Cesare Fiorentini

Prognostic Value of Troponin I in Cardiac Risk Stratification of Cancer Patients Undergoing High-Dose Chemotherapy

Background—In patients with aggressive malignancies who are undergoing high-dose chemotherapy, even minimal elevation of troponin I (TnI) is associated with late left ventricular dysfunction. The time course of the subclinical myocardial damage and its impact on the clinical outcome have never been investigated previously. Methods and Results—In 703 cancer patients, we measured TnI soon after chemotherapy (early TnI) and 1 month later (late TnI). Troponin was considered positive for values ≥0.08 ng/mL. Clinical and left ventricular ejection fraction evaluation (echocardiography) were performed before chemotherapy, 1, 3, 6, and 12 months after the end of the treatment, and again every 6 months afterward. Three different TnI patterns were identified, and patients were grouped accordingly. In 495 patients, both early and late TnI values were <0.08 ng/mL (TnI−/− group); in 145, there was only an early increase (TnI+/− group); and in 63 patients, both values increased (TnI+/+ group). In the TnI−/− group, no significant reduction in ejection fraction was observed during the follow-up, and there was a very low incidence of cardiac events (1%). In contrast, a greater incidence of cardiac events occurred in TnI-positive patients, particularly in the TnI+/+ group (84% versus 37% in the TnI+/− group; P <0.001). Conclusions—TnI release pattern after high-dose chemotherapy identifies patients at different risks of cardiac events in the 3 years thereafter. This stratification allows us to differentiate the monitoring program and to plan, in selected patients, preventive strategies aimed at improving clinical outcome.

Anthracycline-Induced Cardiomyopathy: Clinical Relevance and Response to Pharmacologic Therapy

OBJECTIVES The purpose of this study was to evaluate the clinical relevance of anthracycline-induced cardiomyopathy (AC-CMP) and its response to heart failure (HF) therapy. BACKGROUND The natural history of AC-CMP, as well as its response to modern HF therapy, remains poorly defined. Hence, evidence-based recommendations for management of this form of cardiomyopathy are still lacking. METHODS We included in the study 201 consecutive patients with a left ventricular ejection fraction (LVEF) <or=45% due to AC-CMP. Enalapril and, when possible, carvedilol were promptly initiated after detection of LVEF impairment. LVEF was measured at enrollment, every month for the first 3 months, every 3 months during the first 2 following years, and every 6 months afterward (mean follow-up 36 +/- 27 months). Patients were considered responders, partial responders, or nonresponders according to complete, partial, or no recovery in LVEF, respectively. Major adverse cardiac events during follow-up were also evaluated. RESULTS Eighty-five patients (42%) were responders; 26 patients (13%) were partial responders, and 90 patients (45%) were nonresponders. The percentage of responders progressively decreased as the time from the end of chemotherapy to the start of HF treatment increased; no complete recovery of LVEF was observed after 6 months. Responders showed a lower rate of cumulative cardiac events than partial and nonresponders (5%, 31%, and 29%, respectively; p < 0.001). CONCLUSIONS In cancer patients developing AC-CMP, LVEF recovery and cardiac event reduction may be achieved when cardiac dysfunction is detected early and a modern HF treatment is promptly initiated.

Left ventricular dysfunction predicted by early troponin I release after high-dose chemotherapy

OBJECTIVES We investigated the role of cardiac troponin I (cTnI) in patients with aggressive malignancies treated with high-dose chemotherapy (HDC). BACKGROUND High dose chemotherapy is potentially limited by cardiac toxicity. Considering the fact that cardiac dysfunction may become clinically evident weeks or months after HDC, the availability of an early marker of myocardial injury, able to predict late ventricular impairment, is a current need. METHODS We measured, in 204 patients (45+/-10 years) affected by cancer resistant to conventional treatment, the cTnI plasma concentration after every single cycle of HDC. According to the cTnI value (< or = or >0.4 ng/ml), patients were divided into a troponin positive (cTnI+, n = 65) and a troponin negative (cTnI-, n = 139) group. All patients underwent echocardiographic examination during the following seven months. RESULTS In the cTnI- group, left ventricular ejection fraction (LVEF) progressively decreased after HDC, reaching a maximal reduction after three months; however, myocardial depression was transient and no longer detectable at later follow-up. By contrast, in the cTnI+ group LVEF reduction was more marked and still evident at the end of the follow-up. In cTnI+ patients, a close relationship between the short-term cTnI increment and the greatest LVEF reduction was found (r = -0.87, p<0.0001). CONCLUSIONS The elevation of cTnI in patients undergoing HDC for aggressive malignancies accurately predicts the development of future LVEF depression. In this setting, cTnI can be considered a sensitive and reliable marker of acute minor myocardial damage with relevant clinical and prognostic implications.

