Genetic basis and outcome in a nationwide study of Finnish patients with hypertrophic cardiomyopathy.

AIMS: Nationwide large-scale genetic and outcome studies in cohorts with hypertrophic cardiomyopathy (HCM) have not been previously published. METHODS AND RESULTS: We sequenced 59 cardiomyopathy-associated genes in 382 unrelated Finnish patients with HCM and found 24 pathogenic or likely pathogenic mutations in six genes in 38.2% of patients. Most mutations were located in sarcomere genes (MYBPC3, MYH7, TPM1, and MYL2). Previously reported mutations by our study group (MYBPC3-Gln1061Ter, MYH7-Arg1053Gln, and TPM1-Asp175Asn) and a fourth major mutation MYH7-Val606Met accounted for 28.0% of cases. Mutations in GLA and PRKAG2 were found in three patients. Furthermore, we found 49 variants of unknown significance in 31 genes in 20.4% of cases. During a 6.7 ± 4.2 year follow-up, annual all-cause mortality in 482 index patients and their relatives with HCM was higher than that in the matched Finnish population (1.70 vs. 0.87%; P < 0.001). Sudden cardiac deaths were rare (n = 8). Systolic heart failure (hazard ratio 17.256, 95% confidence interval 3.266-91.170, P = 0.001) and maximal left ventricular wall thickness (hazard ratio 1.223, 95% confidence interval 1.098-1.363, P < 0.001) were independent predictors of HCM-related mortality and life-threatening cardiac events. The patients with a pathogenic or likely pathogenic mutation underwent an implantable cardioverter defibrillator implantation more often than patients without a pathogenic or likely pathogenic mutation (12.9 vs. 3.5%, P < 0.001), but there was no difference in all-cause or HCM-related mortality between the two groups. Mortality due to HCM during 10 year follow-up among the 5.2 million population of Finland was studied from death certificates of the National Registry, showing 269 HCM-related deaths, of which 32% were sudden. CONCLUSIONS: We identified pathogenic and likely pathogenic mutations in 38% of Finnish patients with HCM. Four major sarcomere mutations accounted for 28% of HCM cases, whereas HCM-related mutations in non-sarcomeric genes were rare. Mortality in patients with HCM exceeded that of the general population. Finally, among 5.2 million Finns, there were at least 27 HCM-related deaths annually.

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

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.

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.

Long-term survival after hospitalization for acute heart failure--differences in prognosis of acutely decompensated chronic and new-onset acute heart failure.

AIMS: To analyze the five-year mortality after hospitalization for acute heart failure (AHF) and compare predictors of prognosis in patients with and without a previous history of heart failure. METHODS: Patients with AHF (n=620) from the prospective multicenter FINN-AKVA study were classified as acutely decompensated chronic heart failure (ADCHF) or de-novo AHF if no previous history of heart failure was present. Both all-cause mortality during five years of follow-up and prognostic factors were determined. RESULTS: The overall mortality was 60.3% (n=374) at five years. ADCHF was associated with significantly poorer outcome compared to de-novo AHF; five-year mortality rate 75.6% vs. 44.4% (p<0.001). Initially, mortality was high (33.5% in ADCHF and 21.7% in de-novo AHF after 12 months), but in de-novo AHF the annual mortality declined markedly already after the first year. Compared to de-novo AHF, patients with ADCHF had an increased risk of death for several years after the index hospitalization. A previous history of heart failure was an independent predictor of five-year mortality (adjusted hazard ratio 1.8 (95% CI 1.4-2.2; p<0.001). Older age and impaired renal function were associated with adverse long-term prognosis in both ADCHF and de-novo AHF, while higher systolic blood pressure on admission predicted better outcome. CONCLUSION: The long-term prognosis after hospitalization for AHF is poor, with a significantly different survival observed in patients with de-novo AHF compared to ADCHF. A previous history of heart failure is an independent predictor of five-year mortality. Distinction between ADCHF and de-novo AHF may improve our understanding of patients with AHF.

The type of acute heart failure and the costs of hospitalization.

