Inflammation and acute cardiotoxicity in adult hematological patients treated with CAR-T cells: results from a pilot proof-of-concept study.

AIMS: Chimeric Antigen Receptor-T (CAR-T) cell infusion is a rapidly evolving antitumor therapy; however, cardiovascular (CV) complications, likely associated with cytokine release syndrome (CRS) and systemic inflammation, have been reported to occur. The CARdio-Tox study aimed at elucidating incidence and determinants of cardiotoxicity related to CAR-T cell therapy. METHODS: Patients with blood malignancies candidate to CAR-T cells were prospectively evaluated by echocardiography at baseline and 7 and 30 days after infusion. The study endpoints were i) incidence of cancer therapy-related cardiac dysfunction (CTRCD), CTRCD were also balanced for any grade CRS, but CTRCD occurred of Cardiology Guidelines on Cardio-Oncology (decrements of left ventricular ejection fraction (LVEF) or global longitudinal strain (GLS) and/or elevations of cardiac biomarkers (high sensitivity troponin I, natriuretic peptides) and ii), correlations of echocardiographic metrics with inflammatory biomarkers. RESULTS: Incidence of CTRCD was high at 7 days (59,3%), particularly in subjects with CRS. The integrated definition of CTRCD allowed the identification of the majority of cases (50%). Moreover, early LVEF and GLS decrements were inversely correlated with fibrinogen and interleukin-2 receptor levels (p always ≤ 0.01). CONCLUSIONS: There is a high incidence of early CTRCD in patients treated with CAR-T cells, and a link between CTRCD and inflammation can be demonstrated. Dedicated patient monitoring protocols are advised.

Relation between high-sensitivity troponin I serum levels and myocardial ischemia in patients with suspected chronic coronary syndrome: The reset-MI study.

BACKGROUND: Previous studies showed that exercise may increase cardiac troponin serum levels; whether the occurrence of myocardial ischemia influences the changes of exercise-induced troponin raise, however, remains debatable. METHODS: We prospectively enrolled consecutive patients undergoing for the first time an elective stress myocardial perfusion scintigraphy (MPS) because of clinical suspicion of obstructive coronary artery disease (CAD). Patients were divided into 3 groups based on the evidence and degree of stress-induced myocardial ischemia at MPS: 1) group 1, no myocardial ischemia (≤4 %); 2) group 2, mild myocardial ischemia (5-10 %); 3) group 3, moderate-to-severe myocardial ischemia (≥10 %). High-sensitivity cardiac troponin I (cTnI) was measured immediately before (T0) and 1 hour (T1) and 4 h (T2) after the stress test. RESULTS: One hundred-seven patients (71 males; age 65.6 ± 9.4 years) were enrolled in the study. Serum hs-cTnI concentrations (logarithmic values) significantly increased after MPS, compared to baseline, in the whole population, from 1.47±1.26 ng/L at T0, to 1.68±1.12 ng/L at T1 (p<0.001) and 2.15±1.02 ng/L at T2 (p<0.001 vs. both T0 and T1). The increase in hs-cTnI did not significantly differ between the 3 groups (p = 0.44). The heart rate achieved during the test was the strongest determinant of cTnI increase (p < 0.001) after the stress test. CONCLUSIONS: In patients with suspected CAD, stress MPS induces an increase of cTnI that is independent of the induction and extension/severity of myocardial ischemia and is mainly related to myocardial work, as indicated by the heart rate achieved during the test.

Chimeric antigen receptor-T cell therapy-related cardiotoxicity in adults and children cancer patients: A clinical appraisal.

Chimeric antigen receptor-T (CAR-T) cells therapies represent an innovative immunological treatment for patients suffering from advanced and refractory onco-hematological malignancies. The infusion of engineered T-cells, exposing chimeric receptors on the cell surface, leads to an immune response against the tumor cells. However, data from clinical trials and observational studies showed the occurrence of a constellation of adverse events related to CAR-T cells infusion, ranging from mild effects to life-threatening organ-specific complications. In particular, CAR-T cell-related cardiovascular toxicities represent an emerging group of adverse events observed in these patients, correlated with increased morbidity and mortality. Mechanisms involved are still under investigation, although the aberrant inflammatory activation observed in cytokine release syndrome (CRS) seems to play a pivotal role. The most frequently reported cardiac events, observed both in adults and in the pediatric population, are represented by hypotension, arrhythmias and left ventricular systolic dysfunction, sometimes associated with overt heart failure. Therefore, there is an increasing need to understand the pathophysiological basis of cardiotoxicity and risk factors related to its development, in order to identify most vulnerable patients requiring a close cardiological monitoring and long-term follow-up. This review aims at highlighting CAR-T cell-related cardiovascular complications and clarifying the pathogenetic mechanisms coming at play. Moreover, we will shed light on surveillance strategies and cardiotoxicity management protocols, as well as on future research perspectives in this expanding field.

