Giuseppe Santoro

Long term effects of bosentan treatment in adult patients with pulmonary arterial hypertension related to congenital heart disease (Eisenmenger physiology) : safety, tolerability, clinical, and haemodynamic effect

Background: Oral bosentan is an established treatment for pulmonary arterial hypertension (PAH). Objective: To evaluate safety, tolerability, and clinical and haemodynamic effects of bosentan in patients with PAH related to congenital heart disease (CHD). Patients: 22 patients with CHD related PAH (8 men, 14 women, mean (SD) age 38 (10) years) were treated with oral bosentan (62.5 mg×2/day for the first 4 weeks and then 125 mg×2/day). Main outcome measures: Clinical status, liver enzymes, World Health Organisation (WHO) functional class, resting oxygen saturations and 6-min walk test (6MWT) were assessed at baseline and at 1, 3, 6, and 12 months. Haemodynamic evaluation with cardiac catheterisation was performed at baseline and at 12 month follow-up. Results: 12 patients had ventricular septal defect, 5 atrioventricular canal, 4 single ventricle, and 1 atrial septal defect. All patients tolerated bosentan well. No major side effects were seen. After a year of treatment, an improvement was seen in WHO functional class (2.5 (0.7) v 3.1 (0.7); p<0.05), oxygen saturation at rest (87 (6%) v 81 (9); p<0.001), heart rate at rest (81 (10) v 87 (14) bpm; p<0.05), distance travelled in the 6MWT (394 (73) v 320 (108) m; p<0.001), oxygen saturation at the end of the 6MWT (71 (14) v 63 (17%); p<0.05), Borg index (5.3 (1.8) v 6.5 (1.3); p<0.001), pulmonary vascular resistances index (14 (9) v 22 (12) WU m2; p<0.001), systemic vascular resistances index (23 (11) v 27 (10) WU.m2; p<0.01), pulmonary vascular resistances index/systemic vascular resistances index (0.6 (0.5) v 0.9 (0.6); p<0.05); pulmonary (4.0 (1.3) v 2.8 (0.9) l/min/m2; p<0.001) and systemic cardiac output (4.2 (1.4) v 3.4 (1.1) l/min/m2; p<0.05). Conclusions: Bosentan was safe and well tolerated in adults with CHD related PAH during 12 months of treatment. Clinical status, exercise tolerance, and pulmonary haemodynamics improved considerably.

Bosentan–sildenafil association in patients with congenital heart disease-related pulmonary arterial hypertension and Eisenmenger physiology

OBJECTIVESnThe aim of the present study was to evaluate the safety, tolerability, clinical and haemodynamic impact of add-on sildenafil in patients with congenital heart disease (CHD)-related pulmonary arterial hypertension (PAH) and Eisenmenger physiology after failure of oral bosentan therapy.nnnMETHODSnThirty-two patients with CHD-related PAH (14 male, mean age 37.1 ± 13.7 years) treated with oral bosentan underwent right heart catheterization (RHC) for clinical worsening. After RHC, all patients received oral sildenafil 20mg thrice daily in addition to bosentan. Clinical status, resting transcutaneous oxygen saturation (SpO(2)), 6-minute walk test (6MWT), serology and RHC were assessed at baseline (before add-on sildenafil) and after 6 months of combination therapy.nnnRESULTSnTwelve patients had ventricular septal defect, 8 atrio-ventricular canal, 6 single ventricle, and 6 atrial septal defect. Twenty-eight/32 had Eisenmenger physiology and 4 (all with atrial septal defect) did not. All patients well tolerated combination therapy. After 6 months of therapy, an improvement in clinical status (WHO functional class 2.1 ± 0.4 vs 2.9 ± 0.3; P=0.042), 6-minute walk distance (360 ± 51 vs 293 ± 68 m; P=0.005), SpO(2) at the end of the 6MWT (72 ± 10 vs 63 ± 15%; P=0.047), Borg score (2.9 ± 1.5 vs 4.4 ± 2.3; P=0.036), serology (pro-brain natriuretic peptide 303 ± 366 vs 760 ± 943 pg/ml; P=0.008) and haemodynamics (pulmonary blood flow 3.4 ± 1.0 vs 3.1 ± 1.2l/min/m(2), P=0.002; pulmonary vascular resistances index 19 ± 9 vs 24 ± 16 WU/m(2), P=0.003) was observed.nnnCONCLUSIONSnAddition of sildenafil in adult patients with CHD-related PAH and Eisenmenger syndrome after oral bosentan therapy failure is safe and well tolerated at 6-month follow-up, resulting in a significant improvement in clinical status, effort SpO(2), exercise tolerance and haemodynamics.

