Giancarlo Scognamiglio

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

OBJECTIVES The 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. METHODS Thirty-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. RESULTS Twelve 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. CONCLUSIONS Addition 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.

Aortic and left ventricular remodeling in patients with bicuspid aortic valve without significant valvular dysfunction: A prospective study

BACKGROUND Bicuspid aortic valve (BAV) represents the most common cardiac congenital malformation in the adult age. It is frequently associated with dilatation, aneurysm and dissection of the ascending aorta. The purpose of the following study was to evaluate in patients with BAV: 1) the elastic properties of the ascending aorta, 2) the mechanical function of the left ventricle and 3) stiffness, elasticity and strain of the epi-aortic vessels wall. METHODS Forty BAV patients (28M/12F; age 20.9 ± 4.7 years; range 17-26) with no or mild valvular impairment were recruited with 40 control subjects (25M/15F; age 23.4 ± 3.4 years; range 15-31) matched for age, gender and body surface area (BSA). Aortic strain, aortic distensibility (AoDIS) and aortic stiffness index (AoSI) were derived. Left ventricular strain was acquired. Elastic properties of epi-aortic vessels were evaluated. RESULTS BAVs vs. controls had increased systolic and diastolic aortic diameters (p<0.001). Aortic strain (%) was lower in BAVs than in controls (8.3 ± 3.6 vs. 11.2 ± 2.6; p<0.001) as well as AoDIS (10(-6)cm(2)dyn(-1)) (6.5 ± 2.8 vs. 8.8 ± 2.9; p=0.002), while AoSI was greater in BAVs (6.4 ± 3.5 vs. 3.9 ± 1.2; p<0.001). Both AoDIS and aortic strain were related to aortic size in BAVs and controls. Left ventricular longitudinal (p=0.01), circumferential (p=0.01) and radial (p<0.001) strain (%) were lower in BAVs. No significant differences were found in elastic properties of epi-aortic vessels. CONCLUSIONS Bicuspid aortic valve is associated with an increased aortic stiffness and with a reduction of the aortic and left ventricular deformation properties. Epi-aortic vessels do not seem to be interested by the disease. The use of an echocardiographic method that can estimate the degree of aortic and left ventricular remodeling can provide great benefits in the selection of patients with BAV to be treated and in determining the time for beginning drug therapy.

Therapy for pulmonary arterial hypertension due to congenital heart disease and Down's syndrome

BACKGROUND Oral bosentan is effective in pulmonary arterial hypertension (PAH) related to congenital heart disease (CHD). In patients with Downs syndrome, the effect of bosentan is largely unknown. Aim of the study was to evaluate the long-term effects of bosentan in adult patients with CHD-related PAH with and without Downs syndrome. METHODS WHO functional class, resting oxygen saturation, 6-minute walk test (6 MWT) and hemodynamics were assessed at baseline and after 12 months of bosentan therapy in patients with CHD-related PAH with and without Downs syndrome. RESULTS Seventy-four consecutive patients were enrolled: 18 with and 56 without Downs syndrome. After 12 months of bosentan therapy, both with and without Downs syndrome patients showed an improvement in WHO functional class (Down: 2.5 ± 0.5 vs 2.9 ± 0.6, p=0.005; controls: 2.5 ± 0.5 vs 2.9 ± 0.5, p=0.000002), 6-minute walk distance (Down: 288 ± 71 vs 239 ± 74 m, p=0.0007; controls: 389 ± 80 vs 343 ± 86 m, p=0.00003), and hemodynamics (pulmonary flow, Down: 4.0 ± 1.6 vs 3.5 ± 1.4 l/m/m(2), p=0.006; controls: 3.5 ± 1.4 vs 2.8 ± 1.0 l/m/m(2), p=0.0005; pulmonary to systemic flow ratio, Down: 1.4 ± 0.7 vs 1.0 ± 0.4, p=0.003; controls: 1.1 ± 0.7 vs 0.9 ± 0.3, p=0.012; pulmonary vascular resistance index, Down: 15 ± 9 vs 20 ± 13 WUm(2), p=0.007; controls: 2 0 ± 10 vs 26 ± 15 WUm(2), p=0.002). No differences in the efficacy of therapy were observed between the two groups. CONCLUSIONS Bosentan was safe and well tolerated in adult patients with CHD-related PAH with and without Downs syndrome during 12 months of treatment. Clinical status, exercise tolerance, and pulmonary hemodynamics improved, regardless of the presence of Downs syndrome.

