Martin Hulpke-Wette

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.

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.

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.

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.

Cardiovascular considerations of attention deficit hyperactivity disorder medications: a report of the European Network on Hyperactivity Disorders work group, European Attention Deficit Hyperactivity Disorder Guidelines Group on attention deficit hyperactivity disorder drug safety meeting

Regulatory decisions regarding attention deficit hyperactivity disorder drug licensing and labelling, along with recent statements from professional associations, raise questions of practice regarding the evaluation and treatment of patients with attention deficit hyperactivity disorder. To address these issues for the European community, the European Network for Hyperkinetic Disorders, through its European Attention Deficit Hyperactivity Disorder Guidelines Group, organised a meeting between attention deficit hyperactivity disorder specialists, paediatric cardiovascular specialists, and representatives of the major market authorisation holders for attention deficit hyperactivity disorder medications. This manuscript represents their consensus on cardiovascular aspects of attention deficit hyperactivity disorder medications. Although sudden death has been identified in multiple young individuals on attention deficit hyperactivity disorder medication causing regulatory concern, when analysed for exposure using currently available data, sudden death does not appear to exceed that of the general population. There is no current evidence to suggest an incremental benefit to electrocardiography assessment of the general attention deficit hyperactivity disorder patient. Congenital heart disease patients have an increased prevalence of attention deficit hyperactivity disorder, and can benefit from attention deficit hyperactivity disorder therapies, including medication. The attention deficit hyperactivity disorder specialist is the appropriate individual to evaluate benefit and risk and recommend therapy in all patients, although discussion with a heart specialist is reasonable for congenital heart disease patients. For attention deficit hyperactivity disorder patients with suspected heart disease or risk factor/s for sudden death, assessment by a heart specialist is recommended, as would also be the case for a non-attention deficit hyperactivity disorder patient. The identification of risk factors for sudden death should not automatically exclude the use of attention deficit hyperactivity disorder medication.

Endogenous nitric oxide and soluble tumor necrosis factor receptor levels are enhanced in infants with congenital heart disease

Objective This study was designed to investigate cytokine and nitric oxide levels in pediatric patients suffering from chronic heart failure and to investigate effects of &bgr;-blocker treatment on these levels. Patients Fifteen infants with heart failure resulting from left-to-right shunts with pulmonary overcirculation were compared with 11 infants with cyanotic heart defects with reduced pulmonary blood flow. Four of these patients were finally treated with the &bgr;-blocker propranolol. Measurements Endogenous nitric oxide production was determined by measuring total plasma nitrite/nitrate (Griess method), and levels of soluble tumor necrosis factor receptors type 1 and type 2 (TNF-R1 and TNF-R2, respectively) were measured by commercially available enzyme-linked immunosorbent assay. Main Results In infants with left-to-right shunts, soluble tumor necrosis factor receptor levels were significantly elevated as compared with infants with cyanosis (TNF-R1: 1.7 ± 0.5 vs. 0.8 ± 0.3 ng/mL;p = .0003; TNF-R2: 8.1 ± 4.0 vs. 5.1 ± 3.2 ng/mL;p = .049). In addition, we found a significant correlation between nitrate/nitrite levels and TNF-R1 (r = .70;p = .0001) or TNF-R2 (r = .62;p = .0013), respectively. Furthermore, the tumor necrosis factor receptor levels in four children after &bgr;-blocker treatment were lower as compared with levels before &bgr;-blocker treatment. Conclusions Immune mechanisms, such as cytokine or nitric oxide production, may be involved in pathogenesis of heart failure in children, and may contribute to the beneficial effects of &bgr;-blocker treatment observed in these patients.

β-Receptor downregulation in congenital heart disease: a risk factor for complications after surgical repair?

BACKGROUND Neurohormonal activation in children with heart failure due to congenital heart disease leads to downregulation of myocardial beta-receptors that may influence the postoperative course after cardiothoracic surgery. METHODS Myocardial biopsies of 26 children (aged 14+/-4 months) were obtained from the right atrium during cardiac surgery. Patients were allocated to either of two groups based on the duration of their intensive care unit stay: group 1 comprised those who stayed less than 7 days (n = 17), whereas group 2 comprised those who stayed more than 7 days, plus 3 infants who died during the early postoperative course (n = 9). For beta1- and beta2-mRNA quantitation, real-time polymerase chain reaction with fluorescence-labeled products was used. RESULTS Values for myocardial beta1-receptor gene expression were twice as high in group 1 children compared with group 2 (beta1-receptor 0.12+/-0.07 versus 0.06+/-0.03, p = 0.0016; beta2-receptor 0.12+/-0.07 versus 0.06+/-0.03, p = 0.0071). Beta-receptor gene expression in 16 children who received standard treatment for heart failure averaged lower than in the 10 children who received additional propranolol. CONCLUSIONS Beta-receptor downregulation due to congestive heart failure has an impact on the postoperative course in children with congenital disease and depends on heart failure therapy.

