Erwin Oechslin

Long-term follow-up of 34 adults with isolated left ventricular noncompaction: a distinct cardiomyopathy with poor prognosis

OBJECTIVES We sought to describe characteristics and outcome in adults with isolated ventricular noncompaction (IVNC). BACKGROUND Isolated ventricular noncompaction is an unclassified cardiomyopathy due to intrauterine arrest of compaction of the loose interwoven meshwork. Knowledge regarding diagnosis, morbidity and prognosis is limited. METHODS Echocardiographic criteria for IVNC include-in the absence of significant heart lesions-segmental thickening of the left ventricular myocardial wall consisting of two layers: a thin, compacted epicardial and an extremely thickened endocardial layer with prominent trabeculations and deep recesses. Thirty-four adults (age >16 years, 25 men) fulfilled the diagnostic criteria and were followed prospectively. RESULTS At diagnosis, mean age was 42 + 17 years, and 12 patients (35%) were in New York Heart Association class III/IV. Left ventricular end-diastolic diameter was 65 + 12 mm and ejection fraction 33 + 13%. Apex and/or midventricular segments of both the inferior and lateral wall were involved in >80% of patients. Follow-up was 44 + 40 months. Major complications were heart failure in 18 patients (53%), thromboembolic events in 8 patients (24%) and ventricular tachycardias in 14 patients (41%). There were 12 deaths: sudden in six, end-stage heart failure in four and other causes in two patients. Four patients underwent heart transplantation. Automated cardioverter/defibrillators were implanted in four patients. CONCLUSIONS Diagnosis of IVNC by echocardiography using strict criteria is feasible. Its mortality and morbidity are high, including heart failure, thrombo-embolic events and ventricular arrhythmias. Risk stratification includes heart failure therapy, oral anticoagulation, heart transplantation and implantation of an automated defibrillator/cardioverter. As IVNC is a distinct entity, its classification as a specific cardiomyopathy seems to be more appropriate.

Isolated Noncompaction of the Myocardium in Adults

OBJECTIVE To describe the entity of isolated ventricular noncompaction (IVNC) and present a series of cases of this rare disorder in an adult population. MATERIAL AND METHODS We review a 10-year experience with the diagnosis of IVNC and discuss the clinical, echocardiographic, and pathologic features of this condition. Echocardiographic diagnostic criteria included the absence of coexisting cardiac abnormalities, the presence of prominent and excessive trabeculations of one or more ventricular wall segments, and intertrabecular spaces perfused from the ventricular cavity. Pathologic examination focused on regions with exaggerated trabeculations and deep intertrabecular spaces. RESULTS IVNC is an unexplained arrest of myocardial morphogenesis previously encountered mainly in pediatric patients. Among 37,555 transthoracic echocardiographic studies performed at our hospital between January 1984 and October 1993, 17 cases of IVNC were identified in adult subjects (14 men and 3 women, 18 to 71 years of age). The mean time from onset of symptoms to correct diagnosis was 3.5 +/- 5.7 years, and the mean duration of follow-up was 30 +/- 28 months. Common clinical symptoms were heart failure, ventricular arrhythmias, and a history of embolic events. Two-dimensional echocardiography revealed 10 patients with left ventricular and 7 (41%) with biventricular IVNC. During a 6-year follow-up period, eight patients died and two underwent heart transplantation. CONCLUSION Although the diagnosis of IVNC in an adult population is often delayed because of similarities with more frequently diagnosed conditions, two-dimensional echocardiography will facilitate the diagnosis of IVNC in this subset of patients. Because of the high incidence of heart failure, ventricular arrhythmias, and embolization in adults with IVNC, early diagnosis is important.

