Adrenergic nervous activity in patients after surgical correction of tetralogy of Fallot.

OBJECTIVES: The study was done to define the role of the autonomic nervous system in postoperative tetralogy of Fallot. BACKGROUND: Subsequent to surgical correction of tetralogy of Fallot, patients are at long-term risk of sudden death owing to ventricular electrical instability. The status of the sympathetic nervous system in these patients, known to play an important role in other patients at risk, remains unknown. METHODS: We used (123)I metaiodobenzylguanidine (MIBG) with tomographic imaging, combined with assessment of heart rate variability (HRV), to evaluate the activity of the sympathetic nervous system. We analyzed 22 patients who had undergone total correction of tetralogy of Fallot: 13 with either no or minor ventricular arrhythmias, and 9 with sustained ventricular tachycardia or ventricular fibrillation. RESULTS: Analysis of HRV revealed a reduction in vagal control and sympathetic dominance in all patients compared with a healthy control group of 20 subjects. A significant difference was found in the standard deviation of all the adjacent intervals between normal beats (SDNN) in patients with or without severe ventricular arrhythmias. A significant reduction in uptake of (123)I MIBG was demonstrated 30 min after IV injection, and a trend toward reduction after 5 h, associated with reduced washout indices. These data reflect a decrease in the number of nerve endings in the right and left ventricular walls, and an inhomogeneous distribution of the adrenergic nervous system. The uptake of MIBG was significantly reduced in the patients at risk of ventricular tachycardia or fibrillation. CONCLUSIONS: Subsequent to surgical correction of tetralogy of Fallot, the positive correlation between myocardial uptake of MIBG, SDNN and the QRS dispersion confirmed the usefulness of analysis of the adrenergic nervous system to stratify patients at risk of life-threatening arrhythmias.

Sulfinpyrazone reduces cyclosporine levels: a new drug interaction in heart transplant recipients.

BACKGROUND: Management of cyclosporine (CsA)-associated hyperuricemia in heart transplantation (HT) is difficult. Because of the myelotoxicity of combined allopurinol and azathioprine, we tested sulfinpyrazone. METHODS: We studied 120 HT recipients (109 men; mean age at HT, 52+/-10 years). All had received allopurinol for at least 6 months, which was stopped for 1 month before initiation of sulfinpyrazone. Mean follow-up from HT to onset of sulfinpyrazone (200 mg/day) was 59+/-41 months. We stopped the drug after 6+/-2 months. We compared CsA level and daily dose, serum creatinine, blood urea, and uric acid at onset and before interruption of sulfinpyrazone and, as control, in the last 6 months of allopurinol. RESULTS: Mean uricemia decreased with allopurinol (0.58+/-0.12 vs. 0.41+/-0.07 mmol/liter, p = 0.0001) as well as with sulfinpyrazone (0.51+/-0.13 vs. 0.40+/-0.12 mmol/liter, p = 0.0001). Mean creatinine increased (171+/-42 and 164+/-35 micromol/liter, p = 0.01) with allopurinol, whereas it tended to decrease with sulfinpyrazone (160+/-35 and 154+/-48 micromol/liter, p = NS). Mean urea did not change with allopurinol (14+/-5 vs. 15+/-7 mmol/liter, p = NS), but fell with sulfinpyrazone (14.01+/-5 vs. 12.60 +/-5 mmol/liter, p = 0.0004). Mean CsA levels were constant with allopurinol (193+/-73 vs. 188+/-65 ng/ml, p = NS), although CsA dose was slightly reduced (2.7+/-0.8 vs. 2.6+/-0.8 mg/kg/day, p = 0.007). Conversely, CsA levels dropped with sulfinpyrazone (183+/-89 vs. 121 +/-63 ng/ml, p = 0.0001) despite an increase in CsA daily dose (2.6 +/-0.9 vs. 2.8+/-0.9 mg/kg/day, p = 0.0001). Two subjects were treated for acute rejection. We observed no other side effects. In HT recipients sulfinpyrazone, as an alternative to allopurinol, is effective in achieving metabolic control of hyperuricemia. However, this drug reduced CsA levels, thus the risk of rejection is present.

