Cardiac effects of deferasirox in transfusion-dependent patients with myelodysplastic syndromes: TELESTO study.

Iron overload from repeated transfusions has a negative impact on cardiac function, and iron chelation therapy may help prevent cardiac dysfunction in transfusion-dependent patients with myelodysplastic syndromes (MDS). TELESTO (NCT00940602) was a prospective, placebo-controlled, randomised study to evaluate the iron chelator deferasirox in patients with low- or intermediate-1-risk MDS and iron overload. Echocardiographic parameters were collected at screening and during treatment. Patients receiving deferasirox experienced a significant decrease in the composite risk of hospitalisation for congestive heart failure (CHF) or worsening of cardiac function (HR = 0.23; 95% CI: 0.05, 0.99; nominal p = 0.0322) versus placebo. No significant differences between the arms were found in left ventricular ejection fraction, ventricular diameter and mass or pulmonary artery pressure. The absolute number of events was low, but the enrolled patients were younger than average for patients with MDS, with no serious cardiac comorbidities and a modest cardiovascular risk profile. These results support the effectiveness of deferasirox in preventing cardiac damage caused by iron overload in this patient population. Identification of patients developing CHF is challenging due to the lack of distinctive echocardiographic features. The treatment of iron overload may be important to prevent cardiac dysfunction in these patients, even those with moderate CHF risk.

Role of Arterial Hypertension and Hypertension-Mediated Organ Damage in Cardiotoxicity of Anticancer Therapies.

PURPOSE OF THE REVIEW: Arterial hypertension (AH) is the most common cardiovascular (CV) risk factor in the community and in oncologic patients. It also represents the most important CV condition predisposing to anticancer treatment-related cardiotoxicity. This risk is heightened in the presence of cardiac AH-mediated organ damage (HMOD). Influence of AH and HMOD on the development of cardiotoxicity will be reviewed, with a focus on specific scenarios and implications for management of oncologic patients. RECENT FINDINGS: Not adequately controlled AH before or during anticancer treatments and/or development of AH during or after completion of such therapies have detrimental effects on the clinical course of oncologic patients, particularly if HMOD is present. As overlooking CV health can jeopardize the success of anticancer treatments, the goal for clinicians caring for the oncologic patient should include the treatment of AH and HMOD.

Baseline cardio-oncologic risk assessment in breast cancer women and occurrence of cardiovascular events: The HFA/ICOS risk tool in real-world practice.

BACKGROUND: the European Society of Cardiology Heart Failure Association (HFA) together with the International Cardio-Oncology Society (ICOS) proposed charts for baseline CV risk assessment of cancer patients scheduled to receive anthracyclines and anti-human epidermal growth factor receptor-2 (HER2) agents. METHODS: We investigated HFA/ICOS risk stratification, prescriptions of cardioactive drugs, and occurrence of CV events in a multicentric breast cancer (BC) cohort from 3 Italian Outpatient Cardio-Oncology Clinics. RESULTS: 373 BC patients who underwent a baseline Cardio-Oncologic evaluation were included, of whom 202 scheduled to receive anthracyclines and 171 anti-HER2. Mean age was 60 ± 12 years and 49% of BC patients had ≥2 CV risk factors. In the anthracyclines group, 51% were at low-risk, 43% at medium-risk and 6% at high-risk; while in the anti-HER2 group, 27% patients were at low-risk, 58% at medium-risk and 15% at high-risk. In both groups, a medium-to-high risk was associated with use of cardioactive therapies (p < 0.0001). There were no LVD events in anthracycline recipients, and 16 LVD among anti-HER2 patients. A medium-to-high risk was not associated with LVD occurrence (p = 0.17). CONCLUSIONS: Patients with medium-to-high HFA/ICOS risk were more likely to receive cardioactive therapies, possibly explaining the lack of association of risk categories with LVD occurrence.

Diversity of Cardiologic Issues in a Contemporary Cohort of Women With Breast Cancer.

