Predictive value of elevated neutrophil gelatinase-associated lipocalin levels for assessment of in-hospital adverse outcomes among myocardial infarction patients.

BACKGROUND: Inflammatory biomarkers are known to rise and have predictive value for adverse outcomes in patients with acute coronary ischemia. One of those biomarkers is neutrophil gelatinase-associated lipocalin (NGAL). To date, only very few studies have assessed the prognostic value of NGAL in this setting. We investigated the prognostic utility of elevated NGAL levels on clinical outcomes among ST-elevation myocardial infarction patients. METHODS: High NGAL was defined as values within the 4th quartile. Patients were assessed for major in-hospital adverse clinical events (MACE). Multivariable logistic regression and area under the receiver operating characteristic curve (AUC) were used to further evaluate NGAL association for MACE and discrimination ability. RESULTS: A total of 273 patients were included. patients with high NGAL were at increased risk for MACE (62% vs. 19%; odds ratio 6.88, 95% confidence interval, 3.77-12.54, P  < 0.001). After propensity score matching, the incidence of MACE was significantly higher in patients with high vs. low NGAL levels (69% vs. 6%, P  = 0.002). In multivariable regression, high NGAL level was independently associated with MACE. The discrimination ability of NGAL to identify MACE (AUC 0.823), is significantly better than that of other inflammatory markers. CONCLUSION: Among ST-segment elevation myocardial infarction patients undergoing primary percutaneous coronary intervention, high NGAL levels are associated with adverse outcomes, independent of traditional inflammatory markers.

Apical Ischemia Is a Universal Feature of Apical Hypertrophic Cardiomyopathy.

BACKGROUND: Apical hypertrophic cardiomyopathy (ApHCM) accounts for ≈10% of hypertrophic cardiomyopathy cases and is characterized by apical hypertrophy, apical cavity obliteration, and tall ECG R waves with ischemic-looking deep T-wave inversion. These may be present even with <15 mm apical hypertrophy (relative ApHCM). Microvascular dysfunction is well described in hypertrophic cardiomyopathy. We hypothesized that apical perfusion defects would be common in ApHCM. METHODS: A 2-center study using cardiovascular magnetic resonance short- and long-axis quantitative adenosine vasodilator stress perfusion mapping. One hundred patients with ApHCM (68 overt hypertrophy [≥15 mm] and 32 relative ApHCM) were compared with 50 patients with asymmetrical septal hypertrophy hypertrophic cardiomyopathy and 40 healthy volunteer controls. Perfusion was assessed visually and quantitatively as myocardial blood flow and myocardial perfusion reserve. RESULTS: Apical perfusion defects were present in all overt ApHCM patients (100%), all relative ApHCM patients (100%), 36% of asymmetrical septal hypertrophy hypertrophic cardiomyopathy, and 0% of healthy volunteers (P<0.001). In 10% of patients with ApHCM, perfusion defects were sufficiently apical that conventional short-axis views missed them. In 29%, stress myocardial blood flow fell below rest values. Stress myocardial blood flow was most impaired subendocardially, with greater hypertrophy or scar, and with apical aneurysms. Impaired apical myocardial blood flow was most strongly predicted by thicker apical segments (ß-coefficient, -0.031 mL/g per min [CI, -0.06 to -0.01]; P=0.013), higher ejection fraction (-0.025 mL/g per min [CI, -0.04 to -0.01]; P<0.005), and ECG maximum R-wave height (-0.023 mL/g per min [CI, -0.04 to -0.01]; P<0.005). CONCLUSIONS: Apical perfusion defects are universally present in ApHCM at all stages. Its ubiquitous presence along with characteristic ECG suggests ischemia may play a disease-defining role in ApHCM.

High neutrophil-to-lymphocyte ratio as an early sign of cardiotoxicity in breast cancer patients treated with anthracycline.

BACKGROUND: Cardiotoxicity, defined mainly as left ventricle (LV) dysfunction, is a significant side effect of anthracyclines (ANT) therapy. The need for an early simple marker to identify patients at risk is crucial. A high neutrophil-to-lymphocyte ratio (NLR) has been associated with poor prognosis in cancer patients; however, its role as a predictor for cardiotoxicity development is unknown. OBJECTIVE: Evaluating whether elevated NLR, during ANT exposure, plays a predictive role in the development of cardiotoxicity as defined by LV global longitudinal strain (LV GLS) relative reduction (≥10%). METHODS AND RESULTS: Data were prospectively collected as part of the Israel Cardio-Oncology Registry. A total of 74 female patients with breast cancer, scheduled for ANT therapy were included. NLR levels were assessed at baseline (T1) and during ANT therapy (T2). All patients underwent serial echocardiography at baseline (T1) and after the completion of ANT therapy (T3). NLR ≥ 2.58 at T2 was found to be the optimal predictive cutoff for LV GLS deterioration. A relative LV GLS reduction ≥10% was significantly more common among patients with high NLR (50% vs. 20%, p = .009). NLR ≥ 2.58 at T2 increases the risk for LV GLS reduction by fourfold (odds ratio [OR]: 4.63, 95% confidence interval [CI]: 1.29-16.5, p = .02), with each increase of 1-point NLR adding an additional 15% risk (OR: 1.15, 95% CI: 1.01-1.32, p = .046). CONCLUSIONS: Our study provides novel data that high NLR levels, during ANT exposure, have an independent association with the development of LV dysfunction. Routine surveillance of NLR may be an effective means of risk-stratifying.

