( TTN ),8 and the essential ( MYL3 ) and the regulatory ( MYL2 ) myosin light chain genes have also been associated with FHC.9 This pronounced genetic heterogeneity may be the principal cause of the phenotypic variability that is seen in FHC. Thus, mutations in TNNT2 seem to be associated with sudden death at a young age,10 11 whereas families with mutations in MYBPC3 are generally characterised by progressive hypertrophy and a late onset of clinical manifestation.12 13 Furthermore, it has been proposed that a certain rare form of hypertrophic cardiomyopathy (HCM), asymmetric septal hypertrophy predominantly confined to the midventricular region, known as the midventricular hypertrophy (MVH) phenotype, may be associated with mutations in the two myosin light chain genes.9 However, limited and contradictory clinical information is available on FHC caused by mutations in these genes.9 14 We have studied MYL2 and MYL3 in 68 consecutively collected FHC families from Denmark and in 130 probands from South Africa. We established the frequency of myosin light chain mutations and assessed whether mutations in these two genes do cause a distinct …

Cardiac manifestations of myotonic dystrophy type 1

AIMS To estimate the degree of cardiac involvement regarding left ventricular ejection fraction, conduction abnormalities, arrhythmia, risk of sudden cardiac death (SCD) and the associations between cardiac involvement and cytosine-thymine-guanine (CTG)-repeat, neuromuscular involvement, age and gender in patients with myotonic dystrophy type 1 (MD1). METHODS AND RESULTS A Pub-Med search for the period 1980 to 2010 was performed according to specified criteria. Cardiac parameters including left ventricular ejection fraction (LVEF), conduction abnormalities and arrhythmia were compiled and only studies without ascertainment bias were included. Eighteen studies, 1828 MD1-patients, were included. The prevalence of atrioventricular block grade 1 (AVB1) was 28.2%, QTc>440 ms 22%, QRS>120 ms 19.9%, frequent ventricular premature contractions (VPC) 14.6%, atrial fibrillation/flutter (AF/AFL) 5%, right/left bundle branch block (RBBB/LBBB) 4.4/5.7% and non-sustained ventricular tachycardia (NSVT) 4.1%. Left ventricular systolic dysfunction (LVSD) was reported in 7.2% of the patients. There was an overall positive association between CTG-repeat size and cardiac involvement and between the degree of neuromuscular and cardiac involvement. Male gender and age were positively associated with arrhythmia and conduction abnormalities. The prevalence of pacemaker- (PM) and implantable cardioverter defibrillator-(ICD) implantations were 4.1% and 1.1%, respectively. The risk of SCD in this MD1-population was 0.56% per year. CONCLUSION MD1-patients have a high level of cardiac morbidity and mortality, strongly emphasizing the need of pre-symptomatic screening for arrhythmia and heart failure, as effective and well-documented preventive means are available.

Long-Term Outcome of Percutaneous Transluminal Septal Myocardial Ablation in Hypertrophic Obstructive Cardiomyopathy A Scandinavian Multicenter Study