Skin cancer in heart transplant recipients: risk factor analysis and relevance of immunosuppressive therapy.

BACKGROUND: The frequency of skin tumors of all types and specifically of squamous cell carcinoma (SCC) is increased in heart transplantation (HT), but the predisposing risk factors are controversial. METHODS AND RESULTS: We studied 300 patients (age 49+/-15 years, 258 men, mean follow-up 4.6 years, follow-up range 1 month to 12 years) who were receiving standard double (cyclosporin plus azathioprine) or triple (cyclosporin plus azathioprine plus prednisone) therapy. The first-year rejection score was calculated for endomyocardial biopsy samples (International Society for Heart and Lung Transplantation grade 0=0, 1A=1, 1B=2, 2=3, 3A=4, 3B=5, and 4=6) and used as an indirect marker of the level of immunosuppression. Multivariate analysis (Cox regression) included age at HT, sex, skin type, first-year rejection score, presence of warts and solar keratosis, lifetime sunlight exposure, and first-year cumulative dose of steroids. The incidence of skin tumors of all types increased from 15% after 5 years to 35% after 10 years after HT according to life-table analysis. Age at HT of >50 years (P:=0.03, RR=5.3), skin type II (P:=0.05, RR=2.6), rejection score of 19 (P:=0.003, RR=5.7), solar keratosis (P:=0.001, RR=6.9), and lifetime sunlight exposure of >30 000 hours (P:=0.0003, RR=7.6) were risk factors for SCC. CONCLUSIONS: Older age at HT, light skin type, solar keratosis, greater sunlight exposure, and high rejection score in the first year were independently associated with an increased risk of SCC. The progressive increase in cancer frequency during follow-up and the association with high rejection scores suggest that both the length and level of immunosuppression may be relevant. Because cumulative immunosuppressive load is cumbersome to calculate, a high rejection score in the first year may provide a useful predictor for patients at risk.

Positron emission tomography is a useful tool in differentiating idiopathic from ischemic dilated cardiomyopathy.

We evaluated the utility of positron emission tomography in differentiating patients with idiopathic dilated cardiomyopathy from those with ischemic cardiomyopathy. Twenty consecutive non-diabetic patients with dilatation (end-diastolic volume > or = 120 cc/m2) and reduced systolic function (ejection fraction < or = 40%) of the left ventricle on cineangiography, underwent coronary angiography, F18 fluorodeoxyglucose (F18-FDG) (glucose load technique) and N13-ammonia (N13-NH3) positron emission tomography. A semiquantitative score based on the extension and the severity of the uptake defects was calculated. Endomyocardial biopsy was performed in patients with normal coronary arteries. Ten patients (group A) had normal coronary arteries and histologic features of the endomyocardium fitting with the diagnosis of idiopathic dilated cardiomyopathy. Cineangiography showed critical stenosis of at least one major coronary artery in the other 10 patients (group B). The two groups were similar in age. left ventricular end-diastolic volume and ejection fraction. Both N13-NH3, positron emission tomography and F18-FDG positron emission tomography scores were lower in group A than in group B: 0.1 +/- 0.3 vs. 10.6 +/- 5.1 (P<0.0001) and 2.4 +/- 4.4 vs. 9.9 +/- 4.1 (P<0.0001) respectively. but only N13-NH3 positron emission tomography allowed a complete separation of the two groups (score range 0-1 group A vs. 4-12 group B). The F18-FDG score value showed some overlapping between the two groups (score range 0-12 in the group A vs. 2-17 in the group B). All three idiopathic dilated cardiomyopathy patients with a F18-FDG score value >2 had left bundle branch block on standard ECG. Positron emission tomography imaging with N13-NH3 and F18-FDG provided a complete differentiation between idiopathic dilated cardiomyopathy and ischemic cardiomyopathy patients. However patients with left bundle branch block on ECG could present defects in FDG uptake even if affected by idiopathic dilated cardiomyopathy.