Pulmonary Artery Growth After Palliation of Congenital Heart Disease With Duct-Dependent Pulmonary Circulation: Arterial Duct Stenting Versus Surgical Shunt

OBJECTIVESnThe aim of this study was to compare the pulmonary artery (PA) growth after arterial duct (AD) stenting versus modified Blalock-Taussig shunt (MBTS) in neonates with congenital heart disease with duct-dependent pulmonary circulation (CHD-DPC).nnnBACKGROUNDnArterial duct stenting is increasingly deemed a reliable alternative to surgical shunt in CHD-DPC. A stented duct might better adapt to the PA anatomy than a surgical conduit, thereby promoting a more uniform PA development.nnnMETHODSnThis study enrolled 27 patients with CHD-DPC submitted to AD stenting (n = 13, Group I) or MBTS (n = 14, Group II) at our institution. The PA growth was angiographically assessed with the Nakata and McGoon indexes as well as the individual PA z-scores. The right-to-left PA diameter ratio was considered as index of uniform growth.nnnRESULTSnAfter 10 +/- 5 months, both options had promoted a significant increase of the Nakata index (from 136 +/- 72 mm/m(2) to 294 +/- 99 mm/m(2), p < 0.0001, Group I; from 151 +/- 74 mm/m(2) to 295 +/- 177 mm/m(2), p < 0.003, Group II) and McGoon ratio (from 1.5 +/- 0.3 to 2.1 +/- 0.3, p < 0.0001, Group I; from 1.6 +/- 0.3 to 2.0 +/- 0.5, p < 0.01, Group II). However, the surgical shunt had caused a worsening of the left-to-right PA diameter ratio compared with AD stenting (0.9 +/- 0.1 Group I vs. 1.6 +/- 0.9 Group II, p < 0.01), due to preferential growth of the PA contralateral to the shunt.nnnCONCLUSIONSnPercutaneous AD stenting is as effective as MBTS in promoting a global PA growth in CHD-DPC. In addition, it ensures an even distribution of the pulmonary blood flow, thereby promoting a more balanced pulmonary vascular development than MBTS.

Abnormal regional myocardial deformation properties and increased aortic stiffness in normotensive patients with aortic coarctation despite successful correction: an ABPM, standard echocardiography and strain rate imaging study

The long-term follow-up data subsequent to a successful repair of AoC (aortic coarctation) show that life expectancy remains reduced. Previous standard echocardiographic studies have demonstrated normal or increased systolic cardiac function in patients following successful repair of AoC. SR (strain rate) imaging is a new technique able to detect subclinical myocardial abnormalities. In the present study we investigated whether young patients (without hypertension, as assessed using ambulatory blood pressure monitoring and an exercise test) following successful AoC repair already have abnormal myocardial deformation properties, and the relationship of the deformation properties with aortic stiffness. We studied 166 subjects, 83 AoC non-hypertensive patients (mean age 12+/-4 years) a number of years after successful repair of AoC and 83 age- and sex-matched subjects as controls. Peak systolic SR (1/s) for both regional longitudinal and radial function was assessed. The aortic stiffness index was calculated from the echocardiographically derived thoracic aortic diameters, and the measurement of blood pressure was obtained by cuff sphygmomanometry. The LV (left ventricular) ejection fraction was significantly increased in AoC patients, whereas regional longitudinal SRs were significantly reduced (-1.1+/-0.9 compared with -2+/-0.5, P<0.0001) in patients. The aortic stiffness index was significantly increased in AoC patients (12+/-9, P<0.0001). At multilinear regression analysis, age at repair (P=0.005; coefficient, -0.201; S.E.M., 0.027) and the aortic stiffness index (P=0.0029; coefficient, 0.334; S.E.M., 0.423) predicted longitudinal SR. Despite the presence of a successful repair for AoC, in the absence of hypertension, longitudinal deformation properties were significantly impaired. Moreover, the degree of longitudinal SR impairment was correlated with age at repair and aortic stiffness. Early repair can delay the onset of hypertension in postcoarctectomy patients, but cannot prevent the innate structural and functional abnormalities of the aorta and their deleterious effect on myocardial deformation properties.