Evidence for endothelin-1-mediated vasoconstriction in severe chronic heart failure

Heart failure is commonly associated with high plasma concentrations of endothelin-1, a powerful vasoconstrictor produced by endothelium. The role of endogenously released endothelin-1 in the maintenance of vascular tone in chronic heart failure was assessed by acute administration of an endothelin receptor antagonist, bosentan. 24 patients with chronic heart failure received randomly and double blind two intravenous infusions of either placebo or bosentan (100 mg followed after 60 min by 200 mg). Systemic haemodynamics and plasma endothelin-1 and big-endothelin-1 concentrations were determined before and repeatedly during the 120 min observation period. Baseline endothelin-1 and big-endothelin-1 concentrations, which were above the normal range in all patients, correlated directly with the extent of pulmonary hypertension, with left and right heart filling pressures, and with pulmonary vascular resistance and inversely with cardiac index. Compared with placebo, bosentan reduced mean arterial pressure by 7.7% (95% CI 7.1-9.7), pulmonary artery pressure by 13.7% (10.5-16.9), right atrial pressure by 18.2% (12.0-24.4), and pulmonary artery wedged pressure by 8.6% (5.3-12.0); it increased cardiac index by 13.6% (9.1-18.2), decreased systemic vascular resistance by 16.5% (13.2-19.8), and decreased pulmonary vascular resistance by 33.2% (22.4-44.0). Heart rate did not change. Plasma endothelin-1 concentrations rose more than twofold from baseline in bosentan recipients while big-endothelin-1 concentrations were unchanged. These findings indicate that, in patients with chronic heart failure who have high circulatory endothelin-1 concentrations, this peptide contributes to maintenance of vascular tone. The acute haemodynamic effects of bosentan suggest that chronic endothelin antagonism could be beneficial in such patients.

Mode of death in adults with congenital heart disease

An increasing number of patients with congenital heart disease (CHD) are entering adulthood. Although prior studies have focused on the causes of death in the pediatric population, the modes of death for adults with CHD have not been well defined. In a cross-sectional study performed on a population of 2,609 consecutive adults assessed at a CHD specialty clinic, there were adequate information available in 197 of 199 deceased patients. Mean age at death was 37 +/- 15 years. Mortality was highest in patients with congenitally corrected transposition of the great arteries (26%), tricuspid atresia (25%), and univentricular connection (23%). Youngest mean age at death was observed in patients with tricuspid atresia (27 +/- 5 years), complete transposition of the great arteries (27 +/- 7 years), pulmonary atresia (27 +/- 6 years), and aortic coarctation (29 +/- 6 years). Sudden death (26%) was the most common cause of death followed by progressive heart failure (21%) and perioperative death (18%). Postmortem examinations were performed in 77 of 197 deceased patients (39%) and provided incremental data on the mechanism of death in 22% of autopsies. Thus, the 3 major causes of death in the growing population of adults with CHD are sudden, perioperative, and progressive heart failure.

Troponin as a risk factor for mortality in critically ill patients without acute coronary syndromes

OBJECTIVES We sought to assess the mechanism and prognostic value of elevated troponins in patients without acute coronary syndromes (ACS). BACKGROUND Cardiac troponins are used as specific markers for the diagnosis of ACS. Recent studies reported a considerable number of critically ill patients without ACS as being troponin-positive, especially patients with sepsis, pulmonary embolism, renal failure, and stroke. METHODS We analyzed 58 consecutive, critically ill patients admitted for reasons other than ACS, according to their troponin status. Thirty-day mortality, left ventricular ejection fraction (LVEF), and a panel of inflammatory cytokines were compared between troponin-positive and troponin-negative patients. Relevant coronary artery disease was excluded either by stress echocardiography or autopsy. RESULTS Of the 58 critically ill patients, 32 (55%) without evidence of ACS were troponin-positive. Positive troponin levels were associated with higher mortality (22.4% vs. 5.2%, p < 0.018) and a lower LVEF (p = 0.0006). Troponin-positive patients had significantly higher median levels of tumor necrosis factor (TNF)-alpha, its soluble receptor, and interleukin (IL)-6. A subgroup of 10 aplastic patients was troponin-negative at study entry. Three became troponin-positive during leukocyte recovery and subsequently died, whereas all the others stayed troponin-negative and survived. Flow-limiting coronary artery disease was not demonstrable at autopsy or stress echocardiography in 72% of troponin-positive patients. CONCLUSIONS Elevated troponin is a mortality risk factor for medical intensive care patients admitted for reasons other than ACS. It is associated with decreased left ventricular function and higher levels of TNF-alpha and IL-6.