Analytical expression of effective afterload in aortic and mitral regurgitation.

Effective arterial elastance (Ea) is the coupling parameter between the left ventricle and peripheral circulation in normal subjects. If left ventricular end systolic pressure (Pes), contractility (Es) and Ea are known, left ventricular end diastolic volume (LVEDV) and ejection fraction of the ventricle are completely determined. The aim of this study was to give an analytical expression for Ea in patients with mitral and aortic regurgitation, and predict both LVEDV and the effect of vasodilator therapy on LVEDV. Twenty-three subjects with atypical chest pain, 15 patients with mitral insufficiency and 11 with aortic insufficiency underwent diagnostic cardiac catheterization, coronary angiography, and left ventricular cineangiography, which was analyzed quantitatively. Ea was 2.05 +/- 0.63 in normal subjects, while it was 1.28 +/- 0.71 and 1.57 +/- 0.87 in patients with mitral and aortic insufficiency, respectively. All these groups differed with ANOVA test (p = 0.0031). We tested the ability of the analytical expressions for Ea in normal subjects, and patients with mitral insufficiency or aortic insufficiency to predict measured Ea and LVEDV. Ea and LVEDV were predicted rather accurately in every case (p < 0.0001). We used published data to test the effect of resistance modulation on LVEDV. Predicted and measured LVEDV were linearly correlated both in aortic (p < 0.0001) and mitral insufficiency (p = 0.027). Moreover, in some cases a left ventricular enlargement after vasodilator therapy could be anticipated because of an unbalanced decrease in resistance and heart rate. Ea seems to be the coupling parameter between the left ventricle and the peripheral circulation not only in normal subjects, but also in patients with mitral or aortic regurgitation; its measurement before administering vasodilating drugs may be useful in order to predict the effects on LVEDV, and achieve an optimal ventriculoarterial coupling.

Transaortic gradient is pressure-dependent in a pulsatile model of the circulation.

BACKGROUND AND AIM OF THE STUDY: Although the transvalvular gradient is described as flow-dependent, pressure-dependence of the gradient, irrespective of flow, has not been demonstrated. METHODS: The Sheffield pulse duplicator equipped with a X-Cell 21 porcine valve mounted in the aortic position was used. Transaortic gradient was measured at a constant rate of 80 beats/min, while flow was kept at 2, 5 or 8 l/min, and systemic pressure was increased up to 200 mmHg by adjusting peripheral resistance manually. Valve area was computed with the Gorlin formula. A total of 87 measurements was carried out. RESULTS: For each flow, transvalvular gradient increased linearly with pressure, and computed area decreased. The slope of the pressure-gradient relationship was independent of flow. CONCLUSION: Transaortic gradient depends not only on flow, but also shows pressure-dependency that should be taken into account when evaluating aortic stenosis, especially in hypertensive and hypotensive states.

Accuracy of electrocardiographic and echocardiographic indices in predicting life threatening ventricular arrhythmias in patients operated for tetralogy of Fallot.