Pulmonary vasoreactivity predicts long-term outcome in patients with Eisenmenger syndrome receiving bosentan therapy

Background Vasoreactivity testing is recommended in the management of pulmonary arterial hypertension (PAH), but its clinical relevance in congenital heart disease (CHD)-associated PAH has not been established. Objective To determine whether residual pulmonary vascular responsiveness to intravenous. epoprostenol is predictive of clinical outcome in patients with CHD-PAH and Eisenmenger syndrome. Methods and results A diagnostic right heart catheterisation with reversibility testing using epoprostenol infusion was performed in 38 consecutive patients with CHD-PAH and Eisenmenger syndrome. Patients were treated with bosentan and were assessed every 3u2005months. Clinical worsening was defined as death from any cause, heart–lung or lung transplantation (or on the waiting list for this procedure), hospitalisation for PAH, or symptom exacerbation defined as a ≥20% decrease in the 6u2005min walking distance on two consecutive tests, an increase in WHO functional class, or worsening right heart failure. The mean follow-up was 33±17u2005months. Sixteen patients showed clinical worsening. Although they did not differ from the other patients in their baseline exercise capacity, haemodynamic characteristics and underlying CHD, pulmonary vascular resistance index (PVRi) was less reversible (ΔPVRi 29±21 vs 52±14%, p=0.0003). At univariate analysis, systemic vascular resistance, PVRi and ΔPVRi were significant predictors of clinical worsening. At multivariate Cox proportional hazards regression model, ΔPVRi was found to be the only independent predictor of clinical worsening (HR=0.973, 95% CI 0.95 to 0.99; p=0.01). ΔPVRi ≥25% had a positive and negative predictive value for clinical worsening of 100% and 75.9%, respectively. Conclusion Pulmonary vasoreactivity is a significant predictor of clinical worsening in patients with CHD-PAH.

Hemodynamics of patients developing pulmonary arterial hypertension after shunt closure

BACKGROUNDnPulmonary arterial hypertension (PAH) after shunt closure is associated with a poor prognosis. The aim of this study was to assess retrospectively the hemodynamics of patients developing PAH after shunt closure.nnnMETHODSnHemodynamic data obtained by right heart catheterization (RHC) performed at baseline and after shunt closure were analyzed.nnnRESULTSnTwenty-two patients, 13 with atrial septal defect (ASD), 6 with ventricular septal defect (VSD), 1 with patent ductus arteriosus, 1 with both ASD and VSD, and 1 with complete atrio-ventricular canal have been considered. The mean age at closure was 25.3±20.1 years (range of 3 months to 56.7 years), and the mean age at PAH diagnosis was 37.0±20.8 years (range of 5 to 61.2 years). The time delay between shunt closure and PAH diagnosis was 140.2±100.2 months. At baseline RHC, hemodynamic data were as follows: pulmonary vascular resistance (PVR) of 8.6±2.6 Wood units, PVR index (PVRi) of 10.1±2.7 Wood units∗m(2), mean pulmonary arterial pressure of 43.7±9.7 mmHg, PVR to systemic vascular resistance ratio (PVR/SVR) of 0.70±0.23, and Qp/Qs of 1.6±0.4. In particular, 18/22 (81%) had PVR≥5 Wood units, 21/22 (95%) PVRi≥6 Wood units∗m(2), 21/22 (95%) PVR/SVR≥0.33, and 11/22 (50%) Qp/Qs≤1.5. During the follow-up, 5/22 (22%) patients died and one patient underwent successful double lung transplantation.nnnCONCLUSIONSnHigh baseline values of PVR (≥5 Wood units), PVRi (≥6 Wood units∗m(2)) and PVR/SVR (≥0.33) are common findings in patients who develop PAH late after shunt closure. Large prospective clinical trials are needed to establish the safe limits for shunt closure.