C-reactive protein in adults with pulmonary arterial hypertension associated with congenital heart disease and its prognostic value

Objectives To assess the relationship of C-reactive protein (CRP) to clinical outcome and mortality in adults with pulmonary arterial hypertension (PAH) associated with congenital heart disease (CHD-PAH). Background Approximately 5–10% of adults with congenital heart disease (ACHD) develop PAH, which in turn is associated with substantial morbidity and mortality. Although CRP is known to predict outcome in idiopathic PAH, little is known regarding its prognostic value in CHD-PAH. Methods We obtained and analysed 1936 CRP values in a total of 225 adults with CHD-PAH (median age at study entry 34.0 years (27.0–41.7); 32.9% male, 35% with Down syndrome), performed over a 12-year period. High CRP values related to infection or blood transfusions were excluded from the analysis. Results During a median follow-up of 4.8 years (1149 patients-years), 50 patients died. The median CRP concentration on the last assessment was 5.0 mg/L (IQR 2.0–10.0), higher in deceased patients compared with survivors (11.5 mg/L (6.0–23.0) vs 4.0 mg/L (1.5–8.0), p<0.0001). Following univariate Cox regression analysis, CRP emerged as a strong predictor of mortality (HR 1.18; 95% CI 1.11 to 1.26, p<0.0001) and remained significant after adjustment for age, presence of Down syndrome and advanced PAH therapy. Survival–receiver–operator characteristic analysis identified an optimal cut-off value of 10 mg/L. Patients with CRP >10 mg/L had more than a threefold increased risk of death (HR 3.63, 95% CI 2.07 to 6.38, p<0.0001). Conclusions Serum CRP is a simple but powerful marker of mortality in CHD-PAH patients and should be incorporated in the risk stratification and routine assessment of these patients.

Right Heart and Pulmonary Vessels Structure and Function

The right ventricle (RV) can be described in terms of 3 components: the inlet, the apex, and the infundibulum. In the normal adult, the RV shows an arrangement suited for pumping blood against low resistance, with a mass about one sixth that of left ventricle (LV) mass, and a larger volume than the LV. The RV is able to manage a progressive increase in the afterload by increasing contractility and remodeling. The gold standard measurement of contractility is maximal elastance (Emax), or the ratio between end‐systolic pressure (ESP) and end‐systolic volume (ESV), and the best measurement of afterload is arterial elastance (Ea), or the ratio between ESP and stroke volume (SV). The ratio Emax/Ea defines RV‐arterial coupling. The optimal energy transfer from the RV to the pulmonary circulation is measured at Emax/Ea ratios of 1.5–2. In the presence of pulmonary hypertension, the SV/ESV ratio may be an acceptable surrogate of Emax/Ea. The right atrium (RA) has 3 anatomical components: the appendage, the venous part, and the vestibule. It is a dynamic structure having different functions: reservoir, conduit, and booster pump function. In case of increased afterload, the RA is enlarged, denoting high RA pressure, as a consequence of elevated RV diastolic pressure. RA area is a strong predictor of adverse clinical outcome in pulmonary arterial hypertension. In patients with severe pulmonary hypertension, in several congenital heart diseases, and in Eisenmenger syndrome, symptoms and prognosis are greatly dependent on RV function and its ability to adapt to a chronic increase in afterload.