Background: Women with breast cancer (BC) represent a special population particularly exposed to cardiovascular disease (CVD) risk. However, cardiologic assessment in BC is mostly limited to detection of left ventricular dysfunction cardiotoxicity (LVD-CTX) due to anticancer treatments. Our aim was to comprehensively investigate CV profile and events in a contemporary BC cohort. Methods and Results: Records of BC patients referred for a Cardio-Oncologic evaluation before starting anticancer treatments, between 2016 and 2019, were retrospectively reviewed (n = 508). Information regarding prevalence and control of CV risk factors, and novel CVD diagnoses were extracted. Occurrence of LVD-CTX, CV events other than LVD-CTX and mortality was assessed. Mean age of study population was 64 ± 13 years; 287 patients were scheduled to receive anthracycline and 165 anti-HER2 therapy. Overall, 53% of BC women had ≥2 CV risk factors, and 67% had at least one of arterial hypertension, dyslipidaemia or diabetes mellitus not adequately controlled. Eighteen (4%) patients were diagnosed a previously unknown CVD. Over a mean follow-up of 2.5 ± 1 years, 3% of BC patients developed LVD-CTX, 2% suffered from other CV events and 11% died. CV risk factors were not associated with LVD-CTX, except for family history of CAD. On the contrary, patients with other CV events exhibited a worse CV profile. Those who died more commonly experienced CV events other than LVD-CTX (p = 0.02). Conclusions: BC women show a suboptimal CV risk profile and are at risk of CV events not limited to LVD-CTX. A baseline Cardio-Oncologic evaluation was instrumental to implement CV prevention and to optimize CV therapies.

BMI and acute kidney injury post transcatheter aortic valve replacement: unveiling the obesity paradox.

AIMS: Acute kidney injury (AKI) may complicate transcatheter aortic valve replacement (TAVR) leading to higher mortality. The relationship between AKI, obesity, and mortality, however, is controversial. We sought to investigate the impact of body habitus on the prognostic value of AKI in TAVR. METHODS: Among the 645 patients who underwent successful TAVR in a single high-volume centre, we retrospectively evaluated the association between AKI-TAVR and 30-day, 6-month, and 1-year mortality, and whether this relationship was affected by BMI. AKI was defined according to the Valve Academic Research Consortium-2 criteria. Patients were categorized into three groups by BMI: low-to-normal weight (<25 kg/m2), overweight (25-30 kg/m2), obese (>30.0 kg/m2). RESULTS: Three-hundred and twenty-four (50.2%) patients were low-to-normal weight, 223 (34.6%) overweight, and 98 (15.2%) obese. AKI occurred in 141 (21.9%), similarly across BMI groups. Thirty-day, 6-month, and 1-year mortality rates were 2.2, 3.7, and 7.9%, without differences across BMI groups. Among patients who developed AKI-TAVR, 30-day (8.7 vs. 2.0 vs. 0.0%), 6-month (13.0 vs. 6.1 vs. 4.3%), and 1-year (20.3 vs. 12.2 vs. 4.3%) mortality showed a decreasing trend across increasing BMI categories (all P < 0.05); the same trend was not observed for patients without AKI-TAVR. In multivariate models, AKI was associated with 30-day [odds ratio (OR): 2.46, 95% confidence interval (CI): 1.70-8.67], 6-month (OR: 2.75, 95% CI: 1.32-7.59), and 1-year mortality (OR: 1.84, 95% CI: 1.22-3.71, all P < 0.05). The interaction between AKI and BMI, when added to the models, was consistently significant (all P < 0.05). CONCLUSION: Higher BMI is associated with better survival in TAVR patients who develop AKI.

Impact of bioprosthetic valve type on peri-procedural myocardial injury and mortality after transcatheter aortic valve replacement.

