Salvatore Specchia

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.

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.

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.

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

Patients with repaired tetralogy of Fallot (ToF) featuring severe pulmonary regurgitation (PR) and/or right ventricular (RV) dysfunction have reduced exercise tolerance.

Evaluation by cardiopulmonary exercise test of DDDR versus DDD pacing.

In eight patients (age 62 ± 6 years) a DDDR pacemaker was implanted for sick sinus syndrome (three cases) or second‐ and third‐degree AV block (five cases). In five subjects chronotropic incompetence (maximal heart rate on effort < 110 beats/min) was present before implantation. One month after implantation the patients were randomized to DDDR or DDD pacing for 3 weeks each, with subsequent crossover, and at the end of each period a symptom limited Cardiopulmonary exercise test (25 watts/2 min) was performed and the patients were requested to fill a symptoms questionnaire. Results: DDDR pacing, compared to DDD, was associated with higher maximal heart rates (127 ± 20 vs 110 ± 27 beats/min, P < 0.02), higher (VO2 max (25.4 ± 6.1 vs 21.5 ± 7.8 mL/kg/per min, P < 0.03) and higher VO2 at the anaerobic threshold (20.3 ± 5.0 vs 15.8 ± 4.9 mL/kg per min, P < 0.03), without significant differences in mean exercise time (526 ± 193 vs 472 ± 216 sec, NS). The increase in VO2 max obtained in DDDR versus DDD was significantly related to the increase in maximal heart rate (r = 0.72, P < 0.05) and the increase in VO2 at the anaerobic threshold obtained in DDDR versus DDD was related to the increase in heart rate at the anaerobic threshold (r = 0.81, P < 0.02). In patients with chronotropic incompetence the improvement obtained in DDDR versus DDD was even more significant (VO2 max = 22.7 ± 5.9 vs 16.1 ± 4.4 mL/kg per min, P < 0.03; VO2 at the anaerobic threshold = 18.4 ± 5.1 vs 13.2 ± 2.8 mL/kg per min, P < 0.05; exercise time = 438 ± 132 vs 352 ± 150 sec, P < 0.02). In the population as a whole, no significant differences were found relative to subjective symptoms, meanwhile in patients with chronotropic incompetence a better subjective tolerance was apparent with DDDR than with DDD pacing. In conclusion, DDDR pacing induces a significant improvement of exercice capacity, in comparison to DDD pacing, related to the ability to reach higher heart rates during exercise. This phenomenon is particulary evident in patients with chronotropic incompetence in whom DDDR pacing also is subjectively better tolerated.

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.

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.

Genetic heterogeneity of hypertrophic cardiomyopathy

We studied the pattern of inheritance of hypertrophic cardiomyopathy among 111 first-degree relatives of 30 patients with the disease. Results of segregation analysis suggest a genetic heterogeneity for hypertrophic cardiomyopathy in that both autosomal dominant and autosomal recessive mode of inheritance can occur.

Echocardiographic evaluation of the response to afterload stress test in young asymptomatic patients with chronic severe aortic regurgitation: sensitivity of the left ventricular end-systolic pressure-volume relationship.

The detection of myocardial depression is an important goal in the management of patients with chronic severe aortic regurgitation but may be quite difficult at an early stage by the conventional basal measures of contractility. The response to afterload stress determined by angiotensin challenge and the end-systolic pressure-volume relationship was evaluated echocardiographically in 16 asymptomatic or mildly symptomatic patients with chronic severe aortic regurgitation, ages 15 to 56 years (mean 32 +/- 12). Nine normal subjects, ages 25 to 41 years (mean 31 +/- 5), served as a control group. In the group with aortic regurgitation, end-systolic dimensions were greater than 55 mm in five of 16 patients and fractional shortening was 25% or less in two of 16. In the control group angiotensin caused a decrease of stroke volume index in six out of nine patients (15% at the most) and a mild increase in three. In the group with aortic regurgitation stroke volume index decreased by 15% or more of the basal value in nine of 16 patients and increased or decreased by less than 15% in seven of 16. Ejection fraction decreased in both groups, from 61 +/- 6% to 52 +/- 7% in the control group and from 56 +/- 6% to 45 +/- 5% in the group with aortic regurgitation. Ventricular function curves were derived by relating end-diastolic volume index to stroke work index; seven of 16 patients had abnormal responses reflecting an afterload mismatch.(ABSTRACT TRUNCATED AT 250 WORDS)

Hemodynamic effects of felodipine in congestive heart failure

SummaryThe hemodynamic effects of increasing dosages of felodipine, a new calcium antagonist with selective vasodilator properties, were studied in 13 patients with chronic cardiac failure. A Swan-Ganz thermodilution catheter was positioned in the pulmonary artery and hemodynamic parameters were monitored from 9 am to 6 pm for five days. On the first and the fifth day patients received placebo (P) and on the second, third, and fourth day patients received felodipine 5, 10, and 20 mg, respectively. Symptom-limited exercise tests with a bicycle ergometer were performed on both days of P and on the fourth day. A marked reduction of systemic vascular resistance (SVR) and a significant increase of cardiac index without increments of heart rate (HR) were observed after felodipine at rest. A dose response effect could be demonstrated. During exercise a significant increment of cardiac index and decrease of pulmonary wedge pressure was observed after felodipine. Felodipine showed a potent vasodilator action on systemic circulation with significant changes on both stroke volume and filling pressures at rest and during exercise without side effects.