BACKGROUND: The costs of different classes of acute HF (AHF) are not known. METHODS: AHF patients (N = 620) were divided in a national, prospective, observational study into five clinical classes: cardiogenic shock, pulmonary oedema, congestive HF, hypertensive HF, and right HF. Index episode and 6-month readmissions were assessed and hospitalization costs were evaluated. RESULTS: The length of index episode, ICU/CCU stay and costs of index episode and cumulative 6-month costs differed significantly between the clinical classes. The highest cumulative 6-month hospitalization costs, 25,963 (15,053-44778) € (mean, 95% confidence interval) incurred in cardiogenic shock, followed by pulmonary oedema, 12,912 (11,006-15,148) €, and congestive HF, 9475 (8550-10,500) €. CONCLUSIONS: AHF leads to significant need for hospital care and high costs which differ significantly between clinical classes of AHF.

[Antithrombotic medication of cardiac patient in connection with surgery and minor operations]. / Sydänpotilaan antitromboottinen lääkitys leikkausten ja pientoimenpiteiden yhteydessä.

A major proportion of cardiac patients use long-time antithromobitic medication. It is not uncommon that these patients require surgery and operations. Discontinuation of antithrombotic therapy may be used to decrease risk of hemorrhage, but on the other hand the medication break will make the patient susceptible to thrombotic and thromboembolic complications. The attending physician must decide which is safer: to break the medication or to continue it. Often the best choice is a compromise of the above, i.e. application of a somewhat reduced compensatory antithrombotic therapy.

The use of more than one inotrope in acute heart failure is associated with increased mortality: a multi-centre observational study.

BACKGROUND: Although weakly supported by scientific evidence, according to guidelines the use of inotropes in acute heart failure is indicated in the presence of hypoperfusion refractory to fluid resuscitation. AIMS: We examined the characteristics of the inotrope-treated patients, as well as, their in-hospital mortality. The frequency and dosing of inotropic infusions in patients admitted with acute heart failure was assessed in detail. METHODS: We included 620 consecutive patients with acute heart failure who were admitted to hospital during three months during spring 2004 in an observational multi-centre study. RESULTS: Of the patients 84 (14%) were treated with inotropes. Dopamine was used in 46 (7%), dobutamine 22 (4%), epinephrine 5 (1%), norepinephrine in 33 (5%), and levosimendan in 44 (7%) cases. The in-hospital mortality was 21% in the inotrope-treated group, and 5% in the control group. The mortality was 7% if only one inotrope was used. The mortality increased in proportion to the number of inotropes used. Lower blood pressure at admission, low ejection fraction, elevated C-reactive protein and cardiac markers correlated with the inotrope administration. CONCLUSION: Inotrope administration is a marker of increased mortality in patients with acute heart failure. Still, the use of a single inotrope during hospital stay seems rather safe.

Clinical significance of cardiac troponins I and T in acute heart failure.

BACKGROUND: Elevated cardiac troponin (cTn) levels are relatively common in acute heart failure (AHF). AIMS: To evaluate the prevalence and prognostic significance of elevated cTnI and cTnT in AHF. METHODS: FINN-AKVA is a prospective, multicenter study in AHF. In this analysis, 364 non-ACS patients with measurements of cTnI and cTnT taken on admission and 48 h thereafter were analyzed. RESULTS: Of the 364 AHF patients, 51.1% had cTnI and 29.7% cTnT levels above the cut-off value. Six-month all-cause mortality was 18.7%. Both cTnI (OR 2.0, 95% CI 1.2-3.5, p=0.01) and cTnT (OR 2.6, 95% CI 1.5-4.4, p=0.0006) were associated with adverse outcome. The mortality risk was proportional to the magnitude of cTn release. On multivariable analysis, Cystatin C (OR 6.3, 95% CI 3.2-13, p<0.0001), logNT-proBNP (OR 1.4, 95% CI 1.0-1.8, p=0.03) and systolic blood pressure on admission (/10 mm Hg increase, OR 0.9, 95% CI 0.8-0.9, p=0.0004) were independent risk markers, whereas the troponins were not significantly associated with increased mortality. CONCLUSIONS: cTn elevations are frequent in AHF patients without ACS. cTnI is more often elevated than cTnT. Both cTnI and cTnT elevations are associated with increased mortality proportional to the degree elevation but they do not act as independent risk markers.

