Reiner Buchhorn

Risk of sudden death in the Williams–Beuren syndrome

Williams–Beuren syndrome (WBS) is a genetic disorder characterized by a distinctive facial gestalt, mental retardation, mild growth deficiency, and cardiovascular disease. The occurrence of sudden death in the WBS is known from several case reports, but information about the risk of sudden death as derived from the data of a large cohort of patients is lacking. We analyzed the data of 293 WBS patients who had been treated for 43 years at the same two institutions. We thus collected 5,190 patient years without loss to follow‐up. During this period ten patients died. Five of them died from: reticulosarcoma (1), after accident (1), heart failure (1), following heart surgery (2). Of the remaining five patients, four died suddenly and one died of unknown cause suggestive of sudden cardiac death. Thus, the incidence of sudden death in our WBS cohort amounts to 1/1,000 patient years. This risk of sudden death is comparable to that following surgery for congenital heart disease, and is 25–100‐fold higher compared to the age‐matched normal population.

Propranolol treatment of congestive heart failure in infants with congenital heart disease: The CHF-PRO-INFANT Trial

AIM Infants with congenital heart disease and left-to-right shunts may develop significant clinical symptoms of congestive heart failure in spite of therapy with digoxin and diuretics. We investigated the effects of beta-blockade in infants with severe heart failure. METHODS AND RESULTS We performed a prospective, randomized, open monocenter trial in infants treated with digoxin and diuretics (n=10) in comparison to 10 infants receiving additional beta-blocker therapy. After 17 days on average beta-blocker treated infants (propranolol:1,6 mg/kg/day) improved significantly with respect to Ross heart failure score (3.3+/-2.3 vs. 8.3+/-1.9, P=0.002), lower renin levels (338+/-236 vs. 704+/-490 microU/l, P=0.008) and lower mean heart rates in Holter ECG (118+/-10 vs. 142+/-11 beats/min, P<0.001). While digoxin and diuretic treated infants had unchanged mean heart rate (149+/-8 vs. 148+/-10 beats/min), less decrease of symptoms (Ross Score: 8.5+/-1.7 vs. 6.8+/-2.3, P=0.02) but a significant increase of renin levels (139+/-102 vs. 938+/-607 microU/l, P=0.001). CONCLUSION Additional propranolol treatment but not digoxin and diuretics alone can effectively reduce clinical symptoms of heart failure in infants with congenital heart disease, who suffer from increased neurohormonal activation.

A prospective, randomized, double-blind, placebo controlled trial of beta-blockade in patients who have undergone surgical correction of tetralogy of Fallot

AIMS Our purpose was to evaluate the effect of a treatment over six months with bisoprolol on the surrogate parameters of N-Terminal-pro brain natriuretic peptide, subsequently to be described as brain natriuretic peptide, peak uptake of oxygen, and ventricular function assessed by magnetic resonance imaging in grown ups and adults who had undergone surgical correction of tetralogy of Fallot. METHODS AND RESULTS We designed a prospective, randomized, double-blind, placebo controlled trial. We enrolled 33 patients, aged 30.9 plus or minus 9.5 years in either class 1 or 2 of the grading of the New York Heart Association class with both levels of brain natriuretic peptide greater than 100 pg/ml and a reduced peak uptake of oxygen less than 25 ml/kg/min. During treatment with Bisoprolol, the levels of brain natriuretic peptide increased significantly from 206 plus or minus 95 to 341 plus or minus 250 pg/ml (p< 0.05), and those of atrial natriuretic peptide from 4117 plus or minus 1837 to 5340 plus or minus 2102 fmol/ml (p = 0.0005). These measures remained unchanged in the group of patients receiving the placebo. Peak uptake of oxygen did not differ significantly in either group, nor did treatment have any significant effect on right and left ventricular volumes and ejection fractions as determined by magnetic resonance imaging. The clinical state as judged within the grading system of the New York Heart Association was also unchanged by beta-blockade. CONCLUSION Beta blockade with Bisoprolol seems to have no beneficial effect on asymptomatic or mildly symptomatic patients with right ventricular dysfunction secondary to repaired tetralogy of Fallot with residual pulmonary regurgitation and/or stenosis.

Beta-Blocker Therapy of Severe Congestive Heart Failure in Infants With Left to Right Shunts

We report on the clinical and neurohumoral effects of adding low-dose propranolol to conventional therapy with digoxin and diuretics in 6 infants with severe congestive heart failure due to large left-to-right shunts. A significant decrease in heart failure scores and a decrease of the highly activated renin-angiotensin-1 aldosterone system by approximately 70% strongly suggests a beneficial effect of this new therapeutic approach.