Troponin Testing in Adult Patients Presenting to the Emergency Department for Paroxysmal Supraventricular Tachycardia: A Review.

International guidelines define paroxysmal supraventricular tachycardia (PSVT) as all supraventricular tachyarrhythmias other than atrial flutter and atrial fibrillation. Associate symptoms, such as chest pain and dyspnea, and possible ECG changes during arrhythmia, such as ST depression, may suggest to the emergency physician a diagnosis of acute coronary syndrome (ACS), and thus lead to a request for troponin (cTn) level. Here, we provide a comprehensive synthesis covering published literature on the diagnostic and prognostic role of cTn in patients admitted to Emergency Department (ED) for an episode of PSVT. We performed an extensive evaluation article written in English and available in PubMed and Web of Science by using the following Medical Subject Headings (MeSH): "paroxysmal supraventricular tachycardia" AND/OR "supraventricular tachycardia" AND "Troponin" AND "Emergency Department" AND/OR "coronary artery disease". We also performed hand searching of reference lists of selected articles. A total of 17 articles were finally included. There was great variability about study design, setting and criteria for the definition of PSVT and/or type of troponin. Troponin levels were measured frequently (up to 79%) in patients admitted to ED for PSVT. About 30% of them showed cTn elevation. This elevation appears not to be associated with the presence of CAD. However, c-Tn measurements could retain utility in stratifying those with poorer prognosis among PSVT patients with an elevated cardiovascular risk profile.

Coronary microvascular dysfunction and findings of heart failure with preserved ejection fraction in patients with microvascular angina.

BACKGROUND: Coronary microvascular dysfunction (CMD) may cause symptoms of myocardial ischemia (microvascular angina [MVA]), but recent studies suggested that it might also contribute to the syndrome of heart failure with preserved ejection fraction (HFpEF). In this study we assessed the relation of CMD with findings of HFpEF in MVA patients. METHODS: We enrolled 36 consecutive patients with MVA, in whom we assessed: 1) coronary blood flow (CBF) response to adenosine and cold pressor test (CPT) by color-Doppler echocardiography of the left anterior descending coronary artery; 2) complete echocardiographic examination; 3) N-terminal-pro-B-natriuretic peptide (NT-proBNP); 4) grade of dyspnea by the modified Medical Research Scale. RESULTS: Among patients, 15 had definite HFpEF findings (group 1), 12 had equivocal HFpEF findings (group 2) and 9 had no evidence of HFpEF findings (group 3). Group 1 patients were older, had more cardiovascular risk factors and higher NT-proBNP levels (P=0.018), and showed a higher prevalence of diastolic dysfunction. Left ventricle dimensions and systolic function, however, did not differ among groups. Dyspnea was also not significantly different among groups (P=0.19). CBF to adenosine was 1.85±0.47, 1.78±0.40 1.49±0.32 in group 1, 2 and 3, respectively (P=0.13). Similarly, CBF response to CPT was 1.57±0.4, 1.49±0.2 and 1.45±0.3 in the 3 groups, respectively (P=0.74). Both CBF response to adenosine and CPT showed no relation with the severity of dyspnea symptoms. CONCLUSIONS: Our data suggest that in patients with MVA there is no relation between the grade of impairment of coronary microvascular dilatation and findings of HFpEF.

Cardiovascular involvement in patients affected by multiple myeloma: a comprehensive review of recent advances.

INTRODUCTION: Multiple Myeloma (MM) is hematological neoplasia originating from plasma cells, which accounts for almost 1% of all oncologic malignancies. The median age of patients at diagnosis is about 65 years old and over. In this age group, cardiovascular (CV) diseases often co-exist, increasing the risk of adverse events related to MM treatment. A comprehensive search on the main educational platforms was performed and high-quality original articles and reviews were included. AREAS COVERED: Patients affected by MM are at risk for heart failure, uncontrolled systemic hypertension, accelerated ischemic heart disease, arterial/venous thromboembolism, and arrhythmias. These complications may be due to the effects of chemotherapy on the CV system, which may play on preexisting risk factors, and amyloid deposition at cardiac level. EXPERT OPINION: This review provides an updated overview of the spectrum of CV diseases that may affect MM patients, highlighting possible treatment strategies according to the latest recommendations. Cooperation between onco-hematologist and cardiologist is crucial in managing this population, in particular for adequate risk assessment, early diagnosis of CV complications, and proper treatment.