Treatment of hypertension with nifedipine, a calcium antagonistic agent.

Hemodynamic monitoring after a single dose (10 mg) of nifedipine in 27 primary hypertensive subjects (diastolic pressure ≥ 110 mm Hg) documented that this calcium antagonistic agent exerts a potent arteriolar vasodilating action, which results in prompt (−21% of control at 30 minutes) persistent (−16% of control at 120 minutes) fall in mean arterial pressure associated with a rise in cardiac output pulse rate. The same patients received oral treatment for 3 weeks. Hourly pressure readings showed that 1) the antihypertensive response to each dose lasts 8–12 hours; 2) nifedipine every 6 hours significantly reduced blood pressure throughout the 24 hours, without postural hypotension. Side effects were short-lasting (headache in five patients, palpitation without arrhythmias in eight patients, burning sensation in the face legs in five patients sporadic extrasystoles in five patients) tended disappear with continued treatment. Development of drug resistance, sodium retention, plasma volume expansion, renin release or angina pectoris were not observed during the study. Although these findings seem to differentiate nifedipine from other vasodilators currently used in the treatment of hypertension, broader experience more prolonged trials with nifedipine as an antihypertensive agent will be needed before conclusions can be drawn on these particular aspects.

Early Detection of Anthracycline Cardiotoxicity and Improvement With Heart Failure Therapy

Background— Three types of anthracycline-induced cardiotoxicities are currently recognized: acute, early-onset chronic, and late-onset chronic. However, data supporting this classification are lacking. We prospectively evaluated incidence, time of occurrence, clinical correlates, and response to heart failure therapy of cardiotoxicity. Methods and Results— We assessed left ventricular ejection fraction (LVEF), at baseline, every 3 months during chemotherapy and for the following year, every 6 months over the following 4 years, and yearly afterward in a heterogeneous cohort of 2625 patients receiving anthracycline-containing therapy. In case of cardiotoxicity (LVEF decrease >10 absolute points, and <50%), heart failure therapy was initiated. Recovery from cardiotoxicity was defined as partial (LVEF increase >5 absolute points and >50%) or full (LVEF increase to the baseline value). The median follow-up was 5.2 (quartile 1 to quartile 3, 2.6–8.0) years. The overall incidence of cardiotoxicity was 9% (n=226). The median time elapsed between the end of chemotherapy and cardiotoxicity development was 3.5 (quartile 1 to quartile 3, 3–6) months. In 98% of cases (n=221), cardiotoxicity occurred within the first year. Twenty-five (11%) patients had full recovery, and 160 (71%) patients had partial recovery. At multivariable analysis, end-chemotherapy LVEF (hazard ratio, 1.37; 95% confidence interval, 1.33–1.42 for each percent unit decrement) and cumulative doxorubicin dose (hazard ratio, 1.09; 95% confidence interval, 1.04–1.15 for each 50 mg/m2 increment) were independent correlates of cardiotoxicity. Conclusions— Most cardiotoxicity after anthracycline-containing therapy occurs within the first year and is associated with anthracycline dose and LVEF at the end of treatment. Early detection and prompt therapy of cardiotoxicity appear crucial for substantial recovery of cardiac function.

Nifedipine, a new antihypertensive with rapid action.

Oral (17 cases) or sublingual (9 cases) administration of nifedipine (10 mg), a new coronary dilator, induced a prompt and large pressure reduction in patients with severe primary hypertension. Pressure started to fall within 20 and 5 min after oral and sublingual administration, respectively, and reached the lowest levels in the next 10 min. Maximal mean arterial pressure reduction averaged 36 mm Hg; 120 min after the drug, mean arterial pressure was diminished by 19.5% of control. The hypotension was mediated through diminished peripheral resistance associated with rise of cardiac output and pulse rate. Nifedipine was also administered sublingually in 3 cases with hypertensive encephalopathy and acute left ventricular failure with average systemic and pulmonary arterial pressures from 307/164 and 91/55 mm Hg, respectively, which fell to 237/115 and 68/35 mm Hg 15 min after 10 mg of the drug, and were further reduced to 176189 and to 47/19 mm Hg by an additional 10 mg.

