Francesco Donatelli

Cardiotoxicity of Anticancer Drugs: The Need for Cardio-Oncology and Cardio-Oncological Prevention

Due to the aging of the populations of developed countries and a common occurrence of risk factors, it is increasingly probable that a patient may have both cancer and cardiovascular disease. In addition, cytotoxic agents and targeted therapies used to treat cancer, including classic chemotherapeutic agents, monoclonal antibodies that target tyrosine kinase receptors, small molecule tyrosine kinase inhibitors, and even antiangiogenic drugs and chemoprevention agents such as cyclooxygenase-2 inhibitors, all affect the cardiovascular system. One of the reasons is that many agents reach targets in the microenvironment and do not affect only the tumor. Combination therapy often amplifies cardiotoxicity, and radiotherapy can also cause heart problems, particularly when combined with chemotherapy. In the past, cardiotoxic risk was less evident, but it is increasingly an issue, particularly with combination therapy and adjuvant therapy. Todays oncologists must be fully aware of cardiovascular risks to avoid or prevent adverse cardiovascular effects, and cardiologists must now be ready to assist oncologists by performing evaluations relevant to the choice of therapy. There is a need for cooperation between these two areas and for the development of a novel discipline, which could be termed cardio-oncology or onco-cardiology. Here, we summarize the potential cardiovascular toxicities for a range of cancer chemotherapeutic and chemopreventive agents and emphasize the importance of evaluating cardiovascular risk when patients enter into trials and the need to develop guidelines that include collateral effects on the cardiovascular system. We also discuss mechanistic pathways and describe several potential protective agents that could be administered to patients with occult or overt risk for cardiovascular complications.

Thromboangiitis obliterans of coronary and internal thoracic arteries in a young woman

Coronary artery disease may rarely be due to vasculitis. Angina pectoris and acute myocardial infarction have been reported in patients with Takayasus disease, polyarteritis nodosa, and thromboangiitis obliterans. TM In this article we report a case of Buergers disease localized to coronary and internal thoracic arteries (ITAs) in a young nonsmoking woman. The diagnosis was made by histologic examination of the ITAs that were discarded at the time of bypass surgery. A 39-year-old woman had a 2-year history of epigasmc pain of unknown origin and sporadic episodes of typical angina for the past 8 months. Because of worsening of symptoms she underwent a treadmill exercise test. which showed signs of myocardial ischemia. The patient appeared to be otherwise in good health, without evidence of risk factors including diabetes mellitus, hypercholesterolemia, hypertension, obesity, or family history of isch-

Cardio-oncology in targeting the HER receptor family: the puzzle of different cardiotoxicities of HER2 inhibitors

The HER family of tyrosine kinase receptors includes several members that are clinically important targets in cancer therapies, in particular HER1 (the EGF receptor) and HER2, other members include HER3 and HER4. Trastuzumab, a humanized monoclonal antibody and lapatinib, a tyrosine kinase inhibitor, are drugs that target HER2, which is highly expressed in 20-30% of breast cancers. Trastuzumab is recommended as an adjuvant therapy for lymph node positive, HER2-positive breast cancers, or node-negative cancer with high-risk of recurrence, as well as in stage IV cancers. One serious side effect of trastuzumab is cardiomyocyte dysfunction, resulting in reduced heart contractile efficiency. The incidence of collateral effects on the heart with trastuzumab therapy increases in people with cardiovascular risk factors, heart disease and when combined with other chemotherapeutics. When cardiotoxicity was observed with trastuzumab, several studies have addressed potential cardiac damage of trastuzumab itself and lapatinib. The differences in cardiovascular effects of these two compounds are somewhat unexpected and suggest distinct mechanisms of action, which have clear implications in clinical application and prevention of cardiotoxicity in cardio-oncological approaches.

Color Doppler Echocardiographic Assessment of Atrial Septal Defect Size: Correlation with Surgical Measurements

In patients with atrial septal defect (ASD), color flow Doppler echocardiography provides visualization of the transseptal jet, the maximal dimension of which can be assumed to correspond to the maximal dimension of the true orifice. To test whether color flow Doppler echocardiography can provide an alternative method for measurement of ASD size, we studied 63 consecutive patients with echocardiographic evidence of ASD. In 48 patients the maximal dimension of the jet was measured in the parasternal, apical, or subcostal four-chamber view or in the parasternal short-axis view. In the remaining 15 patients transesophageal echocardiography was performed because of transthoracic views were inadequate. The transesophageal studies also measured, from two-dimensional images, the maximal transverse discontinuity in the atrial septum. All patients underwent surgical repair, during which the surgeon directly measured the maximal dimension of ASD. Linear regression equations were performed to compare transthoracic and transesophageal dimensions to those measured at operation. Correlation coefficients were as follows for transthoracic versus surgical measurements: r = 0.745, standard error = 4.35, p less than 0.001. Transesophageal measurements derived from both two-dimensional images and echocardiographic jet width showed similar excellent correlation with surgical measurements (n = 0.91, standard error = 4.33, p less than 0.001; and r = 0.919, standard error = 4.42, p less than 0.001, respectively). We conclude that ASD size derived from color flow Doppler echocardiography shows a good correlation with the anatomic maximal dimension observed at operation. Both transesophageal color flow Doppler echocardiography of jet width and direct surgical measurement of the defect provide an accurate estimation of ASD size.

Surgical treatment for life-threatening acute myocardial infarction: a prospective protocol.

OBJECTIVE In this paper we describe the preliminary results of a prospective operative protocol designed in order to define the role of emergent myocardial revascularization in extensive acute myocardial infarction and in post-infarction cardiogenic shock. METHODS Entry criteria are: age < 75 years; anterior acute myocardial infarction with ST segment elevation > 4 leads, infero-postero-lateral or inferior and right ventricular within 6 h from onset of chest pain; post-infarction cardiogenic shock within 3 h from onset of shock. From November 1994 to July 1995, after emergency coronary arteriography, 23 patients were treated by coronary artery bypass grafting. Fifteen were operated for extensive acute myocardial infarction (group A, mean age 54.1 +/- 9.4 years) and eight for post-infarction cardiogenic shock (group B mean age 65.0 +/- 8.7 years). Mean time from onset was 4.4 +/- 1.3 h in group A and 2.2 +/- 0.8 h in group B. Mean left ventricular ejection fraction was 39.3 +/- 12.7% in group A and 22.6 +/- 3.5% in group B. Six out of eight group B patients needed intraaortic balloon counterpulsation preoperatively, and 2/8 cardiopulmonary resuscitation. RESULTS Myocardial revascularization consisted in 3.4 +/- 1.1 grafts in group A (vein grafts, except for 8 patients who also received a left internal thoracic artery graft) and 3.3 +/- 1.1 vein grafts in group B. All patients in group B and 3/15 (20%) in group A underwent intraaortic balloon counterpulsation. In-hospital death occurred in 1/15 (6.7%) patients of group A and in 4/8 (50%) patients of group B. At a mean follow-up of 4.1 +/- 3.4 months for group A and 3.9 +/- 2.2 months for group B left ventricular ejection fraction was 43.4 +/- 9.0% in group A and 35.7 +/- 13.1% in group B. CONCLUSIONS Experience of 9 months with this prospective protocol showed its effectiveness in the management of critically ill patients with acute coronary occlusion leading to low mortality rate in acute myocardial infarction and improved survival rate in post-infarction cardiogenic shock.

TachoSil® for postinfarction ventricular free wall rupture

Despite a decline in the last three decades, postinfarction ventricular free wall rupture still complicates more than 3% of acute ST-elevation myocardial infarctions and remains a surgical challenge. TachoSil (Nycomed, Zurich, Switzerland) is an equine collagen patch coated with human fibrinogen and human thrombin, which has recently been used for haemostasis in cardiovascular surgery, but its potential usefulness in free wall rupture has not been reported. Initial clinical experience with an on-pump sutureless technique without cardioplegia, using wide TachoSil patching to achieve free wall rupture repair, has been described.

Evaluation and treatment of secondary tricuspid insufficiency

To define the role of functional tricuspid insufficiency and right ventricular (RV) failure in patients with mitral disease, the data of 121 patients with secondary tricuspid insufficiency that underwent mitral valve replacement (MVR) from January 1982 to December 1987 were analyzed. The mitral hemodynamic lesion was: stenosis in 41 patients (33.9%); insufficiency in 11 (9.1%) and mixed stenosis and insufficiency in 69 (57.0%). NYHA functional class was: II in 4 patients (3.3%), III in 78 (64.5%) and IV in 39 (32.2%). In 100 cases (group 1) with tricuspid insufficiency defined as moderate or severe, a De Vega annuloplasty was performed while in 21 (group 2) with mild tricuspid insufficiency, no tricuspid surgical procedure was performed. Hospital deaths occurred in 17 of 121 patients [14% (CL 10.8-17.0)]. There was no significant difference in hospital mortality between group 1 and group 2 (15% vs 9.5%; P = 0.75). Incremental risk factors for hospital mortality as determined by multivariate analysis, include: cardiothoracic ratio (P = 0.0016), total aortic cross-clamp time (P = 0.006), associated cardiac disease (P = 0.0209) and emergency operations (P = 0.0318). Mean follow-up of surviving patients was 50.1 +/- 28.1 months. Late deaths occurred in 16 patients [15.4% (CL 11.7-18.7)]. The actuarial survival rate was 85.6% and 73.8% at 5 and 9 years, respectively. Nine patients [8.6% (CL 5.9-11.3)] required reoperation. There was no significant difference between group 1 and group 2 in the rate of late cardiac related deaths (5.9% vs 5.3%, P = 0.66) and of tricuspid reoperations (4.7% vs 5.3%, P = 0.62).(ABSTRACT TRUNCATED AT 250 WORDS)

Diet-Derived Phytochemicals: From Cancer Chemoprevention to Cardio-Oncological Prevention

Cardiovascular diseases and cancer are the leading causes of death in most countries. These diseases share many common risk factors as well as pathogenetic determinants, and their incidence is related to age in an exponential manner. Furthermore, it has become apparent that several treatments used in therapy or even in prevention of cancer can impair the structural and functional integrity of the cardiovascular system, giving rise to an interdisciplinary field: cardio-oncology. However, tumors and cardiovascular diseases also share common protective factors: they can be prevented either by avoiding exposure to recognized risk factors, and/or by favoring the intake of protective compounds and by modulating the host defense machinery. These latter approaches are generally known as chemoprevention. A great variety of dietary and pharmacological agents have been shown to be potentially capable of preventing cancer in preclinical models, most of which are of plant origin. Phytochemicals, in particular diet-derived compounds, have therefore been proposed and applied in clinical trials as cancer chemopreventive agents. There is now increasing evidence that some phytochemicals can be also protective for the heart, having the potential to reduce cancer, cardiovascular disease and even anticancer drug-induced cardiotoxicity. We introduce the concept that these compounds induce pre-conditioning, a low level cellular stress that induces strong protective mechanisms conferring resistance to toxins such as cancer chemotherapeutics. Cancer cells and cardiomyocytes have fundamental differences in their metabolism and sensitivity to preconditioning, autophagy and apoptosis, so that dosage of the prevention compounds is important. Here we discuss the mechanisms responsible for the cardiotoxicity of anticancer drugs, the possibility to prevent them and provide examples of diet-derived phytochemicals and other biological substances that could be exploited for protecting the cardiovascular system according to a joint cardio-oncological preventative approach.

Predictors of adverse events after surgical ventricular restoration for advanced ischaemic cardiomyopathy

OBJECTIVE Post-infarction ventricular remodelling has been graded (I-III) according to the loss of systolic left ventricular silhouette curvature changes. Although surgical ventricular restoration (SVR) has been extended to type III ischaemic cardiomyopathy, the results are less satisfactory. We sought to identify geometric and functional predictors of late outcome after SVR. METHODS Among 144 patients who underwent SVR since 1998, a subgroup of 31 patients (age: 65.2+/-7.6 years) was analysed. Inclusion criteria were: type III cardiomyopathy, no associated procedure except coronary artery bypass grafting, prior anterior infarction, absent-to-2+ mitral regurgitation, elective operation, follow-up > or =18 months (mean: 44+/-26; longest: 96 months). Probability of events was estimated with the Kaplan-Meier method. A Cox multivariable regression model was constructed selecting eight potential predictors of four adverse events: death, cardiac death, recurrent heart failure (New York Heart Association class III or IV) and left ventricular re-remodelling, defined as a 25% increase of end-systolic volume index after SVR, or an end-systolic volume index > or =50 ml.m(-2). RESULTS Early and late mortality were zero and 6% (2/31 patients, one cardiac-related death). NYHA class and all echocardiographic functional variables significantly improved early after SVR. Freedom (+/-standard error (SE)) from heart failure was 97%+/-3%, 93%+/-5%, 77%+/-11% and 64%+/-15%, whereas freedom from left ventricular re-remodelling was 97%+/-3%, 80%+/-8%, 60%+/-12% and 39%+/-15%, respectively, 1, 3, 5 and 7 years after SVR. Multivariable analysis identified baseline mitral regurgitation degree and sphericity index as independent predictors of recurrent heart failure (p=0.025; hazard ratio (HR)=7.80 (95% confidence intervals (CIs): 1.29-47.19)) and left ventricular re-remodelling (p=0.047; HR=2.84 (95% CIs: 1.01-7.95)). Both predictors also correlated with a higher recurrence of end-systolic volume index > or =50 ml.m(-2) at late follow-up. CONCLUSIONS Despite advanced cardiomyopathy, SVR determines left ventricular volume reduction and improved systolic function. Baseline absent-to-moderate mitral regurgitation and a more spherical left ventricular geometry predict a less favourable clinical and functional outcome, suggesting a possible rationale for wider indications for combined correction of 2+ mitral regurgitation and undersizing of the mitral annulus, particularly in patients with sphericity index > or =0.75.

Posterior mitral valve restoration for ischemic regurgitation

Chronic ischemic mitral regurgitation is traditionally a complex lesion to repair. Only restrictive annuloplasty has become an accepted strategy to avoid valve replacement, but results are unsatisfactory in some subgroups of patients. We describe an original technique that addresses the pathophysiologic mechanisms responsible for one of the most common subtypes of ischemic mitral regurgitation, ie, asymmetric tethering of the mitral leaflets after inferior myocardial infarction. The technique includes partial detachment of the posterior leaflet from the mitral annulus, annular plication, and posterior cusp plasty.