OBJECTIVE: To validate the accuracy of the prognostic significance of non-invasive clinical diagnostic indices as predictors of sustained ventricular tachycardia (sVT) or fibrillation (VF) in patients undergoing repair for tetralogy of Fallot. METHODS: One way analysis of variance and pairwise comparison of the values with the Bonferroni correction, logistic multivariate analysis, and ordinal logistic analysis were used to study quantitative electrocardiographic and echocardiographic variables in 66 patients who had undergone surgery for tetralogy of Fallot by ventriculotomy at a mean (SD) age of 11.8 (9.5) years. The mean (SD) period of follow up was 16.1 (5.7) years after surgery. RESULTS: Four groups of patients were identified by ECG and 24 hour Holter monitoring: 19 (28.7%) without ventricular arrhythmias, 34 (51.5%) with minor ventricular arrhythmias, seven (10.6%) with non-sustained ventricular tachycardia (nsVT), and six (9.0%) with sVT or VF. One way analysis indicated significant differences in QT dispersion (QTd) and end diastolic volume of the right ventricle (EDVRV) among the groups. Univariate logistic analysis showed EDVRV, QTd, and QRS duration to be significantly associated with sVT or VF. Stepwise multivariate analysis and ordinal logistic analysis showed QTd to be preferable to QRS duration as an indicator, because it was unrelated to EDVRV, and was capable of separating different probability curves for nsVT as opposed to sVT or VF. CONCLUSIONS: Stratification of patients undergoing corrective surgery for tetralogy of Fallot and at risk of life threatening arrhythmias is possible by simple and inexpensive means, which provide sensitive and specific indices.

Computed tomography halo sign in pulmonary nodules: frequency and diagnostic value.

On computed tomography (CT) scanning, a ground-glass opacity zone surrounding a pulmonary nodule has been named the computed tomography (CT) halo sign. To investigate the frequency and diagnostic value of the CT halo sign, the authors reviewed the CT examinations of 305 patients with proven diseases producing solitary or multiple nodules. The CT halo sign was seen in 22 patients (7%). Eleven patients had a solitary nodule; five patients had multiple nodules; and six patients had nodules associated with areas of pulmonary consolidation, or ground-glass opacity, or both. Solitary nodules were the result of bronchioloalveolar carcinoma (n = 5), tuberculoma (n = 2), squamous cell carcinoma, non-Hodgkin lymphoma, myxovirus infection, and metastasis (n = 1 each). Multiple nodules were the result of metastasis (n = 2), Kaposi sarcoma (n = 2), and Wegener granulomatosis (n = 1). Nodules associated with areas of consolidation or ground-glass opacity were the result of metastasis (n = 2), bronchioloalveolar carcinoma, bronchiolitis obliterans organizing pneumonia, eosinophilic pneumonia, and invasive pulmonary aspergillosis (n = 1 each). The data showed that the CT halo sign is a nonspecific finding. It is known that in immunocompromised patients the CT halo sign should suggest invasive pulmonary aspergillosis, Kaposi sarcoma, and lymphoproliferative pulmonary disorders. However, in immunocompetent patients, the authors found that a solitary nodule with the CT halo sign and pseudocavitations has a high likelihood of being a bronchioloalveolar carcinoma.

Heart involvement in muscular dystrophies due to sarcoglycan gene mutations.

Mutations in the sarcoglycan genes cause autosomal-recessive muscular dystrophies. Because sarcoglycan genes and their protein products are highly expressed both in skeletal and cardiac muscle, patients with these mutations might be expected to be at risk to develop dilated cardiomyopathy. We therefore studied 13 patients with alpha-, beta-, gamma-sarcoglycan gene mutations by thorough cardiological assessment. Electrocardiographic or echocardiographic abnormalities were observed in about 30% of cases showing a severe course of muscular dystrophy. No correlation was found between the presence of cardiac abnormalities and the type of mutation or sarcoglycan gene involved. The cardiac involvement was never severe, but it may be detected in early stages of the muscle disease. The absence of overt cardiac dysfunction may be due to lower sarcoglycan protein expression in cardiac than skeletal muscle or to less sarcolemmal instability at the myocardial level, possibly related to the different distribution of forces generated by contraction of the myocardium with respect to proximal limb-girdle muscles.

Effectiveness of fixed minidose warfarin in the prevention of thromboembolism and vascular death in nonrheumatic atrial fibrillation.