Background— Single-center reports on percutaneous transluminal septal myocardial ablation (PTSMA) in patients with hypertrophic obstructive cardiomyopathy have shown considerable differences in outcome. Methods and Results— We report the long-term outcome of 313 PTSMA procedures performed in 279 patients with hypertrophic obstructive cardiomyopathy aged 59±14 years from 1999 to 2010 in 4 Scandinavian centers. Sixty-nine percent of patients had ≥1 comorbidity at baseline. The median (interquartile range) of left ventricular outflow tract gradient at rest was reduced from 58 mm Hg (34 to 89 mm Hg) at baseline to 12 mm Hg (8 to 24 mm Hg) at 1-year (P<0.001) and during Valsalva maneuver from 93 mm Hg (70 to 140 mm Hg) to 21 mm Hg (11 to 42 mm Hg) (P<0.001). The proportion of patients with syncope was reduced from 18% to 2% (P<0.001), and the proportion in New York Heart Association class III/IV was reduced from 94% to 21% (P<0.001). All treatment effects remained stable during the follow-up. New York Heart Association class III/IV at the most recent follow-up (2.9±2.6 years) was associated with diabetes mellitus (P=0.03), chronic obstructive pulmonary disease (P=0.02), and valve disease unrelated to hypertrophic cardiomyopathy (P<0.01). In-hospital mortality was 0.3%. The 1-, 5- and 10-year survival rates were 97%, 87%, and 67%, respectively (P=0.06 versus an age- and sex-matched background population) in all patients and 99%, 94%, and 88%, respectively (P=0.12) in patients aged <60 years (48±9 years, n=141). Age (hazard ratio, 1.07; 95% CI, 1.03 to 1.1) was the only predictor of survival. Conclusions— In this multicenter study, the in-hospital mortality after PTSMA was low despite considerable comorbidities. The hemodynamic and symptomatic effects were sustained long term. The long-term symptomatic outcome was associated with baseline comorbidities. The 10-year survival rate was comparable to that in an age- and sex-matched background population, and age was the only predictor of survival.

Hyperaldosteronemia in Rabbits Inhibits the Cardiac Sarcolemmal Na+-K+ Pump

Aldosterone upregulates the Na(+)-K(+) pump in kidney and colon, classical target organs for the hormone. An effect on pump function in the heart is not firmly established. Because the myocardium contains mineralocorticoid receptors, we examined whether aldosterone has an effect on Na(+)-K(+) pump function in cardiac myocytes. Myocytes were isolated from rabbits given aldosterone via osmotic minipumps and from controls. Electrogenic Na(+)-K(+) pump current, arising from the 3:2 Na(+):K(+) exchange ratio, was measured in single myocytes using the whole-cell patch clamp technique. Treatment with aldosterone induced a decrease in pump current measured when myocytes were dialyzed with patch pipette solution containing Na(+) in a concentration of 10 mmol/L, whereas there was no effect measured when the solution contained 80 mmol/L Na(+). Aldosterone had no effect on myocardial Na(+)-K(+) pump concentration evaluated by vanadate-facilitated [(3)H]ouabain binding or by K(+)-dependent paranitrophenylphosphatase activity in crude homogenates. Aldosterone induced an increase in intracellular Na(+) activity. The aldosterone-induced decrease in pump current and increased intracellular Na(+) were prevented by cotreatment with the mineralocorticoid receptor antagonist spironolactone. Our results indicate that hyperaldosteronemia decreases the apparent Na(+) affinity of the Na(+)-K(+) pump, whereas it has no effect on maximal pump capacity.

The role of sarcomere gene mutations in patients with idiopathic dilated cardiomyopathy

We investigated a Danish cohort of 31 unrelated patients with idiopathic dilated cardiomyopathy (IDC), to assess the role that mutations in sarcomere protein genes play in IDC. Patients were genetically screened by capillary electrophoresis single strand conformation polymorphism and subsequently by bidirectional DNA sequencing of conformers in the coding regions of MYH7, MYBPC3, TPM1, ACTC, MYL2, MYL3, TNNT2, CSRP3 and TNNI3. Eight probands carried disease-associated genetic variants (26%). In MYH7, three novel mutations were found; in MYBPC3, one novel variant and two known mutations were found; and in TNNT2, a known mutation was found. One proband was double heterozygous. We find evidence of phenotypic plasticity: three mutations described earlier as HCM causing were found in four cases of IDC, with no history of a hypertrophic phase. Furthermore, one pedigree presented with several cases of classic DCM as well as one case with left ventricular non-compaction. Disease-causing sarcomere gene mutations were found in about one-quarter of IDC patients, and seem to play an important role in the causation of the disease. The genetics is as complex as seen in HCM. Thus, our data suggest that a genetic work-up should include screening of the most prominent sarcomere genes even in the absence of a family history of the disease.