The predictive value of high sensitivity troponin measurements in patients treated with immune checkpoint inhibitors.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of cancer; however, at the potential cost of serious adverse events including cardiac injury. OBJECTIVE: To assess the baseline and longitudinal changes in high sensitivity-Troponin (hs-Tn) in patients treated with pembrolizumab as a potential predictor for the development of major adverse cardiac events (MACE) and survival. METHODS: We performed a retrospective analysis of cancer patients treated with pembrolizumab at our center. All participants had baseline measurements of hs-TnI prior to initiation of pembrolizumab (T1), with half of the patients performing follow-up measurements at their second encounter for therapy introduction (T2). We first evaluated the prevalence of abnormally elevated serum hs-TnI (> 50 nanogram per liter) at T1 and T2. We then evaluated the predictive value of abnormal levels at T1 or T2 in relation to the development of MACE (composite outcomes of myocarditis, acute coronary syndrome, heart failure, venous thromboembolism, cardiovascular hospitalization and cardiovascular mortality) and all-cause mortality. RESULTS: Among 135 patients, the mean age was 72 years, predominantly male (61%). Abnormally elevated hs-TnI at T1 was observed in 7 (5%) patients and emerged as a significant independent predictor for MACE (HR 8.1, 95% CI 1.67-37.4, p = 0.009) and all-cause mortality (HR 5.37, 95% CI 2.1-13.57, p < 0.001). Abnormally elevated hs-TnI at T2 was observed in 8 (11%) patients and emerged as a significant independent predictor for MACE (HR 10.49, 95% CI 1.68-65.5, p = 0.009), but not for mortality (p = 0.200). CONCLUSIONS: Abnormally elevated baseline and follow-up hs-TnI served as significant independent predictors for MACE, with an increased risk of development being 8-tenfold. Furthermore, elevated baseline hs-TnI showed a predictive value for all-cause mortality. Central illustration: Novel immune checkpoint inhibitor (ICIs) therapy has been found to revolutionize cancer therapy through increased activation of host immune systems to target and reduce tumor burden, but may come at the cost of serious adverse cardiac events. Identification of early biomarkers for the prediction and detection of these events is necessary.

Valvular Heart Disease following Anthracycline Therapy-Is It Time to Look beyond Ejection Fraction?

The association between anthracycline (ANT) and left ventricle (LV) dysfunction is well known; however, data regarding its direct effect on cardiac valve function is limited. We aimed to evaluate how ANT therapy affected valvular function in patients diagnosed with breast cancer. Data were prospectively collected as part of the Israel Cardio-Oncology Registry (ICOR). Patients underwent echocardiography exams at baseline (T1), during ANT therapy (T2), and after completion within 3 months (T3) and 6 months (T4). A total of 141 female patients were included, with a mean age of 51 ± 12 years. From T1 to T4, we observed a significant deterioration in LV ejection fraction (60.2 ± 1.5 to 59.2 ± 2.7%, p = 0.0004) and LV global longitudinal strain (−21.6 (−20.0−−23.0) to −20.0 (−19.1−−21.1)%, p < 0.0001)), and an increase in LV end-systolic diameter (25 (22−27) to 27 (24−30) mm, p < 0.0001). We observed a significant increase in the incidence of new mitral regurgitation (MR) development (4 to 19%, p < 0.0001), worsening with concomitant trastuzumab therapy (6% to 31%, p = 0.003), and a trend for tricuspid regurgitation development (4% to 8%, p = 0.19). ANT therapy is associated with the development of a new valvular disease, mainly MR, which may imply the need for a valvular focus in the monitoring of cancer patients.

Cardiac arrest as first presentation of arrhythmogenic left ventricular cardiomyopathy due to Filamin C mutation: a case report.