Cardiac Surveillance for Early Detection of Late Subclinical Cardiac Dysfunction in Childhood Cancer Survivors After Anthracycline Therapy.

BACKGROUND: In childhood cancer survivors (CCSs) anthracycline-related cardiotoxicity is an important cause of morbidity and late mortality, but the optimal modality of cardiac surveillance still remains to be defined. The aim of this study was to assess whether non-invasive echocardiography-based functional cardiac measures can detect early subclinical myocardial changes in long-term pediatric cancer survivors who received anthracycline therapy. METHODS: Twenty anthracycline-treated long-term CCSs and 20 age, sex, and body surface area matched healthy controls were enrolled in this study. Among cancer survivors, mean age at diagnosis was 6.5 ± 4.4 years, and the mean cumulative anthracycline dose was 234.5 ± 87.4 mg/m2. All subjects underwent a comprehensive functional echocardiographic protocol study including two-dimensional echocardiography (2D Echo), tissue Doppler imaging (TDI), speckle tracking (STE) and three-dimensional echocardiography (3D Echo). Patients were studied at a mean follow-up time of 6.5 ± 2.8 years from the end of therapy. RESULTS: No significant differences in two-dimensional left ventricle ejection fraction (LVEF), diastolic parameters and speckle tracking (STE)-derived myocardial strain were observed between patients treated with anthracyclines and controls. Myocardial performance index was significantly prolonged (p = 0.005) and three-dimensional LVEF was significantly reduced (p = 0.002) in CCSs compared to controls, even though most values were within the normal range. There were no significant correlations between 2D, STE, and 3D echocardiographic parameters and age at diagnosis or duration of follow-up. No significant differences in echocardiographic parameters were found when stratifying cancer patients according to established risk factors for anthracycline cardiomyopathy. CONCLUSIONS: This study found significantly reduced three-dimensional LVEF in CCSs compared with controls, despite no significant differences in two-dimensional LVEF and longitudinal strain values. These findings suggest that long-term CCSs who had received anthracycline therapy may be found to have subclinical features of myocardial dysfunction. However, further studies are needed to demonstrate the validity of new imaging techniques, including STE and 3D Echo, to identify patients at risk for cardiomyopathy in the long-term follow-up of CCSs.

Cardiac Rehabilitation and Endothelial Function.

Endothelial dysfunction is an early abnormality in the process of atherosclerosis and cardiovascular disease and has been associated with worse clinical outcome. Cardiac rehabilitation (CR) has been reported to be helpful to reduce cardiovascular events in various types of cardiac disease, but the mechanisms of its beneficial effects remain only partially known. In this article, we review the studies that assessed the effect of CR on endothelial function in patients with various cardiac conditions. Available data show that CR significantly improves impaired endothelial function in these patients, which may contribute to the beneficial effects of CR on clinical outcome.

Endothelial dysfunction and cardiovascular outcome in asymptomatic patients with type 2 diabetes: A pilot study.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is associated with an increased risk of cardiovascular events, but risk stratification of asymptomatic T2DM patients remains a challenging issue. We conducted a pilot study to assess whether endothelial dysfunction might help identify, among asymptomatic T2DM patients, those at increased risk of cardiovascular events. METHODS: We studied 61 consecutive T2DM patients with no evidence of cardiovascular disease and no insulin therapy. Endothelial function was assessed by flow-mediated dilation (FMD) of the right brachial artery. The primary endpoint was a combination of major cardiovascular events (MACE: cardiovascular death, acute coronary events, coronary interventions, and acute cerebrovascular accidents). FMD was repeated at follow-up in 48 patients (79%). RESULTS: A total of 10 MACE (16.4%) occurred during a mean follow-up of 48 months, including three acute myocardial infarctions, five coronary revascularizations for stable angina, and two acute ischaemic strokes. FMD at enrolment was lower in patients with compared with patients without MACE (3.78 ± 0.97% vs 4.70 ± 1.33%, respectively; P = .04). No other clinical or laboratory variables (age, diabetes duration, glycated haemoglobin, cardiovascular risk factors, drug therapy, and nitrate-mediated dilation) were associated with MACE. FMD at follow-up was also lower in patients with (n = 10) compared with those without (n = 38) MACE (3.66 ± 1.29 vs 4.85 ± 1.92; P = .006). CONCLUSIONS: Our data suggest that assessment of FMD might be helpful to identify patients at increased risk of MACE among individuals with asymptomatic T2DM; accordingly, a large study is warranted to adequately define the clinical utility of FMD assessment in the management of T2DM patients.

Coronary microvascular dysfunction in patients with acute coronary syndrome and no obstructive coronary artery disease.

BACKGROUND: Between 10 and 15% of patients admitted for non-ST-segment elevation acute coronary syndrome (NSTE-ACS) show no obstructive coronary artery disease (NO-CAD) at angiography. Coronary microvascular spasm is a possible mechanism of the syndrome, but there are scarce data about coronary microvascular function in these patients. OBJECTIVES: To assess coronary microvascular function in patients with NSTE-ACS and NO-CAD. METHODS: We studied 30 patients (67 ± 10 years, 19 female) with NSTE-ACS and NO-CAD. Specific causes of NSTE-ACS presentation (e.g., variant angina, takotsubo disease, tachyarrhythmias, etc.) were excluded. Coronary blood flow (CBF) velocity response to IV ergonovine (6 µg/kg up to a maximal dose of 400 µg) was evaluated before discharge by transthoracic Doppler echocardiography. CBF response to IV adenosine (140 µg/kg/min) and cold pressor test (CPT) was also assessed after 1 month. Ten age- and sex-matched patients with non-cardiac chest pain served as controls. Vasoactive tests were repeated after 12 months in 10 NSTE-ACS patients. RESULTS: The ergonovine/basal CBF velocity ratio was 0.79 ± 0.09 and 0.99 ± 0.01 in patients and controls, respectively (p < 0.001). The adenosine/basal CBF velocity ratio was 1.46 ± 0.2 and 3.25 ± 1.2 in patients and controls, respectively (p < 0.001), and the CPT/basal CBF velocity ratio was 1.36 ± 0.2 and 2.43 ± 0.3 in the 2 groups, respectively (p < 0.001). In 10 patients assessed after 12 months, CBF velocity responses to ergonovine, adenosine, and CPT were found to be unchanged. CONCLUSIONS: Patients with NSTE-ACS and NO-CAD exhibit a significant coronary dysfunction, which seems to involve both an increased constrictor reactivity, likely mainly involving coronary microcirculation, and a reduced microvascular dilator function, both persisting at 12-month follow-up.

Microvascular Angina　- Long-Term Exercise Stress Test Follow-up.

BACKGROUND: A sizeable proportion of patients with primary stable microvascular angina (MVA; exercise-induced angina, positive exercise stress test [EST], normal coronary arteries) have recurrent symptoms during follow-up. There have been no previous studies, however, on the long-term results of EST and their correlation with symptom outcome.Methods and Results:Follow-up EST was performed in 71 MVA patients at an average of 16.2 years (range, 5-25 years) from the first EST. Angina status was assessed on weekly frequency of angina episodes and nitroglycerin consumption and by whether symptoms had worsened, improved, or remained unchanged over time. At follow-up EST, 41 patients (group 1) had exercise-induced ischemia, whereas 30 patients (group 2) had negative EST. Compared to group 2, group 1 patients more frequently had exercise-induced dyspnea, and had a greater maximum ST-segment depression and a lower coronary blood flow response to adenosine and cold pressor test, but group 2 patients had a more frequent history of rest angina. No differences between the 2 groups were found at follow-up in angina status or change in symptom status during follow-up. CONCLUSIONS: Electrocardiogram results improve significantly in a sizeable proportion of patients with MVA. Changes in EST results, however, were not associated with clinical outcome.

Exercise test predictors of severe coronary artery disease: Role of ST-segment elevation in lead aVR.

BACKGROUND: The role of exercise stress test (EST)-induced ST-segment elevation (STE) in electrocardiographic lead aVR in predicting severe coronary artery disease (CAD) is controversial. HYPOTHESIS: Assessment of lead aVR during EST can be helpful to identify patients with severe CAD. METHODS: We performed maximal EST in 200 patients undergoing coronary angiography for suspect of CAD. Four angiographic findings of severe CAD were considered: (1) left main (LM) disease; (2) LM or equivalent LM (LM/EQLM) disease; (3) LM or proximal left anterior descending (LAD) artery (LM/proxLAD) disease; and (4) LM or 3-vessel (LM/3V) disease. RESULTS: LM, LM/EQLM, LM/proxLAD, and LM/3V disease were shown in 6 (3%), 13 (6.5%), 33 (16.5%), and 27 (13.5%) patients, respectively. EST-induced STE in aVR occurred in 41 patients (20.5%). ST-segment depression (STD) in ≥5 leads was the only predictor of LM stenosis (odds ratio [OR]: 6.18, 95% confidence interval [CI]: 1.19-32.2, P = 0.03) and the most significant variable associated with LM/proxLAD stenosis (OR: 4.73, 95% CI: 2.0-11.2, P = 0.0001); maximal STD ≥3 mm was the most significant variable associated with LM/EQLM (OR: 7.58, 95% CI: 2.31-24.9, P = 0.001) and LM/3V (OR: 3.86, 95% CI: 1.47-10.1, P = 0.006) CAD. EST-induced STE in aVR was associated with LM/proxLAD disease only (OR: 3.23, 95% CI: 1.44-7.24, P = 0.004). At multivariate analysis, STD in ≥5 leads was the only independent predictor of LM/proxLAD disease (OR: 3.99, 95% CI: 1.58-10.1, P = 0.003). CONCLUSIONS: EST-induced STE in lead aVR does not significantly increase the prediction of severe CAD compared with severity and extension of STD as assessed in the other electrocardiographic leads.

Long-term effects of bariatric surgery on peripheral endothelial function and coronary microvascular function.

BACKGROUND: We previously demonstrated that bariatric surgery (BS) leads to a short-term significant improvement of endothelial function and coronary microvascular function. In this study we assessed whether BS maintains its beneficial effect at long-term follow up. DESIGN: We studied 19 morbidly obese patients (age 43±9years, 12 women) without any evidence of cardiovascular disease who underwent BS. Patients were studied before BS, at 3 months and at 4.0±1.5years follow up. METHODS: Peripheral vascular function was assessed by flow-mediated dilation (FMD) and nitrate-mediated dilation (NMD), i.e., brachial artery diameter changes in response to post-ischemic forearm hyperhaemia and to nitroglycerin administration, respectively. Coronary microvascular function was assessed by measuring coronary blood flow (CBF) response to intravenous adenosine and to cold pressor test (CPT) in the left anterior descending coronary artery. RESULTS: Together with improvement of anthropometric and metabolic profile, at long-term follow-up patients showed a significant improvement of FMD (6.43±2.88 vs. 8.21±1.73%, p=0.018), and CBF response to both adenosine (1.73±0.48 vs. 2.58±0.54; p<0.01) and CPT (1.43±0.30 vs. 2.23±0.48; p<0.01), compared to basal values. No differences in vascular end-points were shown at 3-month and 4-year follow-up after BS. CONCLUSIONS: Our data show that, in morbidly obese patients, BS exerts beneficial and long lasting effects on peripheral endothelial function and on coronary microvascular dilator function.

Thrombus in Transit: A Potentially Life-threatening Complication of Cerebral Sinus Thrombosis.

We report the case of a 41-year-old, 7-weeks-pregnant patient, presenting with headache and generalized seizure due to cerebral venous thrombosis complicated by jugular thrombosis and thrombus dislocation into right cardiac cavities. The patient was treated with intravenous heparin, and underwent embolectomy in extracorporeal circulation. This case illustrates the variability of cerebral venous thrombosis progression and a potentially life-threatening condition even during anticoagulant therapy.

Association of coronary microvascular dysfunction with restenosis of left anterior descending coronary artery disease treated by percutaneous intervention.

BACKGROUND: Several patients with successful percutaneous coronary interventions (PCIs) show evidence of coronary microvascular dysfunction (CMVD), which can be responsible for persistent positivity of electrocardiographic exercise stress test (EST). In this study, we assessed whether post-PCI CMVD may predict clinical outcome in patients undergoing successful elective PCI of an isolated stenosis of the left anterior descending (LAD) coronary artery. METHODS: We studied 29 patients (age 64±6, 23 M) with stable coronary artery disease and isolated stenosis (>75%) of the LAD coronary artery who underwent successful PCI with stent implantation. Coronary blood flow (CBF) velocity response to adenosine and to cold-pressor test (CPT) was assessed in the LAD coronary artery by transthoracic Doppler echocardiography 24h and 3months after PCI. The primary end-point was a combination of death, admission for acute coronary syndromes (ACS) or target vessel revascularization (TVR). RESULTS: No death or ACS occurred during 36months of follow-up, but TVR was performed in 5 patients (17.2%). CBF response to CPT at 3months after PCI was 1.31±0.2 vs. 1.71±0.4 in patients with or without TVR, respectively (p=0.03), whereas CBF response to adenosine at 3months in these two groups was 1.70±0.3 vs. 2.05±0.4 (p=0.059). CONCLUSIONS: Our data suggest that, in patients with successful PCI of LAD coronary artery stenosis, lower CBF response to the endothelium-dependent vasodilator stimulus CPT is associated with long-term recurrence of restenosis.