Mutations in Sarcomere Protein Genes in Left Ventricular Noncompaction

Background— Left ventricular noncompaction constitutes a primary cardiomyopathy characterized by a severely thickened, 2-layered myocardium, numerous prominent trabeculations, and deep intertrabecular recesses. The genetic basis of this cardiomyopathy is still largely unresolved. We speculated that mutations in sarcomere protein genes known to cause hypertrophic cardiomyopathy and dilated cardiomyopathy may be associated with left ventricular noncompaction. Methods and Results— Mutational analysis in a cohort of 63 unrelated adult probands with left ventricular noncompaction and no other congenital heart anomalies was performed by denaturing high-performance liquid chromatography analysis and direct DNA sequencing of 6 genes encoding sarcomere proteins. Heterozygous mutations were identified in 11 of 63 samples in genes encoding &bgr;-myosin heavy chain (MYH7), &agr;-cardiac actin (ACTC), and cardiac troponin T (TNNT2). Nine distinct mutations, 7 of them in MYH7, 1 in ACTC, and 1 in TNNT2, were found. Clinical evaluations demonstrated familial disease in 6 of 11 probands with sarcomere gene mutations. MYH7 mutations segregated with the disease in 4 autosomal dominant LVNC kindreds. Six of the MYH7 mutations were novel, and 1 encodes a splice-site mutation, a relatively unique finding for MYH7 mutations. Modified residues in &bgr;-myosin heavy chain were located mainly within the ATP binding site. Conclusions— We conclude that left ventricular noncompaction is within the diverse spectrum of cardiac morphologies triggered by sarcomere protein gene defects. Our findings support the hypothesis that there is a shared molecular etiology of different cardiomyopathic phenotypes.

Left ventricular non-compaction revisited: a distinct phenotype with genetic heterogeneity?

Non-compaction of the left ventricular myocardium (LVNC) has gained increasing recognition during the last 25 years. There is a morphological trait of the myocardial structure with a spectrum from normal variants to the pathological phenotype of LVNC, which reflects the embryogenic structure of the human heart due to an arrest in the compaction process during the first trimester. It must be cautioned not to overdiagnose LVNC: the morphological spectrum of trabeculations, from normal variants to pathological trabeculations with the morphological feature of LVNC must be carefully considered. The classical triad of complications are heart failure, arrhythmias, including sudden cardiac death, and systemic embolic events. Non-compaction of the left ventricular myocardium can occur in isolation or in association with congenital heart defects (CHDs), genetic syndromes, and neuromuscular disorders among others. The clinical spectrum is wide and the outcome is more favourable than in previously described populations with a negative selection bias. Familial occurrence is frequent with autosomal dominant and X-linked transmissions. Different mutations in sarcomere protein genes were identified and there seems to be a shared molecular aetiology of different cardiomyopathic phenotypes, including LVNC, hypertrophic and dilated cardiomyopathies. Thus, genetic heterogeneity, with an overlap of different phenotypes, and the variability of hereditary patterns, raise the questions whether there is a morphological trait from dilated/hypertrophic cardiomyopathy to LVNC and what are the triggers and modifiers to develop either dilated, hypertrophic cardiomyopathy, or LVNC in patients with the same mutation. The variety in clinical presentation, the genetic heterogeneity, and the phenotype of the first transgenetic animal model of an LVNC-associated mutation question the hypothesis that LVNC be a distinct cardiomyopathy: it seems to be rather a distinct phenotype or phenotypic, morphological expression of different underlying diseases than a distinct cardiomyopathy.

Reoperation in adults with repair of tetralogy of fallot: indications and outcomes.