Clinical course and potential complications of small ventricular septal defects in adulthood: Late development of left ventricular dysfunction justifies lifelong care

BACKGROUND Patients with small ventricular septal defects (VSDs) are thought to have excellent long-term survival, although complications may not be uncommon. METHODS We identified all patients aged ≥ 16 years with native isolated VSD between January 2000 and September 2013. Clinical outcomes were retrospectively reviewed. Transthoracic echocardiograms performed within 2 years of last assessment were reviewed for hemodynamic sequelae. RESULTS Two-hundred-and-thirty-one patients, 100 (43%) male, mean age at last follow-up 34 ± 13 years were studied. During the recorded period there were no deaths. The majority (224/231; 97%) were asymptomatic. Documented arrhythmias occurred in 7 patients (3%), double-chamber right ventricle (DCRV) in 29 (13%), more than mild aortic regurgitation in 6 (3%) and infective endocarditis in 24 (10%) patients. Surgery due to complications associated with VSD was performed in 26 (11%) patients at a median age of 27.6 years (IQR: 16.1-38.7) due to DCRV (n=17, 65%), infective endocarditis (n=6, 23%), progression of left-right shunt (n=2, 8%) and aortic regurgitation (n=1, 4%). At most recent echocardiography (n=164), 10 (6%), had reduced LVEF, 34 (21%) had increased LVEDD and 17 (10%) had LVESD >4.0 cm. Thirty-two patients (25%) with normal LV dimensions had LA enlargement suggesting LV diastolic dysfunction. CONCLUSIONS We report a non-negligible incidence of major complications or clinical events during late follow-up of adult patients with restrictive VSDs. Furthermore, we show co-existing LV dysfunction, systolic or diastolic in a subset of patients. Indication for VSD closure in childhood may be recognized, whereas lifelong follow-up for adult with restrictive VSDs is clearly warranted.

Multimodality imaging in congenital heart disease-related pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) in adult patients with congenital heart disease (CHD) is associated with increased morbidity and mortality. The present review aims to discuss the clinical applications of invasive and non-invasive diagnostic modalities and to describe the strengths and weaknesses of each technique. Chest radiograph is an inexpensive investigation providing information on pulmonary arterial and hilar dilatation, pruning of peripheral pulmonary arteries and cardiomegaly. Transthoracic two-dimensional and Doppler echocardiography is the most widely used imaging tool. It provides information on cardiac anatomy and an estimate of haemodynamics and biventricular remodelling and function. In addition, echocardiography is valuable in assessing prognosis and monitoring the efficacy of therapy. Structural and functional changes associated with CHD-PAH, mainly affecting the right ventricle and pulmonary circulation, may represent an ideal target for evaluation with cardiac magnetic resonance. This non-invasive imaging modality has a low biological impact. CT plays an important role for patients with limited echocardiographic windows and those who are unable to undergo MRI (claustrophobia, poor compliance, presence of a pacemaker/implantable cardioverter defibrillator). It is the modality of choice for detailed assessment of pulmonary vessel obstruction or thrombosis. Finally, heart catheterisation remains the gold standard for diagnosing and confirming PAH in patients with CHD and for shunt evaluation. The diagnostic assessment of CHD-PAH requires great expertise and a deep knowledge of both CHD and PAH pathophysiology and should take place in a tertiary centre, where multiple data can be appropriately integrated and applied clinically.

Right atrial function and prognosis in idiopathic pulmonary arterial hypertension

AIM To determine whether right atrial (RA) function has prognostic value in patients with idiopathic pulmonary arterial hypertension (PAH). METHODS AND RESULTS Overall, 104 patients (70 female, mean age 58±13years) with idiopathic PAH underwent standard Doppler echocardiography and strain and strain rate (SR) analysis before right heart catheterization. At a mean follow-up of 22±7months, 30 patients (29%) had clinical worsening. On Cox multivariable proportional-hazards regression analysis, RA reservoir function measured as peak longitudinal SR (hazard ratio [HR] 0.5; P<0.0001), RA area (HR 1.2; P<0.01), right ventricular (RV) SR (HR 0.6; P<0.0001), cardiac index (HR 0.79; P<0.01), and mixed venous oxygen saturation (HR 0.82; P<0.01) were found to be independent correlates of cardiac events. A RA SR reservoir cut-off value of <1.2s-1 and a RV SR cut-off value of <1s-1 well identified patients at higher risk of clinical worsening (sensitivity 85.5%; specificity 90.4%; test accuracy 88.8%). In particular, event rates and mean survival time free of clinical worsening were: 6.1% and 23.5±2.2months in patients with normal RA and RV SR; 45% and 20.9±5.5months in patients with impaired RA and normal RV SR; 56.2% and 17.7±6.6months in patients with normal RA and impaired RV SR; and 87.5% and 12.9±7.6months in patients with impairment of both RA and RV SR. CONCLUSION Our data suggest that RA function has prognostic value in idiopathic PAH, where a poorer RA function, as explored by strain and SR analysis, is associated with a worse outcome.

