Cardiac Ischemic Events Research Articles

Impaired high-density lipoprotein-associated cholesterol efflux capacity predicts coronary rapid plaque progression

Abstract Background Rapid progression of coronary atherosclerotic plaques is recognized as a surrogate endpoint of cardiac ischemic events. Low high-density lipoprotein (HDL)-associated cholesterol efflux capacity (CEC) has been associated with atherosclerotic cardiovascular disease independent of HDL cholesterol (HDL-C) level. In this study, we aim to investigate the predictive role of CEC in rapid plaque progression (RPP). Methods We consecutively enrolled patients with stable angina from January 2017 to August 2019 in our hospital who underwent elective coronary angiography with at least one untreated coronary lesion. A follow-up angiography was performed at around 12 months. Afterwards, these patients were followed-up for every 3 months to June 2021. The primary endpoint was RPP during the 12-month angiography follow-up. The second endpoint was defined as a composite endpoint of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, or unplanned coronary revascularization. Fluorescence-labeled cholesterol and J774 macrophages were used to measure CEC of ApoB-depleted serum samples. Results A total of 430 patients with 586 coronary lesions were included in the final analysis. During a mean follow-up of 12.7 ± 2.0 months, 120 lesions (20.5%) in 80 patients (18.6%) exhibited RPP. CEC, rather than HDL-C, was inversely associated with the extent of plaque progression (net luminal loss from the lowest to highest CEC quartile: 0.22±0.42 vs. 0.20±0.41 vs. 0.13±0.36 vs. 0.11±0.34 mm, P = 0.035). In multivariate analysis, baseline CEC was inversely associated with RPP independent of conventional risk and protective factors including HDL-C or apolipoprotein A-I. Subgroup analysis demonstrated that the association between CEC and RPP was more prominent in patients with high (≥4.02 mmol/L) than low (<4.02 mmol/L) total cholesterol. Finally, although patients with RPP had higher risk of the composite endpoint than those without RPP (P=0.012), no significant difference was observed between patients in different quartiles of CEC (P=0.720). Conclusions HDL-associated CEC is inversely associated with RPP in patients with coronary artery disease. HDL function assessment behaves as a better diagnostic biomarker than HDL-C for predicting RPP.

Cardiovascular risks of PD1 inhibitor therapy in cancer: impact of prior ischemic events on heart failure - a retrospective cohort study

Abstract Introduction Immune checkpoint inhibitors (ICIs) have transformed cancer therapy, but concerns remain about their cardiac risks. Limited recent basic evidence suggests a possible link between ICIs that target PD1 and adverse cardiac events such as heart failure. Purpose This study explores the connection between PD1 inhibitor therapy and incident heart failure in cancer patients. Methods In our retrospective study at a tertiary medical center, 1,671 cancer patients receiving PD1 inhibitors were analyzed. Individuals with a history of heart failure, who developed myocarditis on PD-1, or had missing data were excluded. Data from pharmacy records and the Research Patient Data Registry provided clinical and ICI-related details. Cases were defined as patients who developed incident heart failure after ICI started. Controls were patients who did not develop incident heart failure after ICI start. Sensitivity analyses, including propensity score matching and comparison with non-ICI-treated cancer patients, ensured result robustness. Multivariate logistic regressions were performed. Results Among 1,671 ICI treated patients, 109 (6.5%) developed heart failure without evidence of myocarditis over a median follow-up of 332.0 days. In both the full cohort and the 3:1 matched cohort (n=380), multivariate logistic regression showed increased odds of incident heart failure in patients with prior ischemic cardiac events: 2.34 (95%CI 1.26-4.16, p=0.005) and 2.11 (95%CI 1.05-4.2, p=0.033) respectively. Among the non-ICI treated cancer patients, multivariate logistic regression found no association between prior ischemic events and incident heart failure (1.23, 95%CI 0.53-2.63, p=0.6), but hypertension showed an association (1.74, 95%CI 1.07-2.87, p=0.027). Conclusion This study emphasizes vigilance for cardiovascular complications in PD1 inhibitor-treated cancer patients. The incidence of heart failure was 6.5% over a follow-up period of less than 1 year. Prior ischemic events correlate with increased heart failure risk, suggesting a need for nuanced patient management. Understanding ICIs' cardiovascular safety is crucial for risk assessment, treatment optimization, and patient well-being.

Advancing Human iPSC-Derived Cardiomyocyte Hypoxia Resistance for Cardiac Regenerative Therapies through a Systematic Assessment of In Vitro Conditioning.