Clinical use of a calcium antagonistic agent (nifedipine) in acute pulmonary edema

Nifedipine induces vascular smooth muscle relaxation through a calcium antagonistic action. The possibility of clinical use of the drug as a ventricular unloading agent has been explored in this study. In patients with hypertensive (seven cases), primary (seven cases) or rheumatic (aortic insufficiency five cases, mitral regurgitation five cases) cardiac disease, nifedipine, administered in a single sublingual dose (10 mg), relieved acute pulmonary edema. Circulatory variations from control were the following: decrease of systemic and pulmonary arterial pressures, and of vascular resistances, of pulmonary wedge pressure, of left ventricular diastolic and systolic dimensions (echocardiography); increase of cardiac and stroke index, of left ventricular mean rate of circumferential fiber shortening, of left and right mean pre-ejection delta P/delta t and mean rate of ejection; improvement of forward output in primary and rheumatic disease. Nifedipine benefits acute congestive heart failure by sustained fall of both preload and afterload and, possibly, by an enhanced contractility. It seems to have an appropriate indication in cases in which left ventricular afterload reduction is desirable.

Short- and long-term efficacy of a calcium-antagonistic agent (nifedipine) combined with methyldopa in the treatment of severe hypertension.

Nifedipine induces a potent vasodilating and antihypertensive effect in man through a calciumantagonistic action. The drug was tested alone and in combination with methyidopa in 23 subjects with uncomplicated primary severe hypertension (diastolic pressure > 120 mm Hg) in a short- and long-term therapeutic trial. Hourly pressure readings during the short-term period showed that the antihypertensive response to nifedipine (10 mg orally) is maximal within 40 minutes and lasts for 8-12 hours. When nifedipine is administered every 6 hours the tendency of blood pressure to rise after each dose is repressed by the next dose, so that pressure remains significantly reduced throughout the 24 hours; when methyidopa is combined (250 mg four times daily) blood pressure is further reduced toward normal, without significant fluctuations during the day. After 10 days of drug combination, the antihypertensive response was mediated through reduction of peripheral vascular resistance associated with increase in cardiac output. Renal function was unchanged or improved and sodium retention and plasma volume expansion were not promoted. In six patients with very severe hypertension (diastolic pressure > 140 mm Hg) complicated by cardiac failure, a dosing regimen every 4 hours of the two compounds promptly relieved dyspnea and lung congestion and, within 2-3 days, stabilized blood pressure to an average of 150/98 mm Hg. Persistence of the antihypertensive efficacy of this drug combination in a dosing regimen every 6 hours and its beneficial effects on heart size, ECG and fundi were documented in 22 subjects (four of whom belonged to the decompensated group) who completed a 12-month follow-up. A tendency in seven cases to ankle pitting or edema was the major side effect of nifedipine; the cause of this effect remains obscure.

Negative influences of ascites on the cardiac function of cirrhotic patients

Right and left ventricular function was evaluated in 21 men with cirrhosis and tense ascites during staged removal of ascitic fluid. During paracentesis it was observed (1) that there was a significant increase in cardiac output, stroke volume, right and left ventricular stroke work and mean rate of systolic ejection; (2) that up to a certain stage of drainage (about 5,000 ml), there was a relationship between the amount of fluid removed and the intraabdominal and right atrial pressures and (3) that there was a direct relationship between improvement of cardiac function and normalization of right atrial pressure. It is believed that the increased intra-abdominal hydrostatic pressure acting upon the diaphragm affects the intrathoracic pressure to such an extent that the transmural filling pressure of the heart is reduced, and the mean pressure and respiratory pulsations of the right atrium increased, all of which impede venous return. Improved cardiac function during paracentesis appears to be due to an augmented filling of the heart and to a larger venous return.

Reference Values for Right Ventricular Volumes and Ejection Fraction With Real-Time Three-Dimensional Echocardiography: Evaluation in a Large Series of Normal Subjects

BACKGROUND The quantification of right ventricular (RV) size and function is of diagnostic and prognostic importance. Recently, new software for the analysis of RV geometry using three-dimensional (3D) echocardiographic images has been validated. The aim of this study was to provide normal reference values for RV volumes and function using this technique. METHODS A total of 245 subjects, including 15 to 20 subjects for each gender and age decile, were studied. Dedicated 3D acquisitions of the right ventricle were obtained in all subjects. RESULTS The mean RV end-diastolic and end-systolic volumes were 49 +/- 10 and 16 +/- 6 mL/m2 respectively, and the mean RV ejection fraction was 67 +/- 8%. Significant correlations were observed between RV parameters and body surface area. Normalized RV volumes were significantly correlated with age and gender. RV ejection fractions were lower in men, but differences across age deciles were not evident. CONCLUSION The current study provides normal reference values for RV volumes and function that may be useful for the identification of clinical abnormalities.