BACKGROUND: Arrhythmogenic left ventricular cardiomyopathy (ALVC) is a rare form of arrhythmogenic cardiomyopathy characterized by fibrofatty replacement of left ventricular myocardium, malignant arrhythmia, and sudden cardiac death. The definition incorporates several genetic causes, including pathogenic variation in the Filamin C gene (FLNC). Although awareness of ALVC has improved, identification remains challenging and diagnostic criteria continue to evolve. CASE SUMMARY: A 50-year-old athletic male was admitted following an out-of-hospital cardiac arrest due to ventricular tachycardia (VT) whilst playing football. Coronary angiography revealed unobstructed epicardial vessels and the diagnosis of ALVC was suggested by cardiovascular magnetic resonance imaging, which demonstrated a mildly dilated and moderately impaired left ventricle with epicardial late gadolinium enhancement in the basal to mid-lateral walls and subendocardial septum. Initial testing with a cardiomyopathy and arrhythmia gene panel was negative but extended testing uncovered a likely pathogenic variant in FLNC. Subsequently, the patient experienced a recurrence of sustained VT necessitating implantable cardioverter-defibrillator (ICD) therapies, ultimately undergoing a combined epicardial and endocardial VT ablation 4 years after presentation. Six months post-ablation, he was asymptomatic and his arrhythmia rendered quiescent. DISCUSSION: Arrhythmogenic cardiomyopathy should be considered in the evaluation of an initially unexplained cardiac arrest. This case characterizes the clinical features of a patient with FLNC cardiomyopathy and emphasizes the utility of genetic testing using modern gene panels in patients with comparable phenotypes. We also demonstrate that optimal medical therapy with antiarrhythmic drugs, exercise restriction, ICD insertion, and catheter ablation can be useful in the management of ALVC with positive outcomes.

Incidence, characteristics and outcomes in very young patients with ST segment elevation myocardial infarction.

OBJECTIVE: ST-segment elevation acute myocardial infarction (STEMI) in very young adults is uncommon. Many studies have focused on the cutoff of 45-50 years old to define young patients with STEMI leaving limited data on the group of very young patients aged less than 35 years old. We investigated the incidence of STEMI in different subgroups of young patients and focused on the characteristics, possible pathogenesis and outcomes in very young patients aged less than 35 years old. METHODS: We retrospectively studied 792 STEMI patients aged less than 55 years who underwent successful primary PCI. We categorized patients as very young if they were or less 35 years old and as young if they were between 36 and 55 years old. Baseline characteristics, angiographic findings, as well as short- and long-term outcomes were compared between the two groups. RESULTS: There were 46 (6%) very young patients (age ≤ 35 years) and 748 (94%) young patients (36 < age ≤ 55 years). Very young patients had fewer atherosclerotic risk factors than young patients, but there was no difference in short- or long-term outcomes. Overt hypercoagulable state was evident serologically (antiphospholipid antibodies) in 2/7 (29%) of screened patients and clinically (left ventricular thrombus or acute coronary thrombosis without an atherosclerotic plaque) in 6/46 patients (13%). CONCLUSION: Very young patients with STEMI constitute a distinct subset of young patients with fewer atherosclerotic risk factors yet comparable outcomes. More efforts should be made screening for serologic and clinical evidence of hypercoagulability in this group of patients.

A practical approach to infarction of the spleen as a rare manifestation of multiple common diseases.

INTRODUCTION: There are insufficient data on the aetiologic factors underlying splenic infarction (SI). Therefore, there is no consensus regarding the appropriate diagnostic approach. METHODS: We conducted a retrospective analysis of all patients admitted with SI from January 2004 to December 2014. Medical records were screened for the clinical presentation, underlying causes, associated medical conditions and methods of patient evaluation. RESULTS: We found 89 subjects with 90 episodes of SI. Presentation of SI was characterized by abdominal, flank and chest pain (82.2%, 18.9%, 7.8%, respectively); leukocytosis (in 67% of tested subjects); elevated LDH (72%), CRP (97.5%) and D-Dimer (100%). The main underlying mechanisms were cardioembolic (54.4%), vascular (20%), haematologic disorders (15.6%) and multiple causes (21.1%). Atrial fibrillation and atherosclerosis were common in older patients (age > 70 years) while antiphospholipid syndrome occurred exclusively in younger individuals. SI was the presentation of previously unknown medical conditions in 38% of patients. Abdominal CT, ECG, echocardiography and blood cultures demonstrated the highest diagnostic yield. CONCLUSIONS: Contributing factors are identified in the majority of SI patients. We recommend CT, ECG, echocardiography and blood cultures in all cases. Atrial fibrillation should be sought in older patients, while APLS and haematologic disorders should be suspected in younger ones. KEY MESSAGES There is no consensus regarding the diagnostic approach and management of splenic infarction. Cardiovascular disease and atrial fibrillation are the main causes for SI in elderly subjects while hematological, infectious and other causes are more prevalent in younger ones. Our data strongly suggests a high diagnostic yield for CT scan, ECG, blood culture and echocardiogram in every patient with SI.