Acute myocardial infarction (MI) is a sudden, severe cardiac ischemic event that results in the death of up to one billion cardiomyocytes (CMs) and subsequent decrease in cardiac function. Engineered cardiac tissues (ECTs) are a promising approach to deliver the necessary mass of CMs to remuscularize the heart. However, the hypoxic environment of the heart post-MI presents a critical challenge for CM engraftment. Here, we present a high-throughput, systematic study targeting several physiological features of human induced pluripotent stem cell-derived CMs (hiPSC-CMs), including metabolism, Wnt signaling, substrate, heat shock, apoptosis, and mitochondrial stabilization, to assess their efficacy in promoting ischemia resistance in hiPSC-CMs. The results of 2D experiments identify hypoxia preconditioning (HPC) and metabolic conditioning as having a significant influence on hiPSC-CM function in normoxia and hypoxia. Within 3D engineered cardiac tissues (ECTs), metabolic conditioning with maturation media (MM), featuring high fatty acid and calcium concentration, results in a 1.5-fold increase in active stress generation as compared to RPMI/B27 control ECTs in normoxic conditions. Yet, this functional improvement is lost after hypoxia treatment. Interestingly, HPC can partially rescue the function of MM-treated ECTs after hypoxia. Our systematic and iterative approach provides a strong foundation for assessing and leveraging in vitro culture conditions to enhance the hypoxia resistance, and thus the successful clinical translation, of hiPSC-CMs in cardiac regenerative therapies.

Variation of retinal and choroidal microvascularization after an exercise stress test in patients with effort angina.

To describe retinal and choroidal vascular changes following an exercise stress test (ET) in patients with effort angina and to determine whether optical coherence tomography angiography (OCT-A) could play a role in the prediction of ischemic cardiac events. Prospective comparative study including patients with effort angina. All patients underwent OCT-A before and after an ET was performed. Blood flow, intercapillary spaces, and vessel density were analyzed in the superficial capillary plexus (SCP) and the deep capillary plexus (DCP). Vessel density in the choriocapillaris and the parameters of the central avascular zone (CAZ) were also analyzed. Of the 38 eyes included in the study, a decrease in blood flow was found in 39.5% in the large SCP vessels, in 50% in the capillaris of the SCP, and in 81.6% in the DCP. An increase in intercapillary spaces was observed in the SCP in 68.4% of eyes and in the DCP in 55.3% of eyes. A statistically significant decrease in the DCP density was observed after an ET (p = 0.03). There were no significant modifications in the CAZ parameters, the SCP density, nor the choriocapillaris density. Patients with a positive ET had a decreased DCP density in 83.3%. Among patients with an increased DCP density, 92.85% had a negatif ET. This pilot study suggests that DCP density significantly decreases after an ET. The DCP appears to be most affected in patients with effort angina. A larger trial is needed to further investigate these hypotheses.

The characteristics of CALR mutations in myeloproliferative neoplasms: a clinical experience from a tertiary care center in Qatar and a literature review

ABSTRACT Background Myeloproliferative neoplasms (MPNs) are hematological disorders characterized by abnormal production of myeloid cells due to genetic mutations. Since 2013, researchers have identified somatic mutations in the Calreticulin (CALR) gene, primarily insertions or deletions, in two Philadelphia chromosome-negative MPNs; essential thrombocytosis (ET) and primary myelofibrosis (PMF), and occasionally in chronic myelomonocytic leukemia (CMML). This study aims to identify the various types of CALR mutations and their impact on CALR-positive MPN patients’ clinical manifestations and outcomes. Methods A single-center retrospective study was conducted. The data was collected from pre-existing records. The study was carried out on Philadelphia-negative MPN patients who were being followed up on at the NCCCR (National Center for Cancer Care and Research) to assess the clinical manifestation and outcome of disease treatment. All patients included, were followed in our center between January 1, 2008, and November 20, 2021. Results A total of 50 patients with CALR-positive MPN were reviewed with a median follow-up of three years (1–11). This cohort included 31 (62%) patients with ET, 10 (20%) patients with PMF, and 9 (18%) patients with prefibrotic myelofibrosis (pre-MF). The study involved 38 (76%) male and 12 (24%) female patients. There were 16 (32%) patients diagnosed before the age of 40, 24 (48%) patients diagnosed between the ages of 40 and 60; and 10 (20%) patients diagnosed after the age of 60. Molecular analysis showed 24 (48%) patients with CALR type 1, 21 (42%) patients with CALR type 2, and 5 (10%) patients with none Type 1, none Type 2 CALR mutations. Two patients have double mutations; 1(2%) with none Type 1, none Type 2 CALR and JAK2 mutations, and 1(2%) with CALR type 1 and MPL mutations. The thrombotic events were 3 (6%) venous thromboembolisms, 3 (6%) abdominal veins thromboses, 2 (4%) strokes, and 4 (8%) ischemic cardiac events. Only 4 (8%) patients progressed to Myelofibrosis and were carrying CALR 1 mutations, and 1 (2%) patient progressed to AML with CALR 2 mutation. Conclusion The data shows a significant rise in CALR-positive MPN diagnoses in younger people, emphasizing the need for a better assessment tool to improve disease management and reduce complications.

Feasibility and Safety of Bridging Antiplatelet Therapy with Cangrelor in Neuro-Oncology: A Preliminary Experience.