Peri-procedural myocardial injury (PPMI) is a common complication after transcatheter valve replacement (TAVR), often remaining clinically silent. The role of valve type on PPMI and the association between PPMI and mortality are still unclear. We sought to evaluate predictors and outcome of PPMI after TAVR, and the impact of self-expandable valve (SEV) vs. balloon-expandable valve (BEV) deployment on PPMI. Consecutive patients who underwent successful TAVR in a single-center from January 2014 to December 2019 were included. PPMI was defined according to a modified Valve Academic Research Consortium (VARC)-2 definition as a post-procedure elevation of troponin (with a peak value ≥ 15-times the upper-reference limit) < 72 h after TAVR. We included 596 patients, of whom 258 (43.3%) were men. Mean age was 83.4 ± 5.5 years. We deployed 368 (61.7%) BEV and 228 (38.3%) SEV. PPMI was observed in 471 (79.0%) patients. At multivariable analysis, SEV (OR 2.70, 95% CI 1.64-4.55, p < 0.001), creatinine clearance (OR 0.98, 95% CI 0.97-1.00, p = 0.011), and baseline ejection fraction (OR 1.05, 95% CI 1.02-1.07, p < 0.001) were independent predictors of PPMI; these findings were also confirmed using a propensity-weighted analysis. Thirty-day and 1-year all-cause mortality rates were 2.5% and 8.1%, respectively. No associations between PPMI and 30-day (p = 0.488) or 1-year (p = 0.139) all-cause mortality were found. Independent predictors of 30-day mortality were increasing EUROSCORE II (HR 1.16 per score point, 95% CI 1.08-1.19, p < 0.001) and life-threatening/major bleeding complications (HR 5.87, 95% CI 1.28-26.58, p = 0.019), whereas EUROSCORE II (HR 1.08, 95% CI 1.04-1.13, p = 0.031) and acute kidney injury (HR 2.59, 95% CI 1.20-5.35, p = 0.020) were related to 1-year mortality. PPMI is frequent after TAVR, but it does not affect 30-day or 1-year all-cause mortality. SEV implantation is associated with an increased frequency of PPMI.

Early infections after successful transcatheter aortic valve replacement are associated with increased short- and long-term mortality: A single-center study.

BACKGROUND: We reviewed frequency, microbiological pattern, predictors, and outcomes of early infections following transcatheter aortic valve replacement (TAVR). METHODS: Five hundred thirty-nine patients who underwent successful TAVR at a single, high-volume center between January 2014 and December 2019 were enrolled. We defined early infections as occurring within 30-day from TAVR. RESULTS: Mean age was 83.5 ± 5.4 years; 230 (42.7%) patients were men. Median follow-up was 12.0 (5.7-18.3) months; 30-day and 1-year death rates were 8/539 (1.5%) and 30/539 (5.6%), respectively. Early infections occurred in 61/539 (11.3%) patients, of whom 2 had infections in two sites. Of the 63 infections, 10 were bloodstream infections (BSI), 5 urinary tract, 27 pulmonary (2 with sepsis), 6 access site infections, 1 enterocolitis, and 14 were clinically diagnosed (no specific site). We observed 31/63 (49.2%) microbiologically-documented infections: Gram+ bacteria were isolated in 12/31 (38.7%), Gram- in 17/31 (54.3%), both Gram+ and Gram- in 2/31 (6.5%); in thirty-two infections no specific pathogen could be isolated (clinically-documented infections). Early infections were more prevalent in patients who died within 30-day (8.2% vs. 0.6%, p < 0.001) or 1-year (14.8% vs. 4.4%, p < 0.001) from TAVR. At multivariable analysis, early infections were independently associated with 30-day (HR: 8.82, 95% CI: 1.11-19.83, p = 0.035) and 1-year mortality (HR: 2.10, 95%CI: 1.28-6.21, p = 0.041). The predictive value for 1-year mortality was maintained even restricting the analysis to documented infections only, or to more severe infections (BSI and pneumonia only) (all p < 0.05). CONCLUSIONS: Early infections occur in 1/10th of TAVR and are associated with increased short- and long-term mortality. Whereas a causal relationship between early infections and the risk of death cannot be unequivocally proven, careful surveillance of infected patients may improve TAVR results.

Cancer Patient With Unusual Dyspnea in the COVID-19 Era: Challenging Management of a Rare Cardiac Tumor.

Heart failure symptoms, in particular dyspnea, may be difficult to frame in a patient with cancer. We report the case of an oncological patient whose dyspnea could have been attributable to various causes and whose management was challenging in the context of the coronavirus disease-2019 pandemic. (Level of Difficulty: Beginner.).

How to Monitor Cardiac Complications of Immune Checkpoint Inhibitor Therapy.

Immune-checkpoint inhibitors (ICIs) represent a successful paradigm in the treatment of cancer. ICIs elicit an immune response directed against cancer cells, by targeting the so-called immune checkpoints, key regulators of the immune system that when stimulated can dampen the immune response to an immunologic stimulus. Such response, however, is not entirely tumor-specific and may result in immune-related adverse events (irAEs), involving a number of organs and systems. Cardiovascular (CV) irAEs are rare, although potentially severe. In particular, several cases of ICI-related myocarditis with life-threatening course have been reported: the possibility of fulminant cases, thus, requires a high level of awareness among both oncologists and cardiologists. Aggressive work-up and management of symptomatic patients taking ICIs is fundamental for early recognition and initiation of specific immunosuppressive therapies. Notably, myocarditis occurs within few weeks from ICIs initiation, offering opportunity for a targeted screening. Troponin testing is the cornerstone of this screening, yet uncertainties remain regarding timing and candidates. Moreover, troponins positivity should be carefully interpreted. We herein review the main aspects of ICI-related myocarditis and suggest a practical approach. In particular, we focus on the opportunities that a baseline CV evaluation offers for subsequent management by collecting clinical and instrumental data, essential for the interpretation of troponin results, for differential diagnosis and for the formulation of a diagnostic and therapeutic workup.

Arterial hypertension in cancer: The elephant in the room.

The great therapeutical success achieved by oncology is counterbalanced by growing evidences of cardiovascular (CV) toxicity due to many antineoplastic treatments. Cardiac adverse events may cause premature discontinuation of effective oncologic treatments or occur as late events undermining the oncologic success. Arterial hypertension is both the most common comorbidity in cancer patients and a frequent adverse effect of anticancer therapies. A pre-existing hypertension is known to increase the risk of other cardiac adverse events due to oncologic treatments, in particular heart failure. Moreover, as a strict association between cancer and CV diseases has emerged over the recent years, various analyses have shown a direct relationship between hypertension and cancer incidence and mortality. Finally, many antineoplastic treatments may cause a rise in blood pressure (BP) values, particularly the novel anti VEGF agents, this possibly compromising efficacy of chemotherapy. Aim of this review is to revise the topic and the many aspects linking arterial hypertension and cancer, and to provide a comprehensive and practical guide of the current treatment approaches.

An increase in myocardial 18-fluorodeoxyglucose uptake is associated with left ventricular ejection fraction decline in Hodgkin lymphoma patients treated with anthracycline.

BACKGROUND: Doxorubicin (DOX)-based chemotherapy for Hodgkin lymphoma (HL) yields excellent disease-free survival, but poses a substantial risk of subsequent left ventricular (LV) dysfunction and heart failure, typically with delayed onset. At the cellular level, this cardiotoxicity includes deranged cardiac glucose metabolism. METHODS: By reviewing the hospital records from January 2008 through December 2016, we selected HL patients meeting the following criteria: ≥ 18 year-old; first-line DOX-containing chemotherapy; no diabetes and apparent cardiovascular disease; 18-fluoro-deoxyglucose positron emission tomography (18FDG-PET) scans before treatment (PETSTAGING), after 2 cycles (PETINTERIM) and at the end of treatment (PETEOT); at least one echocardiography ≥ 6 months after chemotherapy completion (ECHOPOST). We then evaluated the changes in LV 18FDG standardized uptake values (SUV) during the course of DOX therapy, and the relationship between LV-SUV and LV ejection fraction (LVEF), as calculated from the LV diameters in the echocardiography reports with the Teicholz formula. RESULTS: Forty-three patients (35 ± 13 year-old, 58% males) were included in the study, with 26 (60%) also having a baseline echocardiography available (ECHOPRE). LV-SUV gradually increased from PETSTAGING (log-transformed mean 0.20 ± 0.27) to PETINTERIM (0.27 ± 0.35) to PETEOT (0.30 ± 0.41; P for trend < 0.001). ECHOPOST was performed 22 ± 17 months after DOX chemotherapy. Mean LVEF was normal (68.8 ± 10.3%) and only three subjects (7%) faced a drop below the upper normal limit of 53%. However, when patients were categorized by median LV-SUV, LVEF at ECHOPOST resulted significantly lower in those with LV-SUV above than below the median value at both PETINTERIM (65.5 ± 11.8% vs. 71.9 ± 7.8%, P = 0.04) and PETEOT (65.6 ± 12.2% vs. 72.2 ± 7.0%, P = 0.04). This was also the case when only patients with ECHOPRE and ECHOPOST were considered (LVEF at ECHOPOST 64.7 ± 8.9% vs. 73.4 ± 7.6%, P = 0.01 and 64.6 ± 9.3% vs. 73.5 ± 7.0%, P = 0.01 for those with LV-SUV above vs. below the median at PETINTERIM and PETEOT, respectively). Furthermore, the difference between LVEF at ECHOPRE and ECHOPOST was inversely correlated with LV-SUV at PETEOT (P < 0.01, R2 = - 0.30). CONCLUSIONS: DOX-containing chemotherapy causes an increase in cardiac 18FDG uptake, which is associated with a decline in LVEF. Future studies are warranted to understand the molecular basis and the potential clinical implications of this observation.