Adjusted-dose warfarin is effective for stroke prevention in patients with nonrheumatic atrial fibrillation (AF), but the risk of bleeding is high, especially among the elderly. Fixed minidose warfarin is effective in preventing venous thromboembolism with low risk of bleeding and no need for frequent clinical monitoring. Patients > 60 years with nonrheumatic AF were randomized in an open-labeled trial to receive fixed minidose warfarin (1.25 mg/day) or standard adjusted-dose warfarin (International Normalized Ratio [INR] between 2.0 and 3.0). Primary outcome events were ischemic stroke, peripheral or visceral embolism, cerebral or fatal bleeding, and vascular death. Secondary end points were major bleeding, myocardial infarction, and death. This study was discontinued before completion in light of publication of the Stroke Prevention in Atrial Fibrillation III trial, which indicated that low-intensity fixed-dose warfarin treatment (i.e., INR < 1.5) was insufficient for stroke prevention in high-risk patients with nonrheumatic AF. From a total of 1,209 considered patients, 303 were randomized to be studied (150 in the minidose group and 153 in the adjusted-dose group). Mean follow-up was 14.5 months. The rate of cumulative primary events was 11.1% (95% confidence intervals [CI] 4.0 to 18.2) in the fixed minidose group and 6.1% (95% CI 1.1 to 11.1) in the adjusted-dose group (p = 0.29). The rate of ischemic stroke was significantly higher in the minidose group (3.7% vs 0% per year, p = 0.025). Major bleedings were more frequent in standard treatment group (2.6% vs 1% per year, p = 0.19). Most thromboembolic complications occurred at INRs < 1.2, whereas the majority of hemorrhages occurred at INRs > 3.0. No significant difference in primary outcome events was observed in the abbreviated study. However, the significantly increased occurrence of ischemic stroke in the fixed minidose warfarin group suggests that this regimen does not protect patients with nonrheumatic AF.

Postextrasystolic potentiation echocardiography in predicting reversible myocardial dysfunction by surgical coronary revascularization.

Sustained inotropic stimulation, such as dobutamine infusion, has the potential to cause an additional contractile deterioration in viable but chronically hypoperfused and dysfunctioning myocardium, by inducing ischemia. Postextrasystolic potentiation (PESP) represents a potent inotropic stimulus without risk of provoking ischemia, as it is instantaneous. In this study, we assessed the role of PESP-echocardiographic examination in predicting the recovery of regional contractility after coronary revascularization. We examined 105 consecutive patients with multivessel coronary artery disease who were candidates for bypass surgery; 79 were included in this prospective study. Preoperative reversibility of contractile dysfunction in asynergic myocardial regions was determined by PESP, with a coupling interval of 500 msec decreasing to 300 msec, with a progressive decrease by 10 msec. The examination was accompanied by continuous 2-dimensional (2D) echocardiographic monitoring. The assessed sensitivity and specificity were 92% and 87%, respectively; the predictive accuracy was 90%. These results demonstrated that PESP echocardiography is a useful and cost-effective method for identifying viable myocardium in patients undergoing myocardial revascularization.

Ground-glass attenuation in nodular bronchioloalveolar carcinoma: CT patterns and prognostic value.

PURPOSE: The purpose of our study was to assess the CT patterns and prognostic value of ground-glass attenuation in nodular bronchioloalveolar carcinoma (BAC). METHOD: We retrospectively reviewed CT examinations of 22 patients with 24 nodular BACs who underwent surgery. CT and pathologic findings were analyzed and correlated with postoperative course of disease. RESULTS: We detected five patterns of ground-glass attenuation associated with nodular BAC: pure ground-glass nodule (n = 1), ground-glass nodule with superimposed lymphangitis (n = 1), nodule with mixed areas of ground-glass attenuation and consolidation (n = 2), ground-glass halo around nodule (halo sign) (n = 3), and nodule associated with a plurisegmental area of ground-glass attenuation (n = 1). Two patients with the halo sign and a third patient with a plurisegmental area of ground-glass attenuation rapidly developed diffuse pulmonary disease by bronchogenic spread and died a few months after surgery. CONCLUSION: Our series demonstrates that focal BAC may progress to diffuse pulmonary involvement by bronchogenic spread. The presence of a large area of ground-glass attenuation associated with a nodular BAC might be the CT sign of an aggressive biologic behavior. In these cases there is a high likelihood for diffuse disease to develop from bronchogenic spread.