Changing spectrum and outcome of 705 fetal congenital heart disease cases: 12 years, experience in a third-level center

Introduction Congenital heart diseases are the most common prenatal and postnatal malformations. Nowadays, fetal echocardiography is a widely practiced technique; however, the impact of prenatal diagnosis on prognosis of the newborns affected by congenital heart disease remains uncertain. Objective To assess the outcome and the changes in the spectrum of prenatally detected congenital heart disease in our tertiary care centre in 12 years of activity (1995–2006). Methods and results We detected 705 congenital heart diseases: 32% (223) were associated with extracardiac or chromosomal anomalies or both, and 68% (482) were isolated. Termination of pregnancy was chosen in 81% for associated anomalies and 37% for isolated anomalies (P < 0.001). Of these, more than one-third occurred in hypoplasic left heart cases. The general survival rate was 72%; it was significantly lower in the group with associated heart diseases (46 vs. 80%, P < 0.001). Over 12 years we noticed a reduction in the number of multimalformed fetuses and of the hypoplasic left heart cases, and a higher number of aortic arch anomalies detected. During the past 6 years of activity the survival rate obtained has significantly increased (55 to 84%, P < 0.05), the termination rate has significantly decreased (35 to 14%, P < 0.001) and the number of neonatal deaths has significantly decreased (39 to 10%, P < 0.001). Conclusion The survival and the voluntary termination of fetuses with prenatally detected congenital heart diseases are strongly influenced by disease severity and by associated extracardiac or chromosomal anomalies, or both. Over 12 years, the spectrum of fetal congenital heart disease has changed and their outcome has significantly improved.

Patent ductus arteriosus: patho-physiology, hemodynamic effects and clinical complications

During fetal life, patent arterial duct diverts placental oxygenated blood from the pulmonary artery into the aorta by-passing lungs. After birth, decrease of prostacyclins and prostaglandins concentration usually causes arterial duct closure. This process may be delayed, or may even completely fail in preterm infants with arterial duct still remaining patent. If that happens, blood flow by-pass of the systemic circulation through the arterial duct results in pulmonary overflow and systemic hypoperfusion. When pulmonary flow is 50% higher than systemic flow, a hemodynamic “paradox” results, with an increase of left ventricular output without a subsequent increase of systemic output. Cardiac overload support neuro-humoral effects (activation of sympathetic nervous system and renin-angiotensin system) that finally promote heart failure. Moreover, increased pulmonary blood flow can cause vascular congestion and pulmonary edema. However, the most dangerous effect is cerebral under-perfusion due to diastolic reverse-flow and resulting in cerebral hypoxia. At last, blood flow decreases through the abdominal aorta, reducing perfusion of liver, gut and kidneys and may cause hepatic failure, renal insufficiency and necrotizing enterocolitis. Conclusions Large patent arterial duct may cause life-threatening multi-organ effects. In pre-term infant early diagnosis and timely effective treatment are cornerstones in the prevention of cerebral damage and long-term multi-organ failure.

Electrophysiological changes following balloon valvuloplasty and angioplasty for aortic stenosis and coartaction of aorta: clinical evidence for mechano-electrical feedback in humans