Antiplatelet therapy is mandatory for prevention of thrombotic events in patients with a recent history of acute coronary syndromes and/or percutaneous coronary interventions. However, if an urgent surgery is required during antiplatelet therapy, a compromise between the ischemic/thrombotic and hemorrhagic risk has to be reached. Different bridging schemes are reported in the literature, but there is no clear consensus on the optimal treatment strategy in terms of efficacy and safety. Although some indications about the perioperative management of antiplatelet therapy regarding specific surgical specializations are available, balancing the thrombotic and hemorrhagic risk on an individual basis, no evidence referring to neurosurgical or neuro-oncologic procedures is reported. Herein, we present our preliminary experience in the perioperative management of a patient who underwent a neurosurgical procedure for the resection of a primary malignant brain tumor using an intravenous P2Y12 inhibitor (cangrelor) as bridging therapy after a recent acute myocardial infarction treated with primary percutaneous coronary intervention and stenting. The oral P2Y12 inhibitor (clopidogrel) was withdrawn 5 days prior to the surgical procedure and continuous infusion of cangrelor was started 3 days before the surgery at a dose of 0.75 μg/kg/min. Cangrelor was discontinued 2 hours before surgery and resumed 72 hours after tumor resection for further 60 hours. Neither cangrelor-related bleeding nor cardiac ischemic events were observed in the perioperative period and the following 90 days, supporting data regarding the feasibility and safety of this bridging scheme. Further studies are needed to confirm our promising results.

Identification of a mechanism promoting mitochondrial sterol accumulation during myocardial ischemia-reperfusion: role of TSPO and STAR.

Hypercholesterolemia is a major risk factor for coronary artery diseases and cardiac ischemic events. Cholesterol per se could also have negative effects on the myocardium, independently from hypercholesterolemia. Previously, we reported that myocardial ischemia-reperfusion induces a deleterious build-up of mitochondrial cholesterol and oxysterols, which is potentiated by hypercholesterolemia and prevented by translocator protein (TSPO) ligands. Here, we studied the mechanism by which sterols accumulate in cardiac mitochondria and promote mitochondrial dysfunction. We performed myocardial ischemia-reperfusion in rats to evaluate mitochondrial function, TSPO, and steroidogenic acute regulatory protein (STAR) levels and the related mitochondrial concentrations of sterols. Rats were treated with the cholesterol synthesis inhibitor pravastatin or the TSPO ligand 4'-chlorodiazepam. We used Tspo deleted rats, which were phenotypically characterized. Inhibition of cholesterol synthesis reduced mitochondrial sterol accumulation and protected mitochondria during myocardial ischemia-reperfusion. We found that cardiac mitochondrial sterol accumulation is the consequence of enhanced influx of cholesterol and not of the inhibition of its mitochondrial metabolism during ischemia-reperfusion. Mitochondrial cholesterol accumulation at reperfusion was related to an increase in mitochondrial STAR but not to changes in TSPO levels. 4'-Chlorodiazepam inhibited this mechanism and prevented mitochondrial sterol accumulation and mitochondrial ischemia-reperfusion injury, underlying the close cooperation between STAR and TSPO. Conversely, Tspo deletion, which did not alter cardiac phenotype, abolished the effects of 4'-chlorodiazepam. This study reveals a novel mitochondrial interaction between TSPO and STAR to promote cholesterol and deleterious sterol mitochondrial accumulation during myocardial ischemia-reperfusion. This interaction regulates mitochondrial homeostasis and plays a key role during mitochondrial injury.

O36: Patient acceptability and adherence to the COMPASS trial drug recommendations following symptomatic carotid endarterectomy (CEA)

Abstract Introduction The COMPASS trial demonstrated that in patients with atherosclerotic diseases, low-dose rivaroxaban and aspirin provides greater protection against subsequent cardiovascular events than antiplatelet monotherapy (MAPT) alone. Medication adherence is necessary to maximise this benefit and is dependent on patient views. We have assessed this in patients following CEA. Methods Following CEA, the views of 63 patients on the COMPASS drug regime were compared with 54 on MAPT. Views on medications was assessed using the Beliefs about Medicine Questionnaire (BMQ) and drug adherence using the Sidorkiewicz scoring system. Side effects and the incidence of new cardiovascular events were also assessed. Results Both groups had similar age (mean 70.6+/-8.7), gender (M:F 2:1), and deprivation indices. Preoperative co-morbidities were similar between groups, as were intervention indications (TIA or stroke). There was no difference (p<0.05) between the COMPASS drug regime and MAPT in BMQ for “Necessity” (19.6 v 19.1), “Concerns” (11.8v 12.0) or the “Necessity–Concerns differential”(+7.8v+7.1). Drug adherence was similar with the median showing a “High drug adherence”. The incidence of bleeding and drug reaction complications was similar. Numbers of new stroke, ischaemic cardiac events, and peripheral vascular disease diagnoses was similar, as was the combined overall major adverse cardiovascular events (MACE). Conclusions Following CEA, patients’ views on medications and their drug adherence are similar in those on the COMPASS drug regime as on MAPT. We have not identified any patient-related barriers to the use of the COMPASS drug regimen to further reduce cardiovascular events.