Prognostic role of pro- and anti-inflammatory cytokines and their polymorphisms in acute decompensated heart failure.

BACKGROUND: Cytokines play an important role in chronic heart failure (HF), but little is known about their involvement in acute decompensated heart failure (ADHF). AIM: To evaluate the prognostic role of inflammatory cytokines in patients with ADHF. METHODS: Levels of interleukin (IL)-6, tumour necrosis factor alpha (TNF-alpha), IL-10 and N-terminal pro-brain natriuretic peptide (NT-proBNP) were measured in 423 patients with ADHF. In addition, appropriate cytokine gene polymorphisms were determined. Survival was followed up to 12 months, and prognostic factors were evaluated. RESULTS: Elevated levels of IL-6 and TNF-alpha were strongly associated with increased 12-month mortality (P<0.001 for both), whereas the level of IL-10 was predictive only of 6-month mortality (P<0.01). In multivariate analysis IL-6, chronic renal insufficiency, NT-proBNP, age/10 years' increase and TNF-alpha were identified as the most powerful predictors of 12-month mortality. Furthermore, high levels of both IL-6 and NT-proBNP were associated with >7-fold mortality. Cytokine gene polymorphisms were not associated with outcome. CONCLUSIONS: Circulating levels of pro-inflammatory cytokines IL-6 and TNF-alpha, and the level of an anti-inflammatory cytokine IL-10, but not their gene polymorphisms, provide novel and important prognostic information in patients with ADHF. Combining measurements of pro-inflammatory cytokines and NT-proBNP seems a promising tool in the prognostic assessment of these patients.

Primary osteosarcoma of the right heart ventricle and atrium; a case report.

Most primary malignancies of the heart, among them also osteosarcoma are found in the left and very uncommonly in the right ventricle. We report a 75-year-old patient with a primary osteosarcoma sited in the right ventricle occluding the pulmonary outflow. The diagnosis was made when the patient was alive, using echocardiography and computerized scan tomography examinations. Like in previous reports on such malignancies, it was far too late for surgical or other therapeutic interventions, and the histological diagnosis was made post mortem.

Prognostic value of cystatin C in acute heart failure in relation to other markers of renal function and NT-proBNP.

AIMS: Cystatin C, a novel marker of renal function, has been implicated as a prognostic marker in cardiovascular disease. We investigated the prognostic value of cystatin C in acute heart failure (AHF) in comparison to other markers of renal function and NT-proBNP. METHODS AND RESULTS: Patients with cystatin C measurements (n = 480) from a prospective multicentre study on AHF were included. All-cause mortality at 12 months was 25.4%. Cystatin C, creatinine, age, gender, and systolic blood pressure on admission were identified as independent prognostic risk factors. Cystatin C above median (1.30 mg/L) was associated with the highest adjusted hazard ratio, 3.2 (95% CI 2.0-5.3), P < 0.0001. Mortality increased significantly with each tertile of cystatin C. Combining tertiles of NT-proBNP and cystatin C improved risk stratification further. Moreover, in patients with normal plasma creatinine, elevated cystatin C was associated with significantly higher mortality at 12 months: 40.4% vs. 12.6% in patients with both markers within normal range, P < 0.0001. CONCLUSION: Cystatin C is a strong and independent predictor of outcome at 12 months in AHF. Furthermore, cystatin C identifies patients with poor prognosis despite normal plasma creatinine. Cystatin C seems to be a promising risk marker in patients hospitalized for AHF.

Characteristics, outcomes, and predictors of 1-year mortality in patients hospitalized for acute heart failure.

