Multiorgan failure caused by pembrolizumab and axitinib in a woman affected by metastatic clear cell renal cell carcinoma: A case report and literature review.

RATIONALE: Treatment with a combination of immune checkpoint inhibitors (ICIs) (pembrolizumab or nivolumab) and oral Tyrosine Kinase Inhibitors (TKI) targeting angiogenesis (axitinib, cabozantinib or lenvatinib) has shown benefits in terms of efficacy and survival in metastatic renal cell carcinoma (mRCC), with a favorable toxicity profile. However, some rare and serious treatment-related adverse events can be difficult to manage. PATIENT CONCERNS: Here we report the first case of an mRCC patient who, after only 2 administrations of pembrolizumab-axitinib, experienced severe multiorgan failure (MOF) with heart failure, oliguria and acute hepatitis requiring aggressive supportive treatment in intensive care unit. DIAGNOSES: A diagnosis of severe MOF induced by pembrolizumab plus axitinib was considered. INTERVENTIONS: The patient was treated with dobutamine, levosimendan along with high-dose steroids under continuous cardiologic monitoring. OUTCOMES: After treatment, the patient had a full recovery and was discharged from the hospital. LESSONS: We reviewed all the other cases of MOF reported during treatment with combined ICI-TKI in cancer patients in order to summarize incidence, clinical manifestations and management with a specific focus on the need for prompt recognition and aggressive management under multidisciplinary care.

Improved accelerated stability of starch-chia oil fatty acid inclusion complexes formed under mild reaction conditions.

The starch inclusion complexation of sensitive compounds requires the use of conditions that minimize their degradation. This research work is aimed at investigating the effect of an alkaline complexation method employing mild reaction conditions on the physicochemical properties and accelerated stability of inclusion complexes of high amylose corn starch with omega-3 and omega-6 fatty acids. Hydrolyzed chia seed oil, rich in α-linolenic and linoleic fatty acids, was used as guest material and was incorporated at two ratios (10 and 20 % w/w hydrolysate/starch). Under the reaction conditions assessed, it were successfully formed V-type inclusion complexes with a high content of omega-3 and omega-6 (3.9-6 %). The initial hydrolysate concentration did not have a significant effect on the structural (crystallinity, short-range order) and thermal (dissociation temperature, melting enthalpy) properties. The method studied allowed the formation of complexes with an enhanced accelerated oxidative stability, compared to those formed using thermal treatment. The complexes formed using mild conditions with 20 % hydrolysate content had the highest oxidative stability, showing an omega-3 and omega-6 retention >90 % after 6 h of storage at 90 °C, an enhanced stability under thermogravimetric analysis, and flattened Rancimat curves, suggesting an appropriate preliminary behavior as potential carriers of bioactive fatty acids.

Implantable cardioverter defibrillator use in arrhythmogenic right ventricular cardiomyopathy in North America and Europe.

BACKGROUND AND AIMS: Implantable cardioverter-defibrillators (ICDs) are critical for preventing sudden cardiac death (SCD) in arrhythmogenic right ventricular cardiomyopathy (ARVC). This study aims to identify cross-continental differences in utilization of primary prevention ICDs and survival free from sustained ventricular arrhythmia (VA) in ARVC. METHODS: This was a retrospective analysis of ARVC patients without prior VA enrolled in clinical registries from 11 countries throughout Europe and North America. Patients were classified according to whether they received treatment in North America or Europe and were further stratified by baseline predicted VA risk into low- (<10%/5 years), intermediate- (10%-25%/5 years), and high-risk (>25%/5 years) groups. Differences in ICD implantation and survival free from sustained VA events (including appropriate ICD therapy) were assessed. RESULTS: One thousand ninety-eight patients were followed for a median of 5.1 years; 554 (50.5%) received a primary prevention ICD, and 286 (26.0%) experienced a first VA event. After adjusting for baseline risk factors, North Americans were more than three times as likely to receive ICDs {hazard ratio (HR) 3.1 [95% confidence interval (CI) 2.5, 3.8]} but had only mildly increased risk for incident sustained VA [HR 1.4 (95% CI 1.1, 1.8)]. North Americans without ICDs were at higher risk for incident sustained VA [HR 2.1 (95% CI 1.3, 3.4)] than Europeans. CONCLUSIONS: North American ARVC patients were substantially more likely than Europeans to receive primary prevention ICDs across all arrhythmic risk strata. A lower rate of ICD implantation in Europe was not associated with a higher rate of VA events in those without ICDs.