Global IL4Rα blockade exacerbates heart failure after an ischemic event in mice and humans.

Ischemic heart failure continues to be a highly prevalent disease among westernized countries and there is great interest in understanding the mechanisms preventing or exacerbating disease progression. The literature suggests an important role for the activation of interleukin-13 or interleukin-4 signaling in improving ischemic heart failure outcomes after myocardial infarction in mice. Dupilumab, a neutralizing antibody that inhibits the shared IL13/IL4 receptor subunit IL4Rα, is widely used for conditions such as ectopic dermatitis in humans. If global depletion of IL4Rα influences ischemic heart failure, either in mice or in humans taking dupilumab, is unknown. Here, we investigated the pathophysiological effects of global IL4Rα genetic deletion in adult mice after surgically induced myocardial infarction (MI). We also determined heart failure risk in patients with ischemic heart disease and concomitant usage of dupilumab using the collaborative patient data network TriNetX. Global deletion of IL4Rα results in exacerbated cardiac dysfunction associated with reduced capillary size after myocardial infarction in mice. In agreement with our findings in mice, dupilumab treatment significantly increased the risk of heart failure development in patients with preexisting diagnosis of ischemic heart disease. Our results indicate that systemic IL4Rα signaling is protective against heart failure development in adult mice and human patients specifically following an ischemic event. Thus, the compelling evidence presented hereby advocates for the development of a randomized clinical trial specifically investigating heart failure development after myocardial ischemia in patients taking dupilumab for another underlying condition.NEW & NOTEWORTHY A body of literature suggests a protective role for IL4Rα signaling postmyocardial infarction in mice. Here, our observational study demonstrates that humans taking the IL4Rα neutralizing antibody, dupilumab, have increased incidence of heart failure following an ischemic event. Similarly, global IL4Rα deletion in mice exacerbates heart failure postinfarct. To our knowledge, this is the first study reporting an adverse association in humans of dupilumab use with heart failure following a cardiac ischemic event.

Unique quinoline orientations shape the modified aptamer to sclerostin for enhanced binding affinity and bone anabolic potential

Osteogenesis imperfecta is a rare genetic disease characterized by bone fragility and bone formation. Sclerostin could negatively regulate bone formation by antagonizing Wnt signal pathway, whereas impose severe cardiac ischemic events in clinic. Our team has screened an aptamer, which could promote bone anabolic potential without cardiovascular risk. However, the affinity of the aptamer is lower and needs to be improved. In the study, hydrophobic quinoline molecule with unique orientations (7 subtypes) were incorporated into key sites of a bone anabolic aptamer against sclerostin to form a modified aptamer library. Among all the quinoline modifications, 5-quinoline modification could shape the molecular recognition of modified aptamers to sclerostin to facilitate enhancing its binding to sclerostin towards the highest affinity by interacting with newly participated binding sites in sclerostin. Further, 5-quinoline modification could facilitate the modified aptamer attenuating the suppressed effect of the transfected sclerostin on both Wnt signaling and bone formation marker expression levels in vitro, promoting bone anabolism in osteogenesis imperfecta mice (Col1a2+/G610C). The proposed quinoline-oriented modification strategy could shape the molecular recognition of modified aptamers to proteins to facilitate enhancing its binding affinity and therapeutic potency.

Pancoronary plaque characteristics in STEMI patients with rapid plaque progression: An optical coherence tomography study

BackgroundNon-culprit plaque progression is associated with recurrent cardiac ischemic events and worse clinical outcomes. Given that atherosclerosis is a systemic disease, the pancoronary characteristics of patients with rapid plaque progression are unknown. This study aims to identify pancoronary plaque features in patients with ST-segment elevation myocardial infarction (STEMI) with and without rapid plaque progression, focused on the patient level. Methods and resultsFrom January 2017 to July 2019, 291 patients underwent 3-vessel optical coherence tomography imaging at the time of the primary procedure and a follow-up angiography interval of 12 months. The final analysis included 237 patients. Overall, 308 non-culprit lesions were found in 78 STEMI patients with rapid plaque progression, and 465 non-culprit plaques were found in 159 STEMI patients without rapid plaque progression. These patients had a higher pancoronary vulnerability (CLIMA-defined high-risk plaque: 47.4% vs. 33.3%; non-culprit plaque rupture: 25.6% vs. 14.5%) and a significantly higher prevalence of other vulnerable plaque characteristics (i.e., lipid-rich plaque, cholesterol crystal, microchannels, calcification, spotty calcification, and thrombus) at baseline versus those without rapid plaque progression. Lesions with rapid progression were highly distributed at the LAD, tending to be near the bifurcation. In multivariate analysis, age ≥ 65 years was an independent predictor of subsequent rapid lesion progression at the patient level, whereas microchannel, spotty calcification, and cholesterol crystal were independent predictors for STEMI patients ≥65 years old. ConclusionsSTEMI patients with subsequent rapid plaque progression had higher pancoronary vulnerability and commonly presented vulnerable plaque morphology. Aging was the only predictor of subsequent rapid plaque progression.