AIMS: Acute heart failure (AHF) is associated with poor prognosis and requires recurrent hospitalizations. However, studies on AHF characteristics, treatment, and prognostic factors are few. Our aim was to investigate the characteristics, treatment, and 1-year prognosis of AHF and identify prognostic factors in different clinical groups. METHODS AND RESULTS: We conducted a prospective multicentre study with 620 patients hospitalized due to AHF; mean age 75.1 (10.4) years, 50% male. Half of the patients had new-onset heart failure. Acute congestion (63.5%) and pulmonary oedema (26.3%) were the most common clinical presentations. Left ventricular ejection fraction (LVEF) was reported in two-thirds of patients. Half of these had preserved systolic function (LVEF> or =45%). At discharge, 86% of patients had beta-blockers and 76% either ACE-inhibitors or angiotensin receptor blockers in use. The 12-month all-cause mortality was 27.4%. We identified several clinical and biochemical prognostic risk factors in univariate analysis. Independent predictors of 1-year mortality were older age, male gender, lower systolic blood pressure (SBP) on admission, C-reactive protein, and serum creatinine >120 micromol/L. CONCLUSION: We present the characteristics and prognosis of an unselected population of AHF patients. One-year mortality is high, and independent clinical risk factors include age, male gender, lower SBP on admission, C-reactive protein, and renal dysfunction.

Prevalence of sleep apnea syndrome in lone atrial fibrillation: a case-control study.

BACKGROUND: According to several studies, obstructive sleep apnea predisposes to cardiac arrhythmias, but the prevalence of sleep apnea in specific arrhythmias has not been determined. Our case-control study assesses prevalence of sleep apnea syndrome (SAS) in lone atrial fibrillation (AF). METHODS: Patients with AF (n = 59; 48 men and 11 women; mean age, 59 years; age range, 25 to 84 years) without evident cardiovascular diseases, and their 56 gender-matched, age-matched, and cardiovascular morbidity-matched community control subjects underwent an overnight sleep study. RESULTS: Prevalence of SAS in the AF group was 32%, which did not differ from that in control subjects (29%, p = 0.67). In men, mean neck circumference was higher in the AF group (40.9 cm vs 39.5 cm, p = 0.01) than in control subjects. In men, after adjusting for body mass index and waist circumference, neck circumference was independently related to AF, with an odds ratio (OR) of 1.8 (95% confidence interval, 1.3 to 2.5) per 1-cm increase, and an OR of 5.2 (95% confidence interval, 1.6 to 17.0) for values > 40 cm. Compared to control subjects, the AF group reported more daily/almost-daily tiredness (29% vs 4%, p < 0.001), daily/almost-daily sleepiness (27% vs 7%, p = 0.005), and nightly/almost-nightly breathing pauses during sleep (12% vs 2%, p = 0.03). CONCLUSIONS: SAS seems to be common in lone AF. Nevertheless, we could not show SAS to be more common in patients with AF than in gender-matched, age-matched, and cardiovascular morbidity-matched community control subjects. Compared to control subjects, men with AF seem to have thicker necks, and patients with lone AF report more daytime tiredness, daytime sleepiness, and breathing pauses during sleep.

Effect of 3 months of antimicrobial treatment with clarithromycin in acute non-q-wave coronary syndrome.

BACKGROUND: Coronary artery disease, an inflammatory disease, may be caused by infection. We investigated whether the antibiotic clarithromycin would reduce morbidity and mortality in patients with acute non-Q-wave coronary syndrome. METHODS AND RESULTS: Altogether, 148 patients with acute non-Q-wave infarction or unstable angina were randomly assigned to receive double-blind treatment with either clarithromycin or placebo for 3 months. The primary end point was a composite of death, myocardial infarction, or unstable angina during treatment; the secondary end point was occurrence of any cardiovascular event during the entire follow-up period (average 555 days, range 138 to 924 days). There was a trend toward fewer patients meeting primary end-point criteria in the clarithromycin group than in the placebo group (11 versus 19 patients, respectively; risk ratio 0.54, 95% CI 0.25 to 1.14; P=0.10). By the end of the entire follow-up, 16 patients in the clarithromycin group and 27 in the placebo group had experienced a cardiovascular event (risk ratio 0.49, 95% CI 0.26 to 0.92; P=0.03). CONCLUSIONS: Clarithromycin appears to reduce the risk of ischemic cardiovascular events in patients presenting with acute non-Q-wave infarction or unstable angina. No signs of this effect diminishing were observed during follow-up.