BACKGROUNDnBasic research and animal experiments have shown electrophysiological changes during or after changes in mechanical loading. Electrical instability following mechanical stretch has been observed as development of after-depolarisation and dispersion of refractoriness and repolarisation. The aim of the present study was to evaluate the presence of the mechano-electrical feedback in humans, assessing the ventricular repolarisation changes following acute changes in left ventricular pressure.nnnMATERIAL AND METHODSnThe study group comprised 30 consecutive patients (22 M and 8 F, aged 2 days-24 years) affected by severe congenital aortic stenosis and 30 patients (20 M and 10 F, aged 6 months-16 years) affected by severe coartaction of aorta. Ventricular repolarisation was evaluated before and after percutaneous balloon valvuloplasty and angioplasty in terms of absolute measures (JT, JTc, QT, QTc) and in terms of dispersion across the myocardium: QT and QTc dispersion (QTD, QTcD), JT and JTc dispersion (JTD and JTcD) and T-peak to T-end interval (Tp-Te).nnnRESULTSnPatients with severe aortic stenosis and patients with aortic coartaction showed a significant decrease in dispersion of ventricular repolarisation time indexes (QTD, QTcD, JTD, JTcD and Tp-Te) following valvuloplasty and angioplasty.nnnCONCLUSIONSnChanges in hemodynamic loading can also produce electrophysiological effects in humans. Acute reduction in left ventricular pressure overload following balloon valvuloplasty and angioplasty, decreases electrical instability, as expressed by the reduction across the myocardium of the dispersion of ventricular repolarisation.

A standard echocardiographic and tissue Doppler study of morphological and functional findings in children with hypertrophic cardiomyopathy compared to those with left ventricular hypertrophy in the setting of Noonan and LEOPARD syndromes

BACKGROUNDnSeveral clinical and echocardiographic studies describe morphological and functional findings in patients with hypertrophic cardiomyopathy. Less is known regarding morphological and functional characteristics of the left ventricular hypertrophy found in the setting of the Noonan and LEOPARD syndromes.nnnOBJECTIVEnTo compare non-invasively the morphological and functional findings potentially affecting symptoms and clinical outcome in children with hypertrophic cardiomyopathy as opposed to Noonan and LEOPARD syndromes.nnnPATIENTS AND METHODSnWe studied by echo-Doppler 62 children with left ventricular hypertrophy, dividing them into two subgroups matched for age and body surface area. The first group, of 45 patients with a mean age of 7.5 +/- 5.2 years and body surface area of 0.9 +/- 0.44 mq, had idiopathic hypertrophic cardiomyopathy. The second group, of 17 patients, all had left ventricular hypertrophy in the setting of Noonan or LEOPARD syndromes. Their mean age was 6.6 +/- 5 years, and body surface area was 0.8 +/- 0.36 mq. In all patients, we assessed the left ventricular maximal mural thickness, expressed as a Z-score, along with any obstructions in the left and right ventricular outflow tracts. In addition, to define left ventricular diastolic function, we used mitral flow and pulsed Tissue Doppler to record the Ea, Aa, Ea/Aa, E/Ea indexes in the apical 4-chamber view at the lateral corner of the mitral annulus. We also measured the diameters of the coronary arteries in the diastolic frame.nnnRESULTSnCompared to those with hypertrophic cardiomyopathy, those with syndromic left ventricular hypertrophy showed a significantly increased Z-score for mural thickness, and a higher prevalence of obstruction in the left ventricular outflow tract. In addition, the patients with Noonan or LEOPARD syndromes showed a significantly decrease of Ea and increase of Aa, with a decreased Ea/Aa ratio, all suggestive of left ventricular abnormal relaxation. Moreover, the E/Ea ratio was significantly increased in these patients. The presence of right ventricular hypertrophy, mainly associated with dynamic obstruction in the outflow tract, was detected in only 5 of the 17 patients with Noonan or LEOPARD syndromes, as was dilation of the coronary arteries.nnnCONCLUSIONSnCompared to children with hypertrophic cardiomyopathy, those with left ventricular hypertrophy in the setting of Noonan or LEOPARD syndromes show more ventricular hypertrophy and diastolic dysfunction, due to both abnormal relaxation and reduced compliance. They also exhibit an increased prevalence of obstruction of the left ventricular outflow tract, along with dynamic obstruction of the right ventricular outflow tract and dilated coronary arteries. These morphological and functional findings could explain the different symptoms and clinical events, and potentially define the more appropriate therapeutic options in children with left ventricular hypertrophy of different aetiology.