Case report: A case of an anomalous right coronary artery arising from the left coronary cusp.

Abstract
 An anomalous origin of the right coronary artery is usually asymptomatic. It is mostly found incidentally on an invasive diagnostic angiogram. It does lead to an increased risk of sudden cardiac death, especially in younger patients. We present a case of a 41-year-old who had presented to the hospital with complaints of chest pain. The patient was evaluated by cardiology who performed an angiography that identified an anomalous origin of the right coronary artery arising from the left coronary cusp but no evidence of coronary artery disease. Once identified, these anomalous vessels should be corrected surgically, as these conditions increase the risk of sudden cardiac death arrhythmia and ischemic events.
 
 INTRODUCTION
 Anomalous aortic origin of the right coronary artery (AAORCA) is an uncommon congenital malformation with varying clinical presentations ranging from asymptomatic to sudden cardiac death (SCD). Those with symptoms or high-risk lesions are usually managed by unroofing or reimplantation, coronary artery bypass graft (CABG), AAORCA treated with right internal memory artery graft with proximal RCA ligation.
 
 CASE DESCRIPTION
 A 41-year-old female patient with obesity and hypertension presented with a 1-year history of intermittent exertional substernal pressure radiating to left shoulder and back. The pain, which lasted about 10 minutes per episode, had been more frequent and intense over the past week.Upon initial evaluation, she was hypertensive at 150/90 mmHg and heart rate 60 bpm. Blood work was unremarkable, including negative serial troponin levels. Electrocardiography showed sinus bradycardia without ischaemic changes. Anomalous origin of RCA was incidentally discovered from computed tomography (CT) of the chest. Coronary angiography and ascending aortography were then performed, which revealed a patent RCA originating from the left coronary cusp (Fig. 1A). CT heart angiography with reconstruction revealed the RCA ostium in the left coronary cusp with a malignant course between the aorta and pulmonary artery and without an obvious intramural segment
 Discussion:
 
 An anomalous origin of the right coronary artery (RCA) is a rare congenital anomaly that was first described in 1948 by White and Edwards. After carrying out angiography in 126,595 patients, Yamanaka and Hobbs reported the incidence of anomalous origin of the right and left coronary arteries as 136 (0.107%) and 22 (0.017%), respectively. The prevalence of an anomalous origin of RCA (ARCA) arising from the left coronary cusp with an inter-arterial course varies between 0.026% and 0.25%. An ARCA is more common than the anomalous origin of the left coronary artery (ALCA), but the latter is shown to be responsible for up to 85% of sudden cardiac deaths (SCD) related to the anomalous origins of arteries. Most coronary anomalies are detected incidentally on diagnostic angiography and are clinically insignificant; some, however, have been associated with an increased risk of SCD. It is second only to hypertrophic cardiomyopathy as a leading cause of SCD in young athletes. Mechanical compression of the RCA by the great vessels, which dilate and compress the RCA during periods of increased stroke volume, is the usual explanation for coronary ischemia. Patients usually have no ischemic changes on an electrocardiogram (ECG) at rest; however, multi-detector computed tomography (MDCT) is being used to evaluate the course of anomalous vessels outlying their relative positions to the aorta and the pulmonary artery. It also gives additional information regarding any stenotic lesion in these anomalous vessels. Echocardiography (Echo), magnetic resonance angiography (MRA), MCDT, and cardiac catheterization are all complementary diagnostic tools for evaluating anomalous coronary arteries [10]. While it is agreed that surgical correction is the standard of care for ALCA, when found, the management for right ARCA is more complicated. Treatment options for these patients include observation with medical therapy, percutaneous intervention (stenting), or surgery. Early diagnosis of coronary artery anomalies based on the patients’ symptoms can help decrease the incidence of sudden cardiac deaths, fatal arrhythmias, and ischemic events in the high-risk population.
 
 Conclusions 
 
 Coronary anomalies should be suspected in symptomatic young patients with a normal cardiac workup. Non-invasive imaging modalities such as a CTCA can help establish the diagnosis

Generation of Self-Induced Myocardial Ischemia in Large-Sized Cardiac Spheroids without Alteration of Environmental Conditions Recreates Fibrotic Remodeling and Tissue Stiffening Revealed by Constriction Assays.