Serial Troponin for Early Detection of Nivolumab Cardiotoxicity in Advanced Non-Small Cell Lung Cancer Patients.

BACKGROUND: Rare cases of severe myocarditis are reported during treatment with nivolumab. Troponin, a biomarker of cardiac damage, is a key component of the diagnostic workup of many cardiac disorders, including myocarditis. This study investigates the role of troponin to assess cardiac involvement during nivolumab therapy for non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: We evaluated 59 NSCLC patients, analyzing serum samples collected within a translational research study. Troponin above the upper normal limit (0.046 ng/mL) was defined as Tn+, whereas normal but detectable troponin (0.015-0.045) was defined as Tndet. Troponin alterations were interpreted on the grounds of the following elements: peak values and time curve, cardiac comorbidities, signs and symptoms coincident to troponin elevation, ECG, echocardiography, and disease progression. RESULTS: No patient had cardiovascular events. Among 362 available blood samples, Tn+ (max 0.317 ng/mL) was found in 13 determinations belonging to 6 patients. Seven other patients had isolated Tndet. In five patients, Tn+ was attributed to cardiac comorbidities, disease progression, or worsening clinical status. One patient without cardiac history and in good clinical condition had a sustained troponin increase-soon after the start of therapy-and after careful evaluation of all relevant elements, it was interpreted as a marker of nivolumab-related subclinical myocarditis. CONCLUSION: Tn+ may occur in NSCLC patients treated with nivolumab, but in most cases it does not indicate nivolumab cardiotoxicity. In some cases, however, a careful interpretation of troponin alteration, especially at the beginning of therapy, enables identification of subclinical myocarditis, thus allowing early cardiac treatment. IMPLICATIONS FOR PRACTICE: Myocarditis is a rare but serious adverse event of immune checkpoint blockade with nivolumab, which needs to be recognized as soon as possible. This article suggests that troponin, a user-friendly biomarker of myocardial cytotoxicity, might be useful for early detection of immune-mediated myocarditis. However, because troponin abnormalities might also be related to a number of conditions capable of causing myocardial oxygen demand-supply mismatch, a careful cardiac assessment should be performed in non-small cell lung cancer patients in order to properly interpret any troponin increase. According to the available evidence, monitoring troponin during the first weeks of treatment can be considered reasonable.

Potential cardiac risk of immune-checkpoint blockade as anticancer treatment: What we know, what we do not know, and what we can do to prevent adverse effects.