Predictive value of a comprehensive atrial assessment with cardiac magnetic resonance in non-ischemic cardiomyopathy: keep it simple.

Cardiac magnetic resonance (CMR) can provide a multi-parametric evaluation of left atrial (LA) size and function. A complete CMR-based LA assessment might improve the risk stratification of patients with non-ischemic dilated cardiomyopathy (DCM). We performed a comprehensive CMR-based evaluation of LA size and function, in order to assess the prognostic impact of specific LA parameters in DCM. Secondary analysis of a prospective registry (UHSM-CMR study, NCT02326324) including 648 consecutive patients with DCM and CMR evaluation of LA area and LA length. Of these, 456 had complete LA assessment covering reservoir, conduit and booster pump function and including LA reservoir strain evaluated with feature tracking. The heart failure (HF) endpoint included HF hospitalizations, HF death and heart transplant. The arrhythmic endpoint included ventricular arrhythmias (VA) (sustained or treated by implantable defibrillator) and sudden death (SD). At median follow-up of 23 months, 34 patients reached the HF endpoint; in a multivariable model including NYHA class and LVEF, LA length had incremental predictive value. LA length ≥ 69 mm was the best cut-off to predict HF events (adjusted HR 2.3, p = 0.03). Among the 456 patients with comprehensive LA assessment, only LA length was independently associated with the HF endpoint after adjusting for LVEF and NYHA class. By contrast, no LA parameter independently predicted the arrhythmic risk. In DCM patients, LA length is an independent predictor of HF events, showing stronger association than other more complex parameters of LA function. No atrial parameter predicts the risk of VA and SD.

Cardiac Magnetic Resonance as Risk Stratification Tool in Non-Ischemic Dilated Cardiomyopathy Referred for Implantable Cardioverter Defibrillator Therapy-State of Art and Perspectives.

Non-ischemic dilated cardiomyopathy (DCM) is a disease characterized by left ventricular dilation and systolic dysfunction. Patients with DCM are at higher risk for ventricular arrhythmias and sudden cardiac death (SCD). According to current international guidelines, left ventricular ejection fraction (LVEF) ≤ 35% represents the main indication for prophylactic implantable cardioverter defibrillator (ICD) implantation in patients with DCM. However, LVEF lacks sensitivity and specificity as a risk marker for SCD. It has been seen that the majority of patients with DCM do not actually benefit from the ICD implantation and, on the contrary, that many patients at risk of SCD are not identified as they have preserved or mildly depressed LVEF. Therefore, the use of LVEF as unique decision parameter does not maximize the benefit of ICD therapy. Multiple risk factors used in combination could likely predict SCD risk better than any single risk parameter. Several predictors have been proposed including genetic variants, electric indexes, and volumetric parameters of LV. Cardiac magnetic resonance (CMR) can improve risk stratification thanks to tissue characterization sequences such as LGE sequence, parametric mapping, and feature tracking. This review evaluates the role of CMR as a risk stratification tool in DCM patients referred for ICD.

Impact of Cardiac Magnetic Resonance to Arrhythmic Risk Stratification in Nonischemic Cardiomyopathy.

Left ventricular ejection fraction-based arrhythmic risk stratification in nonischemic cardiomyopathy (NICM) is insufficient and has led to the failure of primary prevention implantable cardioverter defibrillator trials, mainly due to the inability of selecting patients at high risk for sudden cardiac death (SCD). Cardiac magnetic resonance offers unique opportunities for tissue characterization and has gained a central role in arrhythmic risk stratification in NICM. The presence of myocardial scar, denoted by late gadolinium enhancement, is a significant, independent, and strong predictor of ventricular arrhythmias and SCD with high negative predictive value. T1 maps and extracellular volume fraction, which are able to quantify diffuse fibrosis, hold promise as complementary tools but need confirmatory results from large studies.