Population pharmacokinetics and pharmacodynamics of sotalol in infants and children with tachycardia

Clinical Pharmacology & Therapeutics (2003) 73, P71–P71; doi:

Nichtinvasive Bestimmung des Kontraktilitätsindex wandspannungsbezogene zirkumferentielle Verkürzungsgeschwindigkeit des linken Ventrikels bei Kindern

Assessment of the myocardial contractility in terms of the velocity of circumferential fiber shortening appropriate to the actual left ventricular endsystolic wall stress requires endsystolic pressure measurement usually done invasively. But for noninvasive evaluation of this parameter, we elaborated an algorithm to derive the endsystolic pressure in the ascending aorta from oscillometric blood pressure measurements. In 99 infants, children, adolescents, and young adults (1 day–37 years, median 5.5 years) we performed direct pressure recordings in the ascending aorta while measuring the arterial blood pressure at the upper arm by the Dinamap 8100 Blood Pressure Monitor. If measured directly, endsystolic (ESPdirekt) and mean aortic pressure (MAPdirekt) correlated well: ESPdirekt) = 1,04 * MAPdirekt)–2.18; r2=0.91; sy.x.=5.1 mm Hg. Comparison between the endsystolic and the mean arterial pressure (MAPDinamap resulted in: ESPdirekt = 1.19 * MAPDinamap–4.8; r2 = 0.74; sy.x. = 8.3 mm Hg. In 52 patients this equation was used to derive the endsystolic pressure from the mean arterial pressure. Then the endsystolic wall stress was determined using the calculated (ESSmDinamap) as well as the directly measured endsystolic pressure (ESSmdirekt): mean difference (ESSmDinamap– ESSmdirekt) = –2.1 kdyn/cm2; 95% confidence limits: –16.2 to 12.1 kdyn/cm2; linear regression: ESSmdirekt = 1.07 * ESSmDinamap– 2.22; r2 = 0.91; sy.x. = 7.1 kdyn/cm2. In n = 12 infants with complex heart defects and severe congestive heart failure due to pulmonary hyperperfusion the contractility was monitored noninvasively to assess the effects of propranolol (1.5 to 2 mg/kg/day) given complementary to digoxin and diuretics. The advantage of noninvasive assessment of the contractility in clinical routine was confirmed by the result that long-term propranolol does not impair myocardial contractility in this setting. Die zirkumferentielle Verkürzungsgeschwindigkeit des linken Ventrikels, die der aktuellen endsystolischen meridionalen Wandspannung angemessen ist, gilt als ein Kontraktilitätsparameter. Er kann echokardiographisch bestimmt werden, sofern der endsystolische Druck in der Aorta ascendens bekannt ist, der normalerweise direkt gemessen wird. Ziel der Untersuchung war es, einen Algorithmus zu finden, mit dem dieser Druckwert aus oszillometrischen Messungen des peripheren Blutdrucks abgeleitet werden konnte, um so eine Möglichkeit zu schaffen, die myokardiale Kontraktilität bei Kindern durch die simultane Anwendung von Echokardiographie und Oszillometrie nichtinvasiv zu ermitteln. Bei n = 99 Kindern, Jugendlichen und Erwachsenen mit verschiedenen Herzfehlern (Alter: 1 Tag–37 Jahre, Median 5,5 Jahre) wurde bei Herzkatheteruntersuchungen der Druck in der Aorta ascendens direkt gemessen. Gleichzeitig erfolgten oszillometrische Blutdruckmessungen am Oberarm mit dem Dinamap-8100-Blutdruckmonitor. Bei den direkten Messungen korrelierten endsystolischer Druck (ESPdirekt) und aortaler Mitteldruck (MAPdirekt) eng: ESPdirekt = 1,04 * MAPdirekt–2,18; r2 = 0,91; sy.x = 5,1 mm Hg. Für die Beziehung zwischen dem direkt gemessenen endsystolischen Druck und dem oszillometrisch gemessenen arteriellen Mitteldruck ergab sich ESPdirekt = 1.19 * MAPDinamap–4,8; r2 = 0,74; sy.x. = 8,3 mm Hg. Mit dieser Gleichung wurde bei n = 52 Patienten aus dem oszillometrisch gemessenen arteriellen Mitteldruck der endsystolische Druck abgeleitet und dann die endsystolische meridionale Wandspannung (ESSmDinamap) berechnet. Sie stimmte gut mit der Wandspannung überein, die auf der Basis der invasiven Druckmessung bestimmt worden war (ESSmdirekt), denn die mittlere Differenz der Einzelwerte betrug Mw (ESSmDinamap– ESSmdirekt) = 2,1 kdyn/cm2, das 95%-Toleranzintervall hatte eine Spannweite von –16,2 bis 12,1 kdyn/cm2 und die Regressionsgleichung lautete ESSmdirekt = 1,07 * ESSmDinamap– 2,22; r2 = 0,91; sy.x. = 7,1 kdyn/cm2. Beispielhaft wurde die myokardiale Kontraktilität nichtinvasiv bei n = 12 herzinsuffizienten Säuglingen mit komplexen angeborenen Herzfehlern und Lungenhyperfusion bestimmt, um zu prüfen, wie sich die Gabe vo Propranolol (1,5–2 mg/kg/d) zusätzlich zu Digoxin und Diuretika auf die myokardiale Kontraktilität auswirkt. Nach sechs Monaten wurde eine Normalisierung der Kontraktilitätsindizes gefunden, die vor Therapiebeginn mehrheitlich erniedrigt waren. Damit konnte gezeigt werden, daß die nichtinvasive Bestimmung der myokardialen Kontraktilität sinnvoll zur Überwachung eines neuen Therapiekonzeptes angewendet werden kann.