A combination of human-induced pluripotent stem cells (hiPSCs) and 3D microtissue culture techniques allows the generation of models that recapitulate the cardiac microenvironment for preclinical research of new treatments. In particular, spheroids represent the simplest approach to culture cells in 3D and generate gradients of cellular access to the media, mimicking the effects of an ischemic event. However, previous models required incubation under low oxygen conditions or deprived nutrient media to recreate ischemia. Here, we describe the generation of large spheroids (i.e., larger than 500 μm diameter) that self-induce an ischemic core. Spheroids were generated by coculture of cardiomyocytes derived from hiPSCs (hiPSC-CMs) and primary human cardiac fibroblast (hCF). In the proper medium, cells formed aggregates that generated an ischemic core 2 days after seeding. Spheroids also showed spontaneous cellular reorganization after 10 days, with hiPSC-CMs located at the center and surrounded by hCFs. This led to an increase in microtissue stiffness, characterized by the implementation of a constriction assay. All in all, these phenomena are hints of the fibrotic tissue remodeling secondary to a cardiac ischemic event, thus demonstrating the suitability of these spheroids for the modeling of human cardiac ischemia and its potential application for new treatments and drug research.

Evaluation of Heart Substructures as a Function of Dose and Radiation-Induced Toxicities in Left-Sided Breast Cancer Radiotherapy

Background. A group of cardiopathies (ischemic, arrhythmic, and pericardial cardiac events) were shown to be associated with doses received by heart substructures following radiotherapy, alerting about the importance of dosimetric evaluation of cardiac structures besides the heart. The aim of this study was to assess the dosimetry of heart and heart substructures of left-sided breast cancer radiotherapy to evaluate possible radiation-induced complications. Methods and Materials. The study enrolled 20 patients treated with 3D-conformal radiotherapy (3DCRT), while intensity-modulated (IMRT) and volumetric-modulated arc radiotherapy (VMAT) plans were simulated for comparative purposes. The organs at risk (OARs) of interest were the heart, ascending aorta, descending aorta, left ventricle, left atrium, right ventricle, right atrium, superior vena cava, inferior vena cava, and pulmonary artery. Results. The percentage of left ventricle included in the radiation field was >5% for all plans (8.92% 3DCRT, 8.30% IMRT, and 6.84% VMAT). A strong correlation between mean heart dose and the percentage of left ventricle overlapping with the radiation fields was observed in 3DCRT (r = 0.784) and IMRT (r = 0.755) plans, and a moderate correlation was shown between tumor volume and the percentage of left ventricle included in the radiation field for all plans. A moderate correlation was observed between body mass index and cardiac structures for the mean dose to the right ventricle (r = 0.640) in conformal plans and V5 of heart (r = 0.528) and left ventricle (r = 0.669) in volumetric-modulated plans. Additionally, moderate to strong correlations were found between maximum heart distance and heart dose in both conformal and modulated plans. Conclusions. Considering possible occurrences of cardiac events during or postradiotherapy, monitoring the heart and its substructures and setting dosimetric thresholds for healthy tissues must be a priority to achieve a personalized and effective treatment.

Carfilzomib-Pomalidomide-Dexamethasone in Anti-CD38 Antibodies and Lenalidomide Relapse/Refractory Multiple Myeloma: A Real Life Monocentric Cohort

Introduction Several powerful agents have been validated in multiple myeloma (MM) in the last decades: proteasome inhibitors (PI), immunomodulators (IMID), monoclonal antibodies against CD38, and immunotherapy targeting T cells cytotoxicity. Despite the improvement of therapy, relapses always occur, leading to relapse/refractory MM (RRMM) associated with dismal outcomes. At each relapse, treatment choice becomes a more and more complex decision. With the recent validation for combination in newly diagnosed MM of Daratumumab/Bortezomib/Lenalidomide and/or Dexamethasone (D) association, Carfilzomib (K), a second-in class PI and Pomalidomide (P), a second-in class IMID seems an exciting association to treat RRMM. Here, we analyzed our real-life experience of KPD in RRMM to evaluate the time to the next treatment (TTNT) in patients at Saint Louis Hospital, Paris. Methods We performed a real-life study of RRMM patients who received KPD triplet (eligible if they received one complete cycle of KPD without other treatments) from 2016 till June 2023. Responses were assessed as per the International Myeloma Working Group. The study was conformed to the Declaration of Helsinki. Results Twenty-seven patients were treated with KPD for RRMM in our center. The median age was 64 years (IQR 55-69 years), with a male ratio of 67% (n=18). The subtype of immunoglobulin was IgG (44%), followed by IgA (40%). Among the 26 (96%) patients with FISH available at relapse and before KPD, del 17p, t(4;14), gain 1q, and del 1p were present in 4 (15%), 7 (27%), 8 (31%) and 4 (15%), respectively. Nine (35%) had high-risk cytogenetics (del 17p or/and t(4;14)). At the first line, 15 (55%) received intensive options with autologous stem cell transplantation (ASCT). The first line was composed of Velcade (70%), anti-CD38 antibodies (19%) or IMID (78%: 48% Lenalidomide and 30% Thalidomide) with Dexamethasone. None had prior exposition to Carfilzomib, but three patients (11%) had exposition to Pomalidomide. Three (11%) patients had extra-medullary disease before KPD. The median number of prior lines of chemotherapy was 2 (IQR 1-3), including 70% of the patients who received KPD at the second or third line. Fifteen (56%) patients were refractory to Bortezomib, 25 (93%) to Lenalidomide, 22 (82%) to anti-CD38 antibodies and one (4%) to Pomalidomide. The median number of KPD cycles was 4 (IQR 2-10). All patients received a weekly dose of Carfilzomib except one who received a bi-weekly dose. Twenty (74%) patients started pomalidomide at 4 mg, one (4%) at 3 mg and 6 (22%) at 2 mg from day 1 into day 21. ORR was 66%: CR (n=1, 4%), VGPR (n=7, 26%) and PR (n=10, 37%). Two (8%) patients had progressive disease at the first evaluation. The median time to treatment response was 3 months (IQR 2-6). The median duration of response was 1 year (95%CI 0.5-NA years). Among the 3 patients with prior exposition to Pomalidomide, two had a response to KPD: one PR and one VGPR. The patient refractory to Pomalidomide had stable disease after 2 cycles and then quickly progressive disease. Concerning the side effects of KPD, cardiac toxicity from carfilzomib was reported, including 2 (8%) ischemic cardiac events, 1 (4%) transient ischemic attack, and 3 (11%) induced hypertension. Also, 2 (8%) patients experimented with acute renal failure and one (4%) with thrombotic microangiopathy (TMA) was observed. Three (11%) patients required hospitalization for infections (one candidemia, one flu linked to the TMA episode and one without documentation). At a median follow-up of 1.6 years (0.7-3 years), the median TTNT and overall survival (OS) was 0.7 years (95%CI 0.4-NA years, figure A) and 2 years (95%CI 0.7-NA years, figure B). The mortality rate was 44% (n=12). Most patients had active myeloma at death (11 of 12 with 10 deaths related to myeloma and one from infection), and one died of infections. Ten (37%) patients continued the KPD combination at the last follow-up including two (8%) patients in a maintenance phase, including 1 for Pomalidomide and Dexamethasone after 15 cycles and one for Pomalidomide alone after 22 cycles of KPD. Conclusion In high-risk RRMM especially refractory to anti-CD38 antibodies and lenalidomide, KPD seems to be a valid option in early relapse. Second and third centers will be included in this real-life cohort of RRMM receiving KPD to increase the power of this analysis.