Late gadolinium enhancement and the risk of ventricular arrhythmias and sudden death in NYHA class I patients with non-ischaemic cardiomyopathy.

AIM: To compare the risk of ventricular arrhythmias (VA) and sudden death (SD) between New York Heart Association (NYHA) class I and NYHA class II-III patients with non-ischaemic cardiomyopathy (NICM). METHODS AND RESULTS: Observational retrospective cohort study including patients with NICM who underwent cardiac magnetic resonance at two hospitals. The primary endpoint included appropriate implantable cardioverter defibrillator (ICD) therapies, sustained ventricular tachycardia, resuscitated cardiac arrest and SD. The secondary endpoint included heart failure (HF) hospitalizations, heart transplant, left ventricular assist device implant or HF death. Overall, 698 patients were included, 33% in NYHA class I. During a median follow-up of 31 months, the primary endpoint occurred in 57 patients (8%), with no differences between NYHA class I and NYHA class II-III cases (7% vs. 9%, p = 0.62). Late gadolinium enhancement (LGE) was the only independent predictor of the primary outcome both in NYHA class I and NYHA class II-III patients. LGE+ NYHA class I patients had a similar cumulative incidence of the primary endpoint as compared to LGE+ NYHA class II-III (p = 0.92) and a significantly higher risk as compared to LGE- NYHA class II-III cases (p < 0.001). The risk of the secondary endpoint was significantly higher in patients in NYHA class II-III as compared to those in NYHA class I (hazard ratio 3.2, p = 0.001). CONCLUSIONS: Patients with NICM in NYHA class I are not necessarily at low risk of VA and SD. Actually, LGE+ NYHA class I patients have a high risk. NYHA class I patients with high-risk factors, such as LGE, could benefit from primary prevention ICD at least as much as those in NYHA class II-III with the same risk factors.

Extracellular volume fraction improves risk-stratification for ventricular arrhythmias and sudden death in non-ischaemic cardiomyopathy.

AIMS: To evaluate whether cardiac magnetic resonance (CMR)-based parametric mapping and strain analysis can improve the risk-stratification for ventricular arrhythmias (VA) and sudden death (SD) in non-ischaemic cardiomyopathy (NICM). METHODS AND RESULTS: Secondary analysis of a prospective single-centre-registry (NCT02326324), including 703 consecutive NICM patients, 618 with extracellular volume (ECV) available. The combined primary endpoint included appropriate implantable cardioverter defibrillator therapies, sustained ventricular tachycardia, resuscitated cardiac arrest and SD. During a median follow-up of 21 months, 14 patients (2%) experienced the primary endpoint. Native T1 was not associated with the primary endpoint. Left ventricular global longitudinal strain lost its significant association after adjustment for left ventricular ejection fraction (LVEF). Among patients with ECV available, 11 (2%) reached the primary endpoint. Mean ECV was significantly associated with the primary endpoint and the best cut-off was 30%. ECV ≥ 30% was the strongest independent predictor of the primary endpoint (hazard ratio 14.1, P = 0.01) after adjustment for late gadolinium enhancement (LGE) and LVEF. ECV ≥ 30% discriminated the arrhythmic risk among LGE+ cases and among those with LVEF ≤ 35%. A simple clinical risk-stratification model, based on LGE, LVEF ≤ 35% and ECV ≥ 30%, achieved an excellent predictive ability (Harrell's C 0.82) and reclassified the risk of 32% of the study population as compared to LVEF ≤ 35% alone. CONCLUSIONS: Comprehensive CMR evaluation in NICM showed that ECV was the only parameter with an independent and strong predictive value for VA/SD, on top of LGE and LVEF. A risk-stratification model based on LGE, LVEF ≤ 35% and ECV ≥ 30% achieved an excellent predictive ability for VA/SD. CLINICAL TRIAL REGISTRATION: UHSM CMR study (NCT02326324) https://clinicaltrials.gov/ct2/show/NCT02326324.