Myocardial dysfunction and adrenergic cardiac innervation in patients with insulin-dependent diabetes mellitus.

BACKGROUND: Insulin-dependent diabetes mellitus (IDDM) is associated with an increased incidence of heart failure due to several factors, and in some cases a specific cardiomyopathy has been suggested. OBJECTIVES: This study sought to assess the mechanisms of exercise-induced left ventricular (LV) dysfunction in asymptomatic patients with IDDM in the absence of hypertensive or coronary artery disease. METHODS: Fourteen consecutive patients with IDDM were enrolled (10 men, 4 women; mean [+/- SD] age 28.5 +/- 6 years); 10 healthy subjects matched for gender (7 men, 3 women) and age (28.5 +/- 3 years) constituted the control group. LV volume, LV ejection fraction (LVEF) and end-systolic wall stress were calculated by two-dimensional echocardiography at rest and during isometric exercise. LV contractile reserve was assessed by post-extrasystolic potentiation (PESP) obtained by transesophageal cardiac electrical stimulation and dobutamine infusion. Myocardial iodine-123 metaiodobenzylguanidine (MIBG) scintigraphy was performed to assess adrenergic cardiac innervation. RESULTS: Diabetic patients were classified into group A (n = 7), with an abnormal LVEF response to handgrip (42 +/- 7%), and group B (n = 7), with a normal response (72 +/- 8%). Baseline LVEF was normal in both group A and B patients (60 +/- 6% vs. 61 +/- 7%, p = NS). In group A patients, the LV circumferential wall stress-LVEF relation showed an impairment in LVEF disproportionate to the level of LV afterload. No significant changes in LVEF occurred during dobutamine (60 +/- 6% vs. 64 +/- 10%, p = NS), whereas PESP significantly increased LVEF (60 +/- 6% vs. 74 +/- 6%, p < 0.001); PESP at peak handgrip normalized the abnormal LVEF (42 +/- 7% vs. 72 +/- 5%, p < 0.001); and MIBG uptake normalized for body weight or for LV mass was lower than that in normal subjects (1.69 +/- 0.30 vs. 2.98 +/- 0.82 cpm/MBq per g, p = 0.01) and group B diabetic patients (vs. 2.79 +/- 0.94 cpm/MBq per g, p = 0.01). Finally, a strong linear correlation between LVEF at peak handgrip and myocardial MIBG uptake normalized for LV mass was demonstrated in the study patients. CONCLUSIONS: Despite normal contractile reserve, a defective blunted recruitment of myocardial contractility plays an important role in determining exercise LV dysfunction in the early phase of diabetic cardiomyopathy. This abnormal response to exercise is strongly related to an impairment of cardiac sympathetic innervation.

Cardiac transplantation in a Duchenne muscular dystrophy carrier.

We report here for the first time the case of a symptomatic DMD carrier, who had a heart transplant for a severe dilated cardiomyopathy. Dystrophin immunohistochemistry, western blot and analysis of X-chromosome inactivation on leucocytes, and skeletal and cardiac muscle biopsies on the explanted heart were performed. The patient was a heterozygote for exons 50-52 deletion in the dystrophin gene. The number of dystrophin-deficient fibres in the heart was much higher than in skeletal muscle. On the other hand, the explanted heart showed a non-skewed pattern of X-chromosome inactivation, as in leukocytes and skeletal muscle. The adverse cardiac course may be explained by the absence of regeneration among cardiomyocytes.