Atenolol vs enalapril in young hypertensive patients after successful repair of aortic coarctation

Late arterial hypertension has been identified as a major predictor for morbidity and mortality in aortic coarctation (AoC) patients. Few data are available about efficacy and tolerability of angiotensin converting enzyme inhibitors vs beta-blockers in young AoC patients. This study aimed to evaluate the tolerability and efficacy on 24-h blood pressure (BP) and left ventricular mass/height2.7 (LVMI), of atenolol vs enalapril. We enrolled consecutive AoC hypertensive patients with (a) no history of BP treatment or after >48 h of withdrawn, (b) aged 6–20 years, (c) body mass index (BMI) <90th percentile for age and sex, (d) >12 months from a successful AoC repair and (e) no major associated cardiovascular abnormalities. All patient were evaluated with 24-h ambulatory BP monitoring, standard echocardiography, strain–strain rate imaging, at enrolment, 3, 6 and 12 months of treatment. We studied 51 AoC patients (13±3.9 years, BMI: 21.4±4.3 kg m–2). Patients were randomly assigned at atenolol treatment (n=26), or enalapril treatment (n=25). The mean follow-up duration was 11±2 months. Both drugs were able to significantly reduce 24-systolic BP (SBP; atenolol: 133±11 mm Hg vs 124±16 mm Hg, P=0.016; enalapril: 135±6 mm Hg vs 127±7 mm Hg, P=0.001). Only enalapril was able to significantly reduce LVMI (47±12  vs 39.6±10 g m–2.7, P=0.016). Only in atenolol group in two cases (7.7%) drug withdrawal was needed because of adverse events. Enalapril and atenolol are similarly effective in reducing SBP. However, only enalapril demonstrated a significant reduction of LVMI. In no case, enalapril was stopped because of adverse events.

Ambrisentan for pulmonary arterial hypertension: long term effects on clinical status, exercise capacity and haemodynamics.

Ambrisentan, an oral endothelin-1-receptor antagonist (ERA) selective for the endothelin A, showed an improvement in WHO functional class, 6 minute walk distance, and time to clinical worsening relative to placebo in randomised, double-blind, placebo-controlled, multicenter, 12-week clinical trials (ARIES study 1 and 2, total n=394) [1]. At this time, the long-term effects of ambrisentan on haemodynamics have not been reported in a prospective study. The aim of this study was to evaluate prospectively the efficacy and safety of ambrisentan treatment in adult patients with pulmonary arterial hypertension by assessing its long term effects on clinical status, exercise capacity, and cardiopulmonary haemodynamics. This was a single-centre, open-label, single-arm, prospective study. All patients with PAH starting oral ambrisentan as first line therapy or combination therapy (based on recommendations of the current ESC/ERS guidelines on pulmonary hypertension) [2] were enrolled after obtaining the informed consent. Clinical status, resting transcutaneous oxygen saturation (SpO2), 6-minute walk distance, serology and right heart catheterization (RHC) were assessed at baseline (before starting ambrisentan therapy) and at 1 year follow-up. The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology [3]. Clinical status evaluation included medical history, assessment of WHO functional class, measurement of systemic arterial pressure, transcutaneous oxygen saturation (SpO2) and heart rate.