Prognostic impact of late gadolinium enhancement at the right ventricular insertion points in non-ischaemic dilated cardiomyopathy.

AIMS: To evaluate the baseline characteristics and the prognostic implications associated with late gadolinium enhancement limited to the right ventricular insertion points (IP-LGE) or present at both the right ventricular insertion points and the left ventricle (IP&LV-LGE) in non-ischaemic dilated cardiomyopathy (DCM). METHODS AND RESULTS: This is a retrospective observational multicentre cohort study including 1165 consecutive patients with DCM evaluated by cardiac magnetic resonance. The primary endpoint included appropriate defibrillator therapies, sustained ventricular tachycardia, resuscitated cardiac arrest, or sudden death. The secondary outcome encompassed heart failure hospitalizations, heart transplant, left ventricular assist device implantation, and end-stage heart failure death. IP-LGE was found in 72 patients (6%), who had clinical characteristics closer to LGE- than to LGE+ patients. During follow-up (median 36 months), none of the IP-LGE patients experienced the primary endpoint. The cumulative incidence of the primary endpoint was similar between IP-LGE and LGE- patients (P = 1), while IP-LGE had significantly lower cumulative incidence when compared with LGE+ patients (P < 0.001). When compared with IP-LGE patients, the cumulative incidence of the secondary endpoint was similar in LGE- cases (P = 0.86) but tended to be higher in LGE+ patients (P = 0.06). Both clinical characteristics and outcomes were similar between IP&LV-LGE patients and the rest of LGE+ cases. CONCLUSIONS: In a large cohort of DCM patients, IP-LGE was associated with similar outcome when compared with LGE- patients and with significant lower risk of ventricular arrhythmias and sudden death when compared with LGE+ cases. Patients with IP&LV-LGE had clinical characteristics and outcomes similar to the rest of LGE+ cases.

Arrhythmic risk prediction in arrhythmogenic right ventricular cardiomyopathy: external validation of the arrhythmogenic right ventricular cardiomyopathy risk calculator.

AIMS: Arrhythmogenic right ventricular cardiomyopathy (ARVC) causes ventricular arrhythmias (VAs) and sudden cardiac death (SCD). In 2019, a risk prediction model that estimates the 5-year risk of incident VAs in ARVC was developed (ARVCrisk.com). This study aimed to externally validate this prediction model in a large international multicentre cohort and to compare its performance with the risk factor approach recommended for implantable cardioverter-defibrillator (ICD) use by published guidelines and expert consensus. METHODS AND RESULTS: In a retrospective cohort of 429 individuals from 29 centres in North America and Europe, 103 (24%) experienced sustained VA during a median follow-up of 5.02 (2.05-7.90) years following diagnosis of ARVC. External validation yielded good discrimination [C-index of 0.70 (95% confidence interval-CI 0.65-0.75)] and calibration slope of 1.01 (95% CI 0.99-1.03). Compared with the three published consensus-based decision algorithms for ICD use in ARVC (Heart Rhythm Society consensus on arrhythmogenic cardiomyopathy, International Task Force consensus statement on the treatment of ARVC, and American Heart Association guidelines for VA and SCD), the risk calculator performed better with a superior net clinical benefit below risk threshold of 35%. CONCLUSION: Using a large independent cohort of patients, this study shows that the ARVC risk model provides good prognostic information and outperforms other published decision algorithms for ICD use. These findings support the use of the model to facilitate shared decision making regarding ICD implantation in the primary prevention of SCD in ARVC.

Risk of cardiac device-related infection in patients with late-onset bloodstream infection. Analysis on a National Cohort.

OBJECTIVES: To determine the incidence of cardiac device-related infection (CDRI) among patients with cardiac device (CD) during late-onset bloodstream infection (BSI) and to identify the risk factors associated with CDRI. METHODS: Patients with a CD (cardiