Predicting and preventing cardiotoxicity in the era of breast cancer targeted therapies. Novel molecular tools for clinical issues

Abstract Treatment of breast cancer (BC) has changed over the last decade with the advent of targeted therapies. Whereas traditional chemotherapy was directed toward all rapidly dividing cells (cancerous or not), several new anti-cancer drugs are mainly tailored to specific genetic pathways of cancer cells. Ideally, the goal of these new therapies is to improve the management of cancer with a specific targeting of the malignant cell and fewer side effects than traditional chemotherapy. Due to the initial success of this approach, an increasing number of targeted drugs entered into clinical development. However, unanticipated side effects of the new drugs, such as cardiotoxicity and heart failure, emerged from several clinical trials. The mechanisms of cardiotoxicity due to traditional chemotherapy and the one due to new drugs seem to be inherently different. In the case of BC, available targeted therapies are probably associated with the abrogation of normal molecular pathways involved in cardiomyocytes and endothelial cells survival/proliferation. The cardiac safety profile of these new drugs asks for a careful patient monitoring and follow up. Herein we will review the cardiotoxicity of BC patients receiving antiERBB2 treatment (Trastuzumab, Lapatinib), VEGF inhibitors (Bevacizumab) and tirosin-kinase inhibitors (Sorafenib, Sunitinib). We will discuss the molecular mechanisms that underlie the risk of cardiotoxicity, and we will examine the molecular tools useful for prediction of heart failure and for identification of subgroups of BC patients more susceptible to cardiac side effects induced by targeted therapies. Attention will be paid in particular to ERBB2 gene and its polymorphisms, as well as to the possible genetic risk stratification of BC patients. Finally, we will discuss the possible clinical strategies to prevent and minimizing the cardiotoxicity of targeted therapies in BC patients, focusing in particular on new drugs combination and on the emerging role of a tight partnership between cardiologists and oncologists

Cardiac Magnetic Resonance in Stable Coronary Artery Disease: Added Prognostic Value to Conventional Risk Profiling

Aims. Cardiovascular magnetic resonance (CMR) permits a comprehensive evaluation of stable coronary artery disease (CAD). We sought to assess whether, in a large contemporaneous population receiving optimal medical therapy, CMR independently predicts prognosis beyond conventional cardiovascular risk factors (RF). Methods. We performed a single centre, observational prospective study that enrolled 465 CAD patients (80% males; 63±11 years), optimally treated with ACE-inhibitors/ARB, aspirin, and statins (76-85%). Assessments included conventional evaluation (clinical history, atherosclerosis RF, electrocardiography, and echocardiography) and a comprehensive CMR with LV dimensions/function, late gadolinium enhancement (LGE), and stress perfusion CMR (SPCMR). Results. During a median follow-up of 62 months (IQR 23-74) there were 50 deaths and 92 major adverse cardiovascular events (MACE). CMR variables improved multivariate model prediction power of mortality and MACE over traditional RF alone (F-test p<0.05 and p<0.001, respectively). LGE was an independent prognostic factor of mortality (hazard ratio [95% CI]: 3.4 [1.3−8.8]); moreover, LGE (3.3 [1.7−6.3]) and SPCMR (2.1 [1.4−3.2]) were the best predictors of MACE. Conclusion. LGE is an independent noninvasive marker of mortality in the long term in patients with stable CAD and optimized medical therapy. Furthermore, LGE and SPCMR independently predict MACE beyond conventional risk stratification

Evidence of Carotid Atherosclerosis Vulnerability Regression in Real Life From Magnetic Resonance Imaging: Results of the MAGNETIC Prospective Study

BackgroundAtherosclerosis vulnerability regression has been evidenced mostly in randomized clinical trials with intensive lipid-lowering therapy. We aimed to demonstrate vulnerability regression in real life, with a comprehensive quantitative method, in patients with asymptomatic mild to moderate carotid atherosclerosis on a secondary prevention program. Methods and ResultsWe conducted a single-center prospective observational study (MAGNETIC [Magnetic Resonance Imaging as a Gold Standard for Noninvasive Evaluation of Atherosclerotic Involvement of Carotid Arteries]): 260 patients enrolled at a cardiac rehabilitation center were followed for 3 years with serial magnetic resonance imaging. Per section cutoffs (95th/5th percentiles) were derived from a sample of 20 consecutive magnetic resonance imaging scans: (1) lipid-rich necrotic core: 26% of vessel wall area; (2) intraplaque hemorrhage: 12% of vessel wall area; and (3) fibrous cap: (a) minimum thickness: 0.06 mm, (b) mean thickness: 0.4 mm, (c) projection length: 11 mm. Patients with baseline magnetic resonance imaging of adequate quality (n=247) were classified as high (n=63, 26%), intermediate (n=65, 26%), or low risk (n=119, 48%), if vulnerability criteria were fulfilled in >= 2 contiguous sections, in 1 or multiple noncontiguous sections, or in any section, respectively. Among high-risk patients, a conversion to any lower-risk status was found in 11 (17%; P=0.614) at 6 months, in 16 (25%; P=0.197) at 1 year, and in 19 (30%; P=0.009) at 3 years. Among patients showing any degree of carotid plaque vulnerability, 21 (16%; P=0.014) were diagnosed at low risk at 3 years. ConclusionsThis study demonstrates with a quantitative approach that vulnerability regression is common in real life. A secondary prevention program can promote vulnerability regression in asymptomatic patients in the mid to long term

Evidence for Biological Age Acceleration and Telomere Shortening in COVID-19 Survivors

The SARS-CoV-2 infection determines the COVID-19 syndrome characterized, in the worst cases, by severe respiratory distress, pulmonary and cardiac fibrosis, inflammatory cytokine release, and immunosuppression. This condition has led to the death of about 2.15% of the total infected world population so far. Among survivors, the presence of the so-called persistent post-COVID-19 syndrome (PPCS) is a common finding. In COVID-19 survivors, PPCS presents one or more symptoms: fatigue, dyspnea, memory loss, sleep disorders, and difficulty concentrating. In this study, a cohort of 117 COVID-19 survivors (post-COVID-19) and 144 non-infected volunteers (COVID-19-free) was analyzed using pyrosequencing of defined CpG islands previously identified as suitable for biological age determination. The results show a consistent biological age increase in the post-COVID-19 population, determining a DeltaAge acceleration of 10.45 ± 7.29 years (+5.25 years above the range of normality) compared with 3.68 ± 8.17 years for the COVID-19-free population (p &lt; 0.0001). A significant telomere shortening parallels this finding in the post-COVID-19 cohort compared with COVID-19-free subjects (p &lt; 0.0001). Additionally, ACE2 expression was decreased in post-COVID-19 patients, compared with the COVID-19-free population, while DPP-4 did not change. In light of these observations, we hypothesize that some epigenetic alterations are associated with the post-COVID-19 condition, particularly in younger patients (&lt; 60 years)