Serial Echocardiographic Assessment of Left Ventricular Filling Pressure and Remodeling among ST-Segment Elevation Myocardial Infarction Patients Treated by Primary Percutaneous Intervention.

BACKGROUND: Acute myocardial infarction and remodeling of the left ventricle is associated with significant changes in systolic and diastolic echocardiographic derived indices. The investigators have tried to determine whether persistence of increased ratio of transmitral flow velocity (E) to early mitral annulus velocity (e'), signifying increased cardiac filling pressure, is associated with left ventricular (LV) remodeling and increased chamber size among patients presenting with ST-segment elevation myocardial infarction, who underwent successful reperfusion with primary percutaneous coronary intervention. METHODS: Fifty-two patients (76% men; mean age, 61 ± 10 years) with first ST-segment elevation myocardial infarctions who underwent primary percutaneous coronary intervention were retrospectively studied. Echocardiography was performed at baseline (days 1-3) and after 178 ± 62 days. Patients were stratified according to E/septal e' ratio >15 and ≤15 in both examinations. All patients received optimal medical therapy according to guidelines and local practice. RESULTS: Patients with maintained or worsened E/septal e' ratios to >15 demonstrated on the second examination worse LV ejection fractions (mean, 45 ± 12% vs 52 ± 8%; P = .03) and higher indexed LV end-diastolic volumes (mean, 81.3 ± 22.9 vs 69.2 ± 13.4 mL/m(2); P = .01) and end-systolic volumes (mean, 33.0 ± 12.2 vs 23.7 ± 13.4 mL/m(2); P = .02) compared with the first examination, representing LV remodeling. Patients with E/septal e' ratios > 15 on the second examination demonstrated a positive correlation between the change in E/septal e' ratio and the change in indexed LV end-diastolic volume (linear R(2) = 0.344, P = .03). CONCLUSIONS: Among patients with ST-segment elevation myocardial infarctions undergoing primary percutaneous coronary intervention, early and persistent elevation of the E/septal e' ratio may be associated with LV remodeling.

Relevance of the thyroid hormones-αvß3 pathway in primary myeloma bone marrow cells and to bortezomib action.

Thyroid hormones (T3 and T4) induce proliferation in multiple myeloma (MM) cell lines via the αvß3 integrin-mitogen-activated protein kinase (MAPK) pathway. We further show in primary MM bone marrow (BM) samples (n = 9) induction of cell viability by 1 nM T3 (13%, p < 0.002) and more potently by 100 nM T4 (21-45%, p < 0.0002) and a quick (1 h) and long-lasting (24 h) pERK activation, which was inhibited in the presence of ß3 but not ß1 blocking antibodies. Involvement of the integrin was further shown by two disintegrins, Arg-Gly-Asp (RGD) and echistatin peptides, which occluded the effects of T3/T4 on viability, proliferating cell nuclear antigen (PCNA) (proliferation marker) and apoptotic gene expression. Lastly, T3/T4 significantly opposed bortezomib (25 nM) cytotoxicy, as confirmed by several methods. In summary, our results imply that endogenous thyroid hormones in myeloma are factors that may support cell growth, with relevance to bortezomib action.

Thyroid hormone is a MAPK-dependent growth factor for human myeloma cells acting via αvß3 integrin.

Experimental and clinical observations suggest that thyroid hormone [l-thyroxine (T(4)) and 3,5,3'-triiodo-l-thyronine (T(3))] can support cancer cell proliferation. T(3) and T(4) promote both tumor cell division and angiogenesis by activating mitogen-activated protein kinase (MAPK) via binding to a hormone receptor on the αvß3 integrin, overexpressed on many cancer cells. We have studied the responsiveness of several MM cell lines to T(3) and T(4) and characterized hormonal effects on cell survival, proliferation, and MAPK activation. Overnight T(3) (1-100 nmol/L) and T(4) (100 nmol/L) incubation enhanced, up to 50% (P < 0.002), MM cell viability (WST-1 assay) and increased cell proliferation by 30% to 60% (P < 0.01). Short exposure (10 minutes) to T(3) and T(4) increased MAPK activity by 2.5- to 3.5-fold (P < 0.03). Pharmacologic MAPK inhibition blocked the proliferative action of T(3) and T(4). Antibodies to the integrin αvß3 dimer and αv and ß3 monomers (but not ß1) inhibited MAPK activation and subsequent cell proliferation in response to thyroid hormone, indicating dependence upon this integrin. Moreover, tetraiodothyroacetic acid (tetrac), a non-agonist T(4) analogue previously shown to selectively block T(3)/T(4) binding to αvß3 receptor site, blocked induction of MAPK by the hormones in a dose-dependent manner. This demonstration of the role of thyroid hormones as growth factors for MM cells may offer novel therapeutic approaches.