High intensity plaque in carotid artery on magnetic resonance imaging predict long term major adverse cardiac and cerebrovascular events

Abstract Background Cardiocerebrovascular diseases remain the major cause of death in the world. The presence of carotid plaque is a surrogate marker for systemic atherosclerosis. High intensity plaque (HIP) in carotid artery on magnetic resonance imaging (MRI) was reported to be associated with the ipsilateral ischemic stroke as well as coronary artery disease. However, few studies have examined the impact of carotid HIP on long-term prognosis of cardiocerebrovascular disease. Purpose We investigated whether HIP in carotid artery associated with long term major adverse cardiac and cerebrovascular events (MACCE). Method We retrospectively analyzed 241 patients suspected carotid artery stenosis and underwent MRI at our hospital between January 2002 and December 2004. Plaque imaging was performed with non-contrast T1 imaging, and we defined as HIP if plaque-to-myocardium signal-intensity ratio (PMR) ≥2.0. Patients were divided into the HIP group (n=134) or non-HIP group (n=107). The outcome of this study was first incidence of ischemic cardiac or cerebrovascular events. Cardiovascular events were defined as cardiac death (sudden death, fetal myocardial infarction) and non-fetal myocardial infarction. Cerebrovascular events were defined as cerebral infarction. We compared the cumulative incidents of MACCE between with or without HIP groups using Kaplan-Meier method and log-rank test. Multivariate Cox regression analysis was carried out to assess whether HIP could be independent predicter of MACCE. Results Median age of study patients was 70 (inter quartile range; 65-75) and 215 (88.1%) patients were male, 185 patients (76.6%) had established vascular diseases. The median follow-up periods were 8.6 years (inter quartile range; 4.0-14.2 years). The presence of HIP was associated with MACCE (p<0.001). Multivariate analysis shows that the presence of HIP was an independent predicting factor for MACCE. When we analyzed incidence of each cardiovascular and cerebrovascular event, the presence of HIP was significantly associated with cerebrovascular events (p=0.004) and cardiovascular events(p=0.03), respectively. Conclusion The presence of carotid HIP was associated with long term prognosis for MACCE. Our findings indicate that carotid HIP is a surrogate marker for vulnerable patients with cardiocerebrovascular disease.

Exercise ECG and myocardial perfusion SPECT show high prognostic value up to four years after examination

Abstract Background Abnormal results of myocardial perfusion SPECT (MPS) or exercise ECG (Ex-ECG) is known to be associated with increased risk of ischemic cardiac events. The predictive value of stress testing however, is influenced by underlying risk factors as well as follow up duration and may vary considerably over time. With traditional Cox proportional hazards analysis the time-varying effects are not sufficiently accounted for. Purpose To evaluate the prognostic longevity of MPS and Ex-ECG using statistical methods that allow hazard ratio changes over time. Methods 908 patients (age 63 years, 49% male, 45% prior ischemic heart disease (IHD)) referred for MPS were prospectively included. Ex-ECG was performed in conjunction with MPS. Registry data were used for follow up. The outcome was a composite of acute myocardial infarction, unstable angina, unplanned revascularization, and cardiovascular death. Cox proportional hazard analysis and smoothed hazard functions with splines were used for risk assessment during follow up. Results Ex-ECG or MPS were abnormal in 198 (22%) or 148 (16%) of patients respectively. The mean follow up time was 8.2±2.6 years and the composite end point was reached in 189 patients (21%). The Kaplan-Meier curves suggest an interaction with time with the risk of event for subjects with abnormal test results being highest in the 2-3 of years after which the curves are approximately parallel (Figure 1). In multivariable models the best fit (lowest Akaike information criterion (AIC) value) was obtained with a logarithmic interaction term for time. With this approach and controlling for known risk factors the hazard ratio (HR) drops to 1 after approximately four years for both Ex-ECG and MPS (Figure 2). Age (HR=1.04, p<0.001), sex (HR=2.0, p<0.001), IHD (HR=1.7, p<0.001) and reduced exercise capacity (HR=0.99, p<0.001) were independent significant predictors of risk. Conclusions The high risk associated with abnormal MPS and Ex-ECG results decrease rapidly over time and after approximately 4 years the predictive value is lost. Thus, the long-term impact on prognosis of stress testing appear questionable. The time-varying effects on risk are substantial and warrant statistical considerations when designing clinical follow up studies of chronic coronary syndrome.

Terminal T-wave concordance is associated with SYNTAX score among left bundle branch block patients suspected of acute coronary syndrome without modified Sgarbossa criteria.

Timely and precise diagnosis of ischemic cardiac events based on electrocardiogram is challengeable among patients with Left Bundle Branch Block (LBBB). The present study aimed to assess the correlation between SYNTAX score and terminal T-wave morphologies among LBBB patients suspected of Acute Coronary Syndrome (ACS) without modified Sgarbossa criteria. This cross-sectional study was conducted on the LBBB patients suspected of ACS without modified Sgarbossa criteria. Binary logistic regression was used to assess the correlation of ischemic heart disease (IHD, SYNTAX score > 0) and SYNTAX score categories with terminal T-wave morphologies including T-wave direction in lead V6 and terminal T-wave concordance in leads I, V5, and V6. This study was done on 93 patients with the mean age of 62.4 ± 9.6 years. More than half of the patients were female (58.1%, 95% CI: 47.4% to 68.2%). Among the participants with IHD, the SYNTAX score categories were correlated to discordant terminal T-wave in leads I, V5, and V6 (OR = 5.71, 95% CI: 1.04 to 31.28, p = 0.04). Among the LBBB patients with acute ischemic cardiac events without modified Sgarbossa criteria, those with discordant terminal T-waves in leads I, V5, or V6 had higher SYNTAX scores and might require more invasive coronary revascularization techniques such as Coronary Artery Bypass Graft (CABG) surgery.

Diurnal Variation of L-Arginine and the Cardiovascular Risk Markers Asymmetric and Symmetric Dimethylarginine and Homoarginine in Rotating Night Shift Workers and Controls.

Asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) interfere with nitric oxide (NO) formation from L-arginine via different mechanisms. ADMA is a biomarker of cardiovascular disease and mortality, whilst SDMA is a biomarker of mortality after ischemic stroke. Homoarginine, another L-arginine-derived amino acid, is associated with stroke and congestive heart failure. Acute ischemic events like myocardial infarction show a time-of-day variation in the timing of their onset, as do NO-mediated vascular function and blood pressure. We studied whether the plasma concentrations of L-arginine-related amino acid metabolites show diurnal variation in a clinical study comparing 12 non-night shift workers with 60 rotating night shift workers. The plasma concentrations of L-arginine-related biomarkers, melatonin, and cortisol were measured every 3 h during a 24-h period. In addition, 24-h blood pressure recordings were performed. In non-night shift workers, L-arginine and homoarginine plasma concentrations showed diurnal variation with a 12-h period, which were both attenuated in night shift workers. ADMA and SDMA showed a 24-h rhythmicity with no significant differences in phase between night shift and non-night shift workers. The plasma profiles of melatonin and cortisol were not significantly different between both groups, suggesting that the rotating night shift work does not have a major influence on central suprachiasmatic nuclei clock timing. In addition, systolic and diastolic blood pressure patterns were similar between both groups. Our data show diurnal variation of dimethylarginines with the timing of their acrophases corresponding to the published timing of the peak incidence of cardiac ischemic events.

Safety of BA.4-5 or BA.1 bivalent mRNA booster vaccines: nationwide cohort study

ObjectiveTo examine the association between the omicron adapted bivalent mRNA covid-19 booster vaccines received as a fourth dose and risk of adverse events.DesignNationwide cohort study.SettingDenmark.Participants2 225 567 adults aged ≥50...