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.

Strong and independent prognostic value of peak circulatory power in adults with congenital heart disease.

BACKGROUND: The identification of patients with adult congenital heart disease (ACHD) who are at higher risk of death is challenging. Peak circulatory power (CircP; expressed as peak exercise oxygen uptake multiplied for peak mean arterial blood pressure) is a strong predictor of death in adults with acquired heart disease. We sought to establish the distribution and the prognostic value of peak CircP across a wide spectrum of patients with ACHD. METHODS: Four hundred thirty-two consecutive patients with ACHD of varying diagnosis underwent cardiopulmonary exercise testing at a single laboratory between 1996 and 2005. Patient age was 32 +/- 10 years. RESULTS: A gradual variation in peak CircP was found across the spectrum of congenital heart defects (P < .0001 at analysis of variance). Reduced peak CircP values were associated with the presence of heart failure symptoms (P < .0001), absence of sinus rhythm (P = .010), and use of antiarrhythmic medications (P = .0013). At a follow-up of 4.4 +/- 2.4 years, 23 patients (5.3%) had died. Peak CircP was a strong predictor of mortality when univariate analysis was used and the strongest independent predictor of mortality among exercise parameters. A peak CircP < or = 1476 mm Hg mlO2 min(-1) kg(-2) was associated with a 15.4-fold increase in the 4-year risk of death. CONCLUSIONS: Peak CircP is abnormal across the spectrum of ACHD. Peak CircP appears as the strongest predictor of adverse outcome in ACHD.

Usefulness of cardiopulmonary exercise to predict long-term prognosis in adults with repaired tetralogy of Fallot.

Adults with tetralogy of Fallot (TOF) have increased long-term mortality. The identification of patients at greater risk for death or cardiac-related morbidity is challenging. This study was conducted to assess the prognostic value of cardiopulmonary exercise testing in adults with repaired TOF. One hundred eighteen consecutive adults with repaired TOF (mean age at repair 4.8 +/- 4.2 years) underwent cardiopulmonary exercise testing at a mean age of 24 +/- 8 years (range 16 to 59). The degree of pulmonary regurgitation, right ventricular function, and right ventricular systolic pressure were determined by transthoracic echocardiography. After the exercise tests, patients were regularly followed up for cardiac-related events. During a mean follow-up of 5.8 +/- 2.3 years (range 0.6 to 9.7), 9 patients died and 18 underwent hospitalization. Peak oxygen uptake (hazard ratio 0.974, 95% confidence interval 0.950 to 0.994), the slope of ventilation (VE) per unit of carbon dioxide production (VCO(2)) (hazard ratio 1.076, 95% confidence interval 1.038 to 1.115), and New York Heart Association functional class (hazard ratio 2.118, 95% confidence interval 1.344 to 3.542) were independent predictors of death or hospitalization. Patients with peak oxygen uptake < or =36% of predicted value and those with VE/VCO(2) slopes >39 were at greater risk for cardiac-related death (5-year mortality 48% vs 0%, p <0.0001, and 31% vs 0%, p <0.0001, respectively). In conclusion, the measurement of peak oxygen uptake and VE/VCO(2) slope in adults with repaired TOF can be prognostically important and could become a powerful tool to rationalize decisions regarding the prevention of premature sudden death and the need for reintervention.

Impact of pulmonary regurgitation and right ventricular dysfunction on oxygen uptake recovery kinetics in repaired tetralogy of Fallot.

BACKGROUND: Patients with repaired tetralogy of Fallot (ToF) featuring severe pulmonary regurgitation (PR) and/or right ventricular (RV) dysfunction have reduced exercise tolerance. AIMS: To assess the impact of PR and of RV function on the ability to recover from exercise in ToF patients. METHODS: 61 consecutive patients aged 23.1+/-12.1 years underwent maximal cardiopulmonary exercise test (CPX), transthoracic echocardiography and magnetic resonance imaging. This data was compared to those of 153 matched healthy subjects. RESULTS: 19 patients (31%) had severe PR. RV dysfunction was noted in 19 patients (31%). Nine patients (15%) had both severe PR and RV dysfunction. Patients had lower peak oxygen uptake (VO2), VO2 slope, carbon dioxide production (VCO2) slope and O2 pulse slope (p < 0.0001), especially those with severe PR and RV dysfunction (p < 0.0001). Heart rate slope was similar between groups. No patient with severe PR and RV dysfunction had a predicted peak VO2 > 40%. CPX had a high sensitivity and specificity to identify patients with severe PR and RV dysfunction. CONCLUSIONS: In ToF patients, severe PR and RV dysfunction lead to delayed recovery from exercise. CPX can identify patients with severe PR and RV dysfunction and may be useful to guide the pulmonary valve replacement decision-making process.

Electrocardiographic remodeling during cardiac resynchronization therapy.

BACKGROUND: More information is required on the relationship between electrical and structural reverse remodeling in patients treated with cardiac resynchronization therapy. METHODS: QRS and JT intervals were investigated during different pacing modes before and 3 months after implantation of a device for biventricular (BiV) pacing in 20 patients with severe drug-refractory heart failure (with left ventricular ejection fraction < 40% and QRS > 120 ms); structural remodeling was evaluated by echocardiography. RESULTS: QRS interval was significantly shortened by BiV pacing both acutely (p=0.002) and at 3 months (p=0.007). No significant change was found in the JT interval. The extent of QRS shortening obtained by BiV pacing showed moderate correlations with the reduction of end-systolic and end-diastolic volumes (r=0.53, p=0.016 and r=0.45, p=0.045, respectively) as well as with increase of left ventricular ejection fraction (r=0.49, p=0.028) at 3 months. The widening of QRS observed during right ventricular (RV) pacing was greater after 3 months of BiV pacing (with respect to acute assessments), suggesting accentuation of pacing-induced electrical dyssynchrony after a period of pacing-induced resynchronization. CONCLUSION: The extent of QRS shortening induced by BiV pacing appears to correlate with the reverse structural remodeling (in terms of reduction in end-systolic volume). The acute changes and the remodeling process occurring at mid-term in the overall population of CRT-treated patients do not appear to involve the JT interval. A period of pacing-induced resynchronization appears to accentuate the potential for RV pacing-driven electrical dyssynchrony.

Acute and chronic haemodynamic effects of biventricular pacing and of switching to different pacing modalities in heart failure patients.

BACKGROUND: In patients with severe heart failure, sinus rhythm and wide QRS complex biventricular (BiV) pacing leads to clinical and haemodynamic improvement, but the immediate reversibility of these changes is not known. METHODS: We assessed the acute and medium-term (3-month) haemodynamic effects of BiV pacing and of switching to other pacing modalities in 21 patients with severe heart failure, sinus rhythm and QRS>or=130 ms. Haemodynamic studies were performed: 1) at the time of implantation of a BiV pacing device, during AAI pacing, atrial synchronous right ventricular (RV) pacing, atrial synchronous left ventricular (LV) pacing and atrial synchronous BiV pacing (all at 100 bpm); 2) after 3 months of continuous BiV pacing--with evaluations being made by switching to RV and the other pacing modalities. RESULTS: At both the acute and medium-term evaluations, BiV pacing provided the greatest improvement in cardiac index. Switching from BiV to RV pacing led to a more marked decrease in the cardiac index at 3 months. No strict correlation was evident between acute and medium-term effects of BiV pacing on cardiac index. CONCLUSION: Cardiac resynchronization by BiV pacing provides acute/medium-term improvements in cardiac index. Sudden, medium-term failure of LV stimulation can lead to an even more pronounced haemodynamic derangement than that inducible by RV pacing at baseline. Acute haemodynamic evaluations do not seem to provide a powerful way for identifying medium-term responders.

Cardiac resynchronization therapy in clinical practice: need for electrical, mechanical, clinical and logistic synchronization.

Considering the relatively short history of cardiac resynchronization therapy (CRT), the amount of available evidence of efficacy is impressive, and effectiveness studies are now required. Transfer of our experimentally gained knowledge into the real world raises issues that call for synchronization among the many specialists involved in chronic heart failure (CHF) management and CRT decision making. From an economic perspective, the demonstrated ability of CRT to reduce hospitalizations could help ease the burden on health systems derived from the growing incidence of CHF. Recent American College of Cardiology/American Heart Association guideline revisions should encourage a synchronized approach to rational deployment of CRT in selected patients. Nevertheless, current QRS criteria for CRT candidacy do not directly address the key issue of identification of patients with a pacing-correctable mechanical dyssynchrony (and in clinical trials, 25-30% of implanted patients did not respond to CRT). Echocardiography could become an important adjunct (or even an alternative) to QRS duration for patient selection; routine implementation would require use of straightforward, reproducible measurements, possibly obtainable on standard equipment. Echocardiography could also help optimize site location, although this would not eliminate lead placement problems. A series of issues remain open for investigation, including the potential of CRT in patients with atrial fibrillation, impact of devices with defibrillation ability, effects of electrical/pharmacological tailoring, need for confirmation that efficacy of CRT extends into the long term and possible use of CRT in mild CHF. Interdisciplinary synchronization in the various phases of CRT (screening, proposing, implementing, optimizing and monitoring) should eventually help develop a coordinated system for patient referral.

Determinants of cardiopulmonary functional improvement after transcatheter atrial septal defect closure in asymptomatic adults.

OBJECTIVES: We sought to evaluate the course of cardiopulmonary function after transcatheter atrial septal defect (ASD) closure and to identify the physiopathologic mechanisms leading to this change. BACKGROUND: Conflicting reports exist on cardiopulmonary functional improvement in asymptomatic adults after transcatheter closure of a secundum ASD. METHODS: Thirty-two consecutive adults (13 males; age 42.6 +/- 16.7 years) underwent maximal cardiopulmonary exercise testing and transthoracic echocardiography both on the day before and six months after transcatheter ASD closure. Mean pulmonary artery pressure, pulmonary to systemic flow ratio (Qp/Qs), and ASD diameter were measured before closure. RESULTS: Peak oxygen uptake (Vo(2)) (p < 0.001), peak oxygen pulse (p = 0.0027), and vital capacity (p = 0.0086) improved after ASD closure, although peak heart rate did not. A significant correlation was found between peak Vo(2) improvements and Qp/Qs (p = 0.0013). Left ventricular ejection fraction (LVEF) (p < 0.0001) and left ventricular end-diastolic diameter (LVEDD) (p < 0.0001) significantly increased after six months, although left ventricular end-systolic diameter did not. Right ventricular long- and short-axis dimensions decreased (both p < 0.0001). Peak Vo(2) and of peak oxygen pulse improvements correlated to both LVEF (p = 0.0009 and 0.0019, respectively) and LVEDD (p < 0.0001 and 0.032, respectively) increments. The decrease of both long- and short-axis right ventricular dimensions positively correlated to both LVEF and LVEDD improvements. The improvement in LVEF correlated to Qp/Qs (p = 0.0026). CONCLUSIONS: Transcatheter ASD closure leads to a significant improvement in cardiopulmonary function within six months, via an increase in peak oxygen pulse. An increase in both left ventricular stroke volume and cardiac output due to a positive ventricular interaction is the mechanism leading to improved peak Vo(2).

Recovery kinetics of oxygen uptake is prolonged in adults with an atrial septal defect and improves after transcatheter closure.

BACKGROUND: In adults with an atrial septal defect (ASD) transcatheter closure leads to an improvement of peak oxygen uptake (VO2), but the kinetics of recovery of VO2 after maximal exercise in this patient population and the impact of transcatheter ASD closure have never been investigated. METHODS: Twenty consecutive patients underwent a maximal cardiopulmonary exercise test both the day before and 6 months after transcatheter ASD closure. For comparison, an age- and sex-matched group consisting of 53 healthy adults was built. The constant decay of VO2, CO2 production (VCO2), minute ventilation (VE), and heart rate (HR), expressed as the first-degree slope of a single linear relation, were calculated for the first minute of recovery. RESULTS: Patients with an ASD had a prolonged VO2 slope (P =.0012), VCO2 slope (P =.0003), and VE slope (0.013) when compared with control subjects. Six months after transcatheter ASD closure, significant improvements of VO2 slope (P =.0043) and of VCO2 slope (P =.0022) were recorded, so that no difference was found when compared with those of the control group (P =.1 and P =.06, respectively). The VE slope and HR slope did not change after closure. A significant association between VO2 slope and peak VO2 in the group of patients with ASD was shown by the Spearman correlation, both before (r = 0.67, P =.0012) and after ASD closure (r = 0.71, P =.0004). CONCLUSIONS: A limited cardiopulmonary reserve in adults with no symptom who have an ASD appears to affect not only maximal exercise responses but also the recovery phase. Transcatheter ASD closure induces a significant improvement of the ability of recovering from maximal exercise and eliminates the difference with a healthy population.

Serial versus isolated assessment of clinical and instrumental parameters in heart failure: prognostic and therapeutic implications.

BACKGROUND: In heart failure (HF), it is not known whether analysis of serial changes in prognostic parameters provides incremental information with respect to comprehensive isolated clinical and instrumental assessments. METHODS: We analyzed time-related changes in a period > or =6 months in a broad panel of clinical and instrumental (electrocardiographic, echocardiographic, hemodynamic, and cardiopulmonary) parameters in 105 patients with HF (age, 53 +/- 10 years; 88% men; 55% New York Heart Association classification III-IV; EF, 24% +/- 6%). RESULTS: Among the time-related parameters, QRS widening (adjusted RR per 10 ms, 1.21; 95% CI, 1.10-1.48; P =.003) and peak oxygen uptake (pVO2) decrease (adjusted RR per mL/Kg/min, 1.11; 95% CI, 1.01-1.22; P =.034) provided independent, incremental information for predicting cardiac death/need for heart transplantation (CD/HT) with respect to the entire panel of isolated readings. The overall rate of CD/HT-free survival after 12 months was 60% +/- 5%. Patients who were clinically stable with QRS widening and pVO2 decrease values of <10% had a better CD/HT event-free survival rate at 1 year (92% +/- 5% vs 50% +/- 6%; P <.001). CONCLUSIONS: This study indicates that analysis of time-related changes in prognostic parameters provides relevant incremental prognostic information and may help in the risk stratification of patients with HF and the selection of candidates for HT. In particular, patients who were clinically stable and had QRS widening and a pVO2 decreases <10% in a period > or =6 months appear to be characterized by a good prognosis and may not be suitable candidates for HT.

Idiopathic thrombocytopenic purpura and coronary artery disease: comparison between coronary artery bypass grafting and percutaneous coronary intervention.

Idiopathic thrombocytopenic purpura (ITP) is an autoimmune disorder characterized by a low platelet count and an increased risk of bleeding. At the same time, ITP patients present an increased risk of thrombosis and atherosclerosis related to the high presence of haemostatic factors and chronic steroid therapy. Although relatively rare, the association of ITP and coronary artery disease represents a complex therapeutic challenge. In particular, no recommendations exist regarding the best management approach. We reviewed the literature making a comparison between coronary artery bypass grafting and percutaneous coronary intervention.

Accuracy of oxygen uptake efficiency slope in adults with congenital heart disease.

BACKGROUND: Given its linearity throughout exercise, oxygen uptake efficiency slope (OUES) obtained with a sub-maximal exercise is considered a reliable predictor of exercise capacity. We sought to assess the linearity of OUES across different exercise stages in adults with various forms of congenital heart disease. METHODS: Using cardiopulmonary exercise testing, we studied 23 patients after a Fontan operation, and 30 patients after atrial repair for complete transposition of the great arteries, at a mean age of 24+/-10 years. Thirty-five healthy volunteers were used as controls. OUES was calculated from 100% (OUES), the first 50% (OUES(50)), and the last 50% (OUES(50-100)) of the entire exercise duration. RESULTS: Peak oxygen uptake and OUES were reduced in Fontan patients when compared to atrial repair or control subjects (p<0.05). However, whereas in atrial repair and in control subjects OUES(50), OUES(50-100), and OUES appeared to be similar (p>0.05), in Fontan patients OUES(50) appeared to be lower than OUES(50-100) (1.38+/-0.46 vs. 1.78+/-0.51, p=0.01) and OUES (1.38+/-0.46 vs. 1.72+/-0.56, p=0.032). The difference between OUES(50) and OUES(50-100) appeared particularly large in cyanotic Fontan patients (1.40+/-0.42 vs. 1.93+/-0.68, p=0.001), whereas no difference was observed in Fontan patients with normal saturation (1.33+/-0.59 vs. 1.37+/-0.67, p=0.922). CONCLUSIONS: In cyanotic Fontan patients, OUES(50) differs substantially from OUES(50-100) and OUES. Therefore, OUES(50) is unable to predict maximal exercise capacity in this population.

Long-term impact of transcatheter atrial septal defect closure in adults on cardiac function and exercise capacity.

BACKGROUND: The long-term impact of transcatheter atrial septal defect (ASD) closure on right ventricular (RV) remodeling and exercise capacity is unknown. METHODS: We studied with cardiopulmonary exercise testing and transthoracic echocardiography 29 adults (age 42.3+/-16.4 years) with hemodynamically significant ASD just before transcatheter defect closure and after 6 and >36 months from closure. RESULTS: Compared to 6 months after closure, a further improvement of peak oxygen uptake (p<0.001) and of the slope of ventilation/carbon dioxide production (p<0.001) was observed 3 years after the procedure, so that peak oxygen uptake appeared to be within the normal range in 23/29 patients (79%). Right ventricular short-axis (p<0.05) and long-axis (p<0.05) diameters further decreased beyond the 6-month period. The long-term improvement in exercise capacity correlated with pulmonary-to-systemic flow ratio (R=0.55, p=0.003) and with percentage decrease in RV short-axis diameter (R=0.59, p=0.002), but it did not correlate with age at closure (R=0.25, p=0.46). All patients who did not achieve a normal exercise capacity after 3 years from closure had a severely depressed pre-closure peak oxygen uptake (<50% of predicted). CONCLUSIONS: Adults who undergo transcatheter ASD closure may experience a further improvement in exercise capacity in the long term. The long-term improvement in exercise capacity is associated to an improvement in cardiac form and function and is not influenced by age at closure. Even if the majority of patients may reach a normal exercise capacity after ASD closure, an abnormal exercise capacity may persist in those patients that had a peak oxygen uptake below 50% of predicted value before the procedure.

Long-term follow-up of patients with doxorubicin-induced cardiac toxicity after chemotherapy for osteosarcoma.

The overall survival of patients with osteosarcoma of the extremity with localized disease has greatly improved in recent decades and today about half of them are long-term survivors (i.e. more than 10 years). Owing to the increased number of long-term survivors, late side effects of combined chemotherapy are more evident and have been better studied. Doxorubicin-induced cardiac toxicity is still an important and ominous side effect even if the percentage of affected patients is low. In this study, we report the incidence of clinically symptomatic cardiac toxicity induced by doxorubicin, in our series of 755 patients with localized osteosarcoma of the extremity, who had been treated from 1983 to 2000 with different protocols at our institution. Thirteen (1.7%) patients developed a clinically symptomatic cardiac toxicity (New York Heart Association class II-IV). Six of them died. Of the seven still alive, three needed a heart transplant. The case report of these 13 patients is described in detail. A higher incidence of cardiac toxicity was noted in women patients (eight women=2.5% and five men=1.1%). Cumulative dose and dose intensity (cumulative dose/week of treatment) are the most important risk factors in developing doxorubicin-related cardiomyopathy.

Conversion of atriopulmonary Fontan to extracardiac total cavopulmonary connection improves cardiopulmonary function.

BACKGROUND: Experimental studies showed that extracardiac total cavopulmonary connection provides superior hemodynamics than atriopulmonary Fontan. METHODS: We prospectively assessed the impact of conversion of atriopulmonary Fontan to extracardiac total cavopulmonary connection on exercise capacity and cardiac function in 6 consecutive patients. RESULTS: Six months after conversion to extracardiac total cavopulmonary connection, we observed an increase in peak oxygen uptake in all patients (p=0.01;+17%). This improvement was associated to an increase of peak O(2) pulse (p=0.01;+16%), but no change in peak heart rate, arterial oxygen saturation at peak exercise, and pulmonary function. Ventricular ejection fraction did not change significantly after surgery. Conversion was associated with an improvement in heart failure symptoms as assessed by the New York Heart Association classification. Patients who had undergone additional anti-arrhythmia surgery for atrial fibrillation had no recurrence of arrhythmia at follow-up. CONCLUSION: Data indicate that conversion to extracardiac total cavopulmonary connection is associated with an improvement of cardiopulmonary function and heart failure symptoms. Improved exercise capacity is due to an increase in O(2) pulse and may reflect an improved cardiac stroke volume after the operation.

Static and dynamic predictors of adverse events in patients with intermediate cardiopulmonary capacity referred for heart transplantation.

BACKGROUND: Chronic heart failure (CHF) patients with intermediate cardiopulmonary capacity referred for heart transplantation are at "medium risk," and are not amenable to further stratification based solely on peak VO(2.) Accordingly, we analyzed whether time-related and/or non-time-related parameters could provide incremental prognostic information in CHF patients with intermediate cardiopulmonary capacity. METHODS: We analyzed 134 patients with a peak VO(2) of 10 to 18 ml/kg/min (age 54 +/- 9 years, 66% males) and a left ventricular ejection fraction (LVEF) of 27% +/- 8% who underwent an extensive clinical/instrumental (electrocardiogram, echocardiogram, cardiopulmonary exercise test) index evaluation; for all patients, an equivalent pre-study evaluation (performed >or=6 months before) was also available. RESULTS: Among index-evaluation parameters, systolic blood pressure (p < 0.001), LVEF (p = 0.036), and presence of severe mitral regurgitation (p = 0.006) independently predicted cardiac death/need for heart transplantation. Stable clinical condition from pre-study to index-evaluation accompanied by <10% QRS widening and <10% decrease in peak VO(2) provided incremental prognostic information with respect to all index-evaluation parameters (p = 0.014). CONCLUSIONS: CHF patients with intermediate peak VO(2) who display "stable" CHF present a lower incidence of adverse cardiac events, particularly in the absence of hypotension, severe mitral regurgitation, and severe reduction of LVEF. Such a stratification might be clinically useful for deciding between medical treatment alone and consideration for heart transplantation.