Cancer immunotherapy has become a well-established treatment option for some cancers after the development of a family of drugs targeting the so-called immune checkpoints, such as CTLA4 and PD-1 with PD-L1. These co-receptors/ligands inhibit the activation of T-cell, thus preventing an excessive inflammatory response. Tumors exploit these pathways to induce immune tolerance to themselves. Thus, the main effect of checkpoint-blocking drugs is to awake an immune response primarily directed against cancer cells. Nonetheless, as the immune response elicited by these drugs is not completely tumor-specific, their use may actually cause several adverse effects, including adverse cardiovascular effects. In this review, we will discuss the principles and potentiality of immunotherapy for cancer treatment, the experimental and clinical data on the role of CTLA4 and PD-1 with PD-L1 as immune-checkpoints in the cancer environment and in the cardiovascular system, and strategies aimed at preventing possible cardiovascular adverse effects of immune-checkpoint blockers.

Ivabradine in Cancer Treatment-Related Left Ventricular Dysfunction.

BACKGROUND: Patients developing cancer treatment-related left ventricular dysfunction (CTrLVD) require a prompt therapy. Hypotension, dizziness, and fatigue often limit the use of angiotensin-converting enzyme inhibitors (ACEi), angiotensin receptor blockers (ARB), and ß-blockers (BB) in cancer patients who may already be afflicted by these symptoms. Ivabradine is a heart rate-lowering drug that does not cause hypotension and may be used in heart failure with reduced left ventricular ejection fraction (LVEF). OBJECTIVE: The aim of this paper was to investigate the role of ivabradine to treat CTrLVD. METHODS: A retrospective analysis in a cohort of 30 patients with CTrLVD (LVEF < 50%) receiving ivabradine on top of the maximal tolerated dose of ACEi/ARB and BB was performed. We evaluated cardiovascular treatment, oncologic treatment, LVEF, functional class (New York Heart Association [NYHA]), and fatigue during the study period. RESULTS: Ivabradine was initially started at the dose of 2.5 mg/b.i.d. in most patients and then carefully titrated. Hypotension (70%) and fatigue (77%) were the main causes limiting the treatment with ACEi/ARB and BB. After a mean follow-up of 6.5 months, LVEF increased from 45.1% (SD = 6.4) to 53.2% (SD = 3.9; p < 0.001). When patients were analyzed according to the type of cancer therapy, no difference in LVEF changes across the groups was found. NYHA class ameliorated in 11 patients, while fatigue improved in 8 patients. No serious cardiovascular side effects were reported. CONCLUSIONS: The ability to improve symptoms and LVEF in unfit cancer patients makes ivabradine a reasonable pharmacological tool for treating CTrLVD.

A Score-Based Approach to 18F-FDG PET Images as a Tool to Describe Metabolic Predictors of Myocardial Doxorubicin Susceptibility.

PURPOSE: To verify the capability of 18F-fluorodeoxy-glucose positron emission tomography/computed tomography (FDG-PET/CT) to identify patients at higher risk of developing doxorubicin (DXR)-induced cardiotoxicity, using a score-based image approach. METHODS: 36 patients underwent FDG-PET/CT. These patients had shown full remission after DXR-based chemotherapy for Hodgkin's disease (DXR dose: 40-50 mg/m² per cycle), and were retrospectively enrolled. Inclusion criteria implied the presence of both pre- and post-chemotherapy clinical evaluation encompassing electrocardiogram (ECG) and echocardiography. Myocardial metabolism at pre-therapy PET was evaluated according to both standardized uptake value (SUV)- and score-based approaches. The capability of the score-based image assessment to predict the occurrence of cardiac toxicity with respect to SUV measurement was then evaluated. RESULTS: In contrast to the SUV-based approach, the five-point scale method does not linearly stratify the risk of the subsequent development of cardiotoxicity. However, converting the five-points scale to a dichotomic evaluation (low vs. high myocardial metabolism), FDG-PET/CT showed high diagnostic accuracy in the prediction of cardiac toxicity (specificity = 100% and sensitivity = 83.3%). In patients showing high myocardial uptake at baseline, in which the score-based method is not able to definitively exclude the occurrence of cardiac toxicity, myocardial SUV mean quantification is able to further stratify the risk between low and intermediate risk classes. CONCLUSIONS: the score-based approach to FDG-PET/CT images is a feasible method for predicting DXR-induced cardiotoxicity. This method might improve the inter-reader and inter-scanner variability, thus allowing the evaluation of FDG-PET/CT images in a multicentral setting.