Interleukin-1 and related proteins in cardiovascular disease in adults and children.

Interleukin-1 (IL-1) is a key mediator in the cytokine network, controlling important functions in the immune system, during development, infection, inflammation, cell-differentiation, tissue remodelling, and even cell death. The agonistic isoforms of IL-1 (i.e., IL-1alpha and IL-1beta), the IL-1 receptor antagonists, the receptors and receptor-associated proteins, as well as the recently identified IL-18 and its receptor belong to the IL-1 family of proteins. Activation of the IL-1beta and IL-18 precursors is performed enzymatically by caspase-1, previously termed IL-1beta-converting enzyme (ICE). This molecule is the founding member of the caspase family of enzymes, which are involved in maturation of cytokines and in initiation and execution of apoptotic processes. It has been suggested that cytokines and apoptosis are involved in pathogenesis of cardiovascular diseases such as atherosclerosis, chronic heart failure, myocarditis, cardiomyopathy, or stroke. Since IL-1, like TNF, is a central mediator in the cytokine network, it may act as a potent activator of cardiovascular cells. We know that cells of the vessel wall and the heart can produce IL-1 and respond to this mediator by production of other cytokines or regulation of other cardiovascular cell functions. Thus, this report summarizes general information about the molecules of the IL-1 family of proteins, including the caspases, as well as data regarding these proteins in relation to the vessel wall and the heart and their role in cardiovascular disease in adults and children. The summarized information indicates a role of these molecules in regulation of local inflammatory responses during cardiovascular disease.

Activity of the renin-angiotensin-aldosterone and sympathetic nervous system and their relation to hemodynamic and clinical abnormalities in infants with left-to-right shunts

We studied neurohormonal, clinical and invasively measured hemodynamic data of 47 infants with left-to-right shunts and varying degrees of congestive failure. When referred to a clinical heart failure score, plasma renin activities (r=0.71) and norepinephrine levels (r=0.43) are significantly increased. Arterial hypotension seems to be the hemodynamic trigger of renin release (r=-0.72), but not decreased systemic cardiac index (r=-0.43), the magnitude of the left-to-right shunt (r=0.33) or a reduced ejection fraction (r=0.12). These data indicate neurohormonal activation in infants with left-to-right shunts with preserved myocardial function is similar to the activation in adults with heart failure secondary to myocardial pump failure. These findings have to be considered for optimal medical treatment of these infants with angiotensin-converting enzyme inhibitors or beta-blockers.

Chances of employment in women and men after surgery of congenital heart disease: comparisons between patients and the general population.

OBJECTIVE It was examined whether women and men (17-45 years) with operated congenital heart disease differ with respect to chances of employment. Patients were compared with the general population. DESIGN Patients (n = 314) were classified by type of surgery (curative, reparative, palliative) as indicator of initial severity of disease. The second classification was performed according to a system proposed by the New York Heart Association in order to take reported impairments into account. Controls (n = 1165) consisted of a 10% random sample drawn from the German Socio-Economic Panel. RESULTS Chances of full-time employment decreased as disease severity increased. Chances of part-time and minor employment were higher in patients than among controls. These general effects were because of male patients, while the employment patterns of women did not differ from the control group. Independent of patient status, women were more likely to have lower rates of full-time employment, and the rates of part-time and minor employment were higher. CONCLUSION Long-term adaptation to impairments as a result of congenital heart disease differs between women and men with respect to employment status. While female patients do not differ from the general population, males may lower their engagement in paid work.

Effects of therapeutic beta blockade on myocardial function and cardiac remodelling in congenital cardiac disease.

BACKGROUND Cardiac remodelling is now recognised as an important aspect of cardiovascular disease progression and is, therefore, emerging as a therapeutic target in cardiac failure due to different etiologies. Little is known about the influence of different therapies for cardiac failure on the remodelling seen in infants with congenital cardiac disease. METHODS During follow-up of a prospective and randomized trial, we investigated therapeutic effects on neurohormonal activation, ventricular function, and myocardial gene expression. We compared the data from 8 infants with severe congestive heart failure due to left-to-right shunts, who received digoxin and diuretics alone, to 9 infants who received additional treatment with propranolol. RESULTS In these infants, beta-adrenergic blockade significantly reduced highly elevated levels of renin, from 284 +/- 319 microU/ml compared to 1061 +/- 769 microU/ml. Systolic ventricular function was normal in both groups, but diastolic ventricular function was improved in those receiving propranolol, indicated by significantly lower left atrial pressures, lower end-diastolic pressures, and less pronounced ventricular hypertrophy, the latter estimated by lower ratios of myocardial wall to ventricular cavity areas on average of 42%. Further hemodynamic parameters showed no significant differences between the groups, except for the lower heart rate in infants treated with propranolol. In those treated with digoxin and diuretics, there was a significant downregulation of beta2-receptor and angiotensin-2 receptor genes, and up-regulation of endothelin A receptor and connective tissue growth factor genes, that were partially prevented by additional treatment with propranolol. CONCLUSIONS Beta-blockade is a new therapeutic approach for congestive heart failure in infants with congenital cardiac disease, producing with significant benefits on neurohormonal activation, diastolic ventricular function, and cardiac remodelling.

Effectiveness of low dose Captopril versus Propranolol therapy in infants with severe congestive failure due to left-to-right shunts

UNLABELLED To evaluate the therapeutical effects of the angiotensin converting enzyme inhibitor Captopril to the beta-blocker Propranolol in infants with congestive failure due to pulmonary overcirculation, we retrospectively analysed clinical, neurohormonal and hemodynamic data in 22 infants, 11 of whom were treated with Captopril (Group 1), 11 with Propranolol (Group 2). Age, weight, number of palliative operations, plasma renin activities and pulmonary to systemic flow ratios (3.5 vs. 3.5) were not significantly different prior to Captopril or Propranolol therapy. If treatment with digoxin and diuretics did not succeed, the infants were additionally treated with Captopril (1 mg/kg) for a mean of 7.4 months, or with 1.9 mg/kg Propranolol for 9.2 months. RESULTS 1 mg/kg Captopril did not effectively suppress angiotensin converting enzyme in the steady state at trough level (92+/-52 vs. 87+/-50 nmol/min/ml). In the Propranolol group, the clinical heart failure score (2.6+/-1.5 vs. 7. 4+/-2.5) and plasma renin activities (14+/-10 vs. 101+/-70 ng/ml/h) were significantly lower, compared to the Captopril group. Length of hospital stay (23+/-9 vs. 52+/-24 days) was lower and weight gain (126+/-38 vs. 86+/-84 g/week) was higher within 3 months after starting Propranolol therapy. Significantly lower left atrial pressures (6.2+/-2.2 vs. 13.4+/-9.2 mmHg) and lower endiastolic ventricular pressures (7.6+/-2.5 vs. 12.6+/-4.0 mmHg) during pre-operative cardiac catheterization indicated a better diastolic ventricular function under chronic Propranolol treatment. CONCLUSION Although high dose Captopril was not evaluated in this study, when compared to patients on low Captopril dosages, infants who received Propranolol treatment showed improvement in heart failure scores, shorter lengths of hospital stay, lower plasma renin activities and better diastolic ventricular functions.

Is the Ability index superior to the NYHA classification for assessing heart failure?: comparison of two classification scales in adolescents and adults with operated congenital heart defects.

BackgroundHeart failure (HF) is a major problem in the long-term follow-up of adolescents and adults with congenital heart disease (ACHD) after cardiac surgery. The functional status of ACHD may be assessed in terms of the NYHA classification or the Ability index (ABILITY).ObjectiveThe purpose of our study was to examine which of the two classification systems is more closely related to objectively defined HF.MethodsNT-pro brain natriuretic peptide (N-BNP) and maximal oxygen uptake (VO2max) were measured in 360 consecutive ACHD patients. HF was defined as an elevated N-BNP level ≥100 pg/ml combined with a reduced VO2max ≤25 ml/kg/min.ResultsThere were no significant differences between the NYHA and ABILITY in grading HF in these patients. In both classifications, the risk of HF increases continuously over the classes and grades from odds ratio (OR) 1 in NYHA I/ABILITY 1 to an OR=3.4 in NYHA II/ ABILITY 2 up to 11.6 or 5.4 (ns) in NYHA III/ABILITY 3. Thus in the highest scores HF is found in 70–77% of the patients. The fact that in NYHA class I and ABILITY grade 1, 15% and 19% of the patients exhibited HF according to the measured indices underscores the discrepancy between subjective and objective assessment of the individual patients condition.ConclusionThe NYHA classification and the Ability index take different approaches to the patients with congenital heart defects but are equally suitable for the judgement of HF in post surgical ACHD.