Fernando M. Picchio

Wide spectrum of presentation and variable outcomes of isolated left ventricular non-compaction

Objectives: To investigate diagnostic routes, echocardiographic substrates, outcomes and prognostic factors in patients with isolated ventricular non-compaction (IVNC) identified by echocardiographic laboratories with referral from specialists and primary care physicians. Patients and design: Since 1991, all patients with suspected IVNC were flagged and followed up on dedicated databases. Patients were divided into symptom-based and non-symptom-based diagnostic subgroups. Results: 65 eligible patients were followed up for 6–193 months (mean 46 (SD 44). In 53 (82%) patients, IVNC was associated with variable degrees of left ventricular (LV) dilatation and hypokinesia, and in the remaining 12 (18%) LV volumes were normal. Diagnosis was symptom based in 48 (74%) and non-symptom based in 17 (26%) (familial referral in 10). The non-symptom-based subgroup was characterised by younger age, lower prevalence of ECG abnormalities, better systolic function and lower left atrial size, whereas the extent of non-compaction was not different. No major cardiovascular events occurred in the non-symptom-based group, whereas 15 of 48 (31%) symptomatically diagnosed patients experienced cardiovascular death or heart transplantation (p  =  0.01, Kaplan–Meier analysis). Independent predictors of cardiovascular death or heart transplantation were New York Heart Association class III–IV, sustained ventricular arrhythmias and left atrial size. Conclusions: IVNC is associated with a broad spectrum of clinical and pathophysiological findings, and the overall natural history and prognosis may be better than previously thought. Adult patients with incidental or familial discovery of IVNC have an encouraging outlook, whereas those who have symptoms of heart failure, a history of sustained ventricular tachycardia or an enlarged left atrium have an unstable course and more severe prognosis.

Effect of sildenafil on haemodynamic response to exercise and exercise capacity in Fontan patients

AIMS We sought to assess the effects of sildenafil on exercise capacity and haemodynamic response to exercise in Fontan patients. METHODS AND RESULTS We prospectively studied 27 patients with Fontan circulation (age 22.8 +/- 4.9 years). All patients underwent a baseline exercise test with non-invasive measurement of cardiac index (CI) and pulmonary blood flow (PBF) index, and peak exercise oxygen uptake (VO(2)). After the baseline test, patients were randomly assigned to receive either a single 0.7 mg/kg body weight oral dose of sildenafil citrate (n = 18) or no treatment (control group, n = 9). After 1 h of rest, all patients performed a second exercise test. All patients completed the study protocol. The dose of sildenafil ranged from 25 to 50 mg. The change in peak VO(2), the primary endpoint, was greater in the sildenafil group (9.4 +/- 5.2%) than in the control group (0.3 +/- 4.1%, P < 0.05). Sildenafil increased rest and peak exercise PBF index (P < 0.01 and P < 0.05 vs. control group, respectively), as well as rest and peak exercise CI (P < 0.001 and P < 0.05 vs. control group, respectively), without altering rest or peak exercise transcutaneous arterial blood oxygen saturations (P > 0.05 vs. control group for both). No patient reported serious adverse events after sildenafil. CONCLUSION In Fontan patients, oral administration of a single dose of sildenafil improves exercise capacity and haemodynamic response to exercise.

Predictors of morbidity and mortality in contemporary Fontan patients: results from a multicenter study including cardiopulmonary exercise testing in 321 patients

AIMS previous studies have established an association between exercise intolerance and increased morbidity and mortality in congenital heart disease patients. We aimed to clarify if exercise intolerance is associated with poor outcome in Fontan patients and to identify risk factors for mortality, transplantation, and cardiac-related hospitalization. METHODS AND RESULTS a total of 321 Fontan patients (57% male, mean age 20.9 ± 8.6 years) who underwent cardiopulmonary exercise testing (CPET) at four major European centres between 1997 and 2008 were included. During a median follow-up of 21 months, 22 patients died and 6 patients underwent cardiac transplantation (8.7%), resulting in an estimated 5-year transplant-free survival of 86%. Parameters of CPET were strongly related to increased risk of hospitalization, but-with the exception of heart rate reserve-unrelated to risk of death or transplantation. In contrast, patients with clinically relevant arrhythmia had a 6.0-fold increased risk of death or transplantation (P < 0.001). Furthermore, patients with atriopulmonary/-ventricular Fontan had a 3.7-fold increased risk of death or transplantation compared with total cavopulmonary connection patients (P= 0.009). The combination of clinically relevant arrhythmia, atriopulmonary/-ventricular Fontan, and signs of symptomatic or decompensated heart failure was associated with a particularly poor outcome (3-year mortality 25%). CONCLUSION on short-term follow-up, most parameters of CPET are associated with increased risk of hospitalization but not death or transplantation in contemporary Fontan patients. Only decreased heart rate reserve and a history of clinically relevant arrhythmia, atriopulmonary/-ventricular Fontan, and/or heart failure requiring diuretic therapy are associated with poor prognosis, potentially identifying patients requiring medical and/or surgical attention.