OBJECTIVE The purpose of this study is to review indications, surgical procedures, and outcomes in adults with repaired tetralogy of Fallot referred for reoperation. METHOD Sixty consecutive adults (age >/= 18 years) who underwent reoperation between 1975 and 1997 after previous repair of tetralogy of Fallot were reviewed. Mean age at corrective repair was 13.3 +/- 9.6 years and at reoperation 33.3 +/- 9.6 years. Mean follow-up after reoperation is 5.0 +/- 4.9 years. RESULTS Long-term complications of the right ventricular outflow tract (n = 45, 75%) were the most common indications for reoperation: severe pulmonary regurgitation (n = 23, 38%) and conduit failure (n = 13, 22%) were most frequent. Less common indications were ventricular septal patch leak (n = 6) and severe tricuspid regurgitation (n = 3). A history of sustained ventricular tachycardia was present in 20 patients (33%) and supraventricular tachycardia occurred in 9 patients (15%). A bioprosthetic valve to reconstruct the right ventricular outflow tract was used in 42 patients. Additional procedures (n = 115) to correct other residual lesions were required in 46 patients (77%). There was no perioperative mortality. Actuarial 10-year survival is 92% +/- 6%. At most recent follow-up, 93% of the patients are in New York Heart Association classification I or II. Sustained ventricular tachycardia occurred in 4 patients (7%) during follow-up. CONCLUSIONS Long-term complications of the right ventricular outflow tract were the main reason for reoperation. Mid-term survival and functional improvement after reoperation are excellent.

Sudden Cardiac Death in Adult Congenital Heart Disease

Background— Sudden cardiac death (SCD) is a major cause of mortality in adults with congenital heart disease (CHD). The aim of this study was to determine the adult CHD population at risk of SCD and the clinical parameters associated with SCD. Methods and Results— We performed a multicenter case-control study. Patients who died suddenly as a result of proven or presumed arrhythmia were included (cases). For each case, 2 controls matched on diagnosis, type of surgical intervention, age, and gender were included. From 3 databases including 25 790 adults with CHD, 1189 deaths (5%) were identified, of whom 213 patients (19%) died suddenly. Arrhythmic death occurred in 171 of 1189 patients. The underlying cardiac lesions were mild, moderate, and severe CHD in 12%, 33%, and 55% of the SCD cases, respectively. Clinical variables associated with SCD were supraventricular tachycardia (odds ratio [OR], 3.5; 95% confidence interval [CI], 1.5–7.9; P=0.004), moderate to severe systemic ventricular dysfunction (OR, 3.4; 95% CI, 1.1–10.4; P=0.034), moderate to severe subpulmonary ventricular dysfunction (OR, 3.4; 95% CI, 1.1–10.2; P=0.030), increased QRS duration (OR, 1.34 [per 10-ms increase]; 95% CI, 1.10–1.34; P=0.008), and QT dispersion (OR, 1.22 [per 10-ms increase]; 95% CI, 1.22–1.48; P=0.008). Conclusions— The clinical parameters found to be associated with SCD in adults with a broad spectrum of CHD, including systemic right ventricles, are similar to those in ischemic heart disease. Moreover, even those patients with mild cardiac lesions are potentially at risk for SCD. This highlights the need for further prospective studies as well as vigilant ongoing follow-up of the adult with CHD.

Depression and anxiety in adult congenital heart disease: Predictors and prevalence

BACKGROUND Adult congenital heart disease (ACHD) patients face unique medical and social challenges that may contribute to psychological difficulties. The goals of this study were to identify predictors of symptoms of depression and anxiety and evaluate the prevalence of mood and anxiety disorders among North American ACHD patients. METHODS In this cross-sectional study, consecutive patients were recruited from two ACHD outpatient clinics. All patients completed self-report psychosocial measures and a subset was randomly selected to participate in structured clinical interviews. Linear regression models were used to predict symptoms of depression and anxiety. RESULTS A total of 280 patients (mean age=32 years; 52% female) completed self-report measures. Sixty percent had defects of moderate complexity and 31% had defects of great complexity. Significant predictors of depressive symptoms were loneliness (p<0.001), perceived health status (p<0.001), and fear of negative evaluation (p=0.02). Predictors of anxiety symptoms were loneliness (p<0.001) and fear of negative evaluation (p<0.001). Disease severity and functional class did not predict mood or anxiety symptoms. Fifty percent of interviewed patients (29/58) met diagnostic criteria for at least one lifetime mood or anxiety disorder, of whom 39% had never received any mental health treatment. CONCLUSIONS The results confirm an increased risk and under-treatment of mood and anxiety disorders in ACHD patients. Social adjustment and patient-perceived health status were more predictive of depression and anxiety than medical variables. These factors are modifiable and therefore a potential focus of intervention.