Management of Pulmonary Arterial Hypertension Associated with Congenital Systemic-to-Pulmonary Shunts and Eisenmenger’s Syndrome

A large proportion of patients with congenital heart disease (CHD), in particular those with relevant systemic-to-pulmonary shunts, will develop pulmonary arterial hypertension (PAH) if left untreated. Persistent exposure of the pulmonary vasculature to increased blood flow, as well as increased pressure, may result in pulmonary obstructive arteriopathy, which leads to increased pulmonary vascular resistance that, if it approaches or exceeds systemic resistance, will result in shunt reversal. Eisenmenger’s syndrome, the most advanced form of PAH associated with CHD, is defined as CHD with an initial large systemic-to-pulmonary shunt that induces severe pulmonary vascular disease and PAH, with resultant reversal of the shunt and central cyanosis.The histopathological and pathobiological changes seen in patients with PAH associated with congenital systemic-to-pulmonary shunts, such as endothelial dysfunction of the pulmonary vasculature, are considered similar to those observed in idiopathic or other associated forms of PAH. A pathological and pathophysiological classification of CHD with systemic-to-pulmonary shunt leading to PAH has been developed that includes specific characteristics, such as the type, dimensions and direction of the shunt, extracardiac abnormalities and repair status. A clinically oriented classification has also been proposed.The prevalence of PAH associated with congenital systemic-to-pulmonary shunts in Western countries has been estimated to range between 1.6 and 12.5 cases per million adults, with 25–50% of this population affected by Eisenmenger’s syndrome.Clinically, Eisenmenger’s syndrome presents with multiple organ involvement, with progressive deterioration of function over time. The signs and symptoms of Eisenmenger’s syndrome in the advanced stages include central cyanosis, dyspnoea, fatigue, haemoptysis, syncope and right-sided heart failure. Survival of patients with Eisenmenger’s syndrome is clearly less than that of the general population, but appears to be better than that of patients with idiopathic PAH in a comparable functional class.The treatment strategy for patients with PAH associated with congenital systemic-to-pulmonary shunts and, in particular, those with Eisenmenger’s syndrome is based mainly on clinical experience rather than being evidence based. General measures include recommendations for physical activity, pregnancy, infections, air travel, exposure to high altitudes and elective surgery, and that psychological assistance be provided as necessary. Phlebotomies are required only when hyperviscosity of the blood is evident, usually when the haematocrit is >65%. The use of supplemental oxygen therapy is controversial and it should be used only in patients in whom it produces a consistent increase in arterial oxygen saturation. Oral anticoagulant treatment with warfarin can be initiated in patients with pulmonary artery thrombosis and absent, or only mild, haemoptysis.The following three classes of drugs targeting the correction of abnormalities in endothelial dysfunction have been approved recently for the treatment of PAH: (i) prostanoids; (ii) endothelin receptor antagonists; and (iii) phosphodiesterase-5 inhibitors. The efficacy and safety of these compounds have been confirmed in uncontrolled studies in patients with PAH associated with corrected and uncorrected congenital systemic-to-pulmonary shunts, as well as in patients with Eisenmenger’s syndrome. One randomized controlled trial reported favourable short- and long-term outcomes of treatment with the orally active dual endothelin receptor antagonist bosentan in patients with Eisenmenger’s syndrome. Lung transplantation with repair of the cardiac defect or combined heart-lung transplantation are options for Eisenmenger’s syndrome patients with a poor prognosis. A treatment algorithm based on the one used in the treatment of PAH patients is proposed for patients with PAH associated with corrected and uncorrected congenital systemic-to-pulmonary shunts and Eisenmenger’s syndrome.

Natural History of Exercise Capacity After the Fontan Operation: A Longitudinal Study

BACKGROUND Previous studies have shown that older Fontan patients and those with an underlying morphologically right ventricle have lower exercise capacity. We sought to assess the natural history of exercise capacity after the Fontan operation in individual patients, and to identify the factors influencing the rate of decrease of exercise capacity over time. METHODS We studied, longitudinally, 53 Fontan patients with cardiopulmonary exercise tests (average 3.2 +/- 1.1 tests for each patient). Age at the first test was 14 +/- 6 years. Time intervals between tests ranged from 1 to 16 years (average, 7.7 +/- 4.0 years). The morphology of the functionally single ventricle was left in 29 patients (55%) and right in 24 patients (45%). Twenty-two patients had undergone a total cavopulmonary connection (TCPC) at a mean age of 5.9 +/- 2.8 years. Thirty-one patients had undergone an atriopulmonary or an atrioventricular connection at an age of 6.9 +/- 4.4 years. Exercise capacity was expressed as percentage of predicted peak oxygen uptake (VO2). RESULTS Overall, peak VO2 decreased at a rate of -2.6 +/- 2.7%/year. Ventricular morphology (r = 0.525, p = 0.0001) and type of Fontan operation (r = 0.381, p = 0.0057) appeared as the only predictors of the rate of decrease of peak VO2 at multivariate analysis. Patients with an underlying left ventricular morphology (-1.7 +/- 2.0 vs -3.7 +/- 3.2%/year, p = 0.005), and those who underwent a TCPC (-1.9 +/- 1.8 vs -3.3 +/- 3.2%/year, p = 0.042), had the lowest rate of decrease in peak VO2. CONCLUSIONS Exercise capacity progressively declines in Fontan subjects. The decline of exercise capacity seems to be slower in patients with an underlying left ventricular morphology and in those who received a TCPC.

Ventilatory Efficiency and Aerobic Capacity Predict Event-Free Survival in Adults With Atrial Repair for Complete Transposition of the Great Arteries

OBJECTIVES The goal of this study was to assess the prognostic value of the cardiopulmonary exercise test (CPET) in patients who received a Mustard and Senning (M/S) operation. BACKGROUND Patients who received an M/S operation have increased long-term risk of cardiovascular morbidity and mortality. Limited information is available on how to stratify risk in this population. METHODS Between 1996 and 2007, 274 adults (age 26.3 +/- 8.9 years, range 16 to 50 years) who had received a Mustard (n = 144) or Senning (n = 130) operation in infancy were studied with CPET. During a follow-up of 3.9 +/- 2.3 years (range 0.2 to 10.8 years), 12 patients died at an age of 36 +/- 14 years, and 46 patients required a cardiac-related emergency (<24 h from the onset of symptom/condition) hospital admission at an age of 30 +/- 11 years. RESULTS At multivariate Cox analysis, the slope of ventilation per unit of carbon dioxide output (VE/VCO(2) slope) (hazard ratio: 1.088, p < 0.0001) and percentage of predicted peak oxygen uptake (Vo(2)%) (hazard ratio: 0.979, p = 0.0136) were the strongest predictors of death/cardiac-related emergency hospital admission among demographic, clinical, and exercise variables. A VE/VCO(2) slope > or =35.4 (hazard ratio: 10.7, 95% confidence interval [CI]: 7.8 to 24.6), and a peak Vo(2)% < or =52.3% (hazard ratio: 3.4, 95% CI: 2.5 to 8.2) were associated with an increased 4-year risk of death/cardiac-related emergency hospital admission. Patients who had both a VE/VCO(2) slope > or =35.4 and a peak Vo(2)% < or =52.3% of predicted value were at highest risk (4-year event rate: 78.8%). CONCLUSIONS CPET provides important prognostic information in adults with M/S operation. Subjects with enhanced ventilatory response to exercise or those with poor exercise capacity have a substantially higher 4-year risk of death/cardiac-related emergency hospital admission.

Turner's syndrome: cardiologic profile according to the different chromosomal patterns and long-term clinical follow-Up of 136 nonpreselected patients.

The preferential association between Turners syndrome and congenital heart defects (CHD) have been well known since the first description by Morgagni. There are few studies about the different cardiologic problems stemming from different chromosomal patterns of X monosomies. We reviewed a large series of 136 patients with Turner syndrome without cardiologic preselection, 29 of whom had some kind of CHD (21.5%). Partial anomalous pulmonary venous drainage (PAPVD; 2.9%), aortic valve disease (stenosis and/or incompetence) (AoVD; 5.1%), aortic coarctation (AoCo; 4.4%), and bicuspid aortic valve (BicAo; 14.7%) are much more frequent in Turners syndrome than in the normal population, with the difference being statistically highly significant. In our cases, only the 45, X subjects showed severe CHD and multiple lesions, whereas the X-ring pattern was associated with an elevated prevalence of BicAo. Patients with X-deletion showed no signs of congenital heart malformations. Eleven patients, all with 45, X pattern, and significant CHD, underwent cardiac surgery at a mean age of 7.7 ± 5.3 years (range 7 days–18 years) without complications. At follow-up of 3–18 years (8.6 ± 5.2), we were unable to observe any type of evolution of the remaining untreated cardiovascular anomalies.

A pilot study on the effects of carvedilol on right ventricular remodelling and exercise tolerance in patients with systemic right ventricle

BACKGROUND Patients with atrial repair for transposition of the great arteries and patients with congenitally corrected transposition have a right ventricle (RV) in the systemic position and they may develop RV dysfunction and exercise intolerance with advancing age. No data is available on the effect of carvedilol in patients with dysfunctional systemic RV. METHODS We studied with cardiovascular magnetic resonance (CMR), cardiopulmonary exercise testing, and standard 12-leads electrocardiogram, 8 adults (median age 26 years, range 18-31) with chronic stable heart failure and systemic RV dysfunction (6 patients with atrial repair and 2 patients with congenitally corrected transposition). Assessment was done before and after 12 months of carvedilol administration. The initial dose was 3.125 mg twice daily, and the target dose was 25 mg twice a day. RESULTS Carvedilol administration was safe and the target dose was achieved in 5/8 (62%) patients. Right ventricular end-diastolic (119 ± 31 vs. 112 ± 28 ml/m², p=0.01) and end-systolic volumes decreased (79 ± 17 vs. 65 ± 14 ml/m², p=0.006), and RV ejection fraction improved (34 ± 6 vs. 42 ± 7%, p=0.004). Left ventricular ejection fraction increased (44 ± 8 vs. 49 ± 9%, p=0.01), suggesting a positive biventricular remodelling. Peak oxygen uptake did not change with carvedilol (26.8 ± 5.3 vs. 27.3 ± 5.7 ml O₂/Kg/min, p=0.58), whereas exercise duration increased (13.4 ± 2.6 vs. 17.3 ± 3.1 min, p=0.008). CONCLUSIONS In this small cohort, carvedilol administration was safe and it was associated with positive RV remodelling as well as improved exercise duration.

Prevalence and predictors of neoaortic regurgitation after arterial switch operation for transposition of the great arteries

BACKGROUND The fate of the native pulmonary valve after arterial switch operation is still unknown and may become a cause for a secondary aortic valve operation during adult life. We evaluated the prevalence and predictive factors associated with neoaortic valvular regurgitation by a retrospective study of children who underwent arterial switch operation for transposition of the great arteries. METHODS The onset of neoaortic valvular regurgitation was correlated with demographic data, cardiac anatomy, surgical technique, and postoperative ventricular function. The size of the neoaortic root and ascending aorta was measured in a selected subset of patients. RESULTS Among 253 survivors, 173 were eligible for the study. After a median follow-up time of 8.2 years, 61 patients showed echocardiographic or angiographic evidence of valvular incompetence, which was progressive in 14 cases; this led to surgical intervention in 2 patients, and there was 1 operative death. At multivariate analysis, the onset of valvular regurgitation was correlated with the trap-door technique for coronary reimplantation (P <.01). A smooth transition from the aortic sinus to the ascending aorta, with loss of the normal sinotubular junction geometry, may be associated with valvular incompetence. CONCLUSIONS After arterial switch operation, there is an increasing frequency of neoaortic regurgitation, which may lead to significant valvular dysfunction later in life. The trap-door type of coronary reimplantation is associated with an increased risk for valvular dysfunction, possibly because of a distortion of the sinotubular junction geometry. For this reason, we recommend the punch technique for repair in all but the most complicated coronary pattern.

Heart Transplantation in Hypertrophic Cardiomyopathy

Heart transplantation (HT) is the sole therapeutic option for selected patients with hypertrophic cardiomyopathy (HC) and refractory heart failure. However, the results of HT have not been systematically investigated in HC. We assessed the pathophysiologic profile of HT candidates and the outcome after transplantation in 307 patients with HC consecutively evaluated at our tertiary referral center from 1987 to 2005; follow-up was 9.9+8.2 years. Outcome of recipients with HC was compared with that of 141 patients who underwent transplantation for idiopathic dilated cardiomyopathy at our center over the same period. Of 21 patients with HC who entered the transplantation list, 20 had end-stage evolution with systolic dysfunction and 1 had an extremely small left ventricular cavity with impaired filling and recurrent cardiogenic shock during paroxysmal atrial fibrillation. Of 33 study patients with HC who showed end-stage evolution during follow-up, the 23 who were included on the waiting list or died from refractory heart failure (2 patients) were significantly younger than the 10 patients who remained clinically stable (37+/-14 vs 57+/-17 years, p=0.004). Of the 21 HT candidates, 18 underwent transplantation during follow-up. In heart transplant recipients, 7-year survival rate was 94% and not different from that of the 141 patients who received transplants for idiopathic dilated cardiomyopathy (p=0.66). In conclusion, long-term outcome after HT in patients with HC is favorable and similar to that of patients with idiopathic dilated cardiomyopathy. In patients with end-stage HC, young age is associated with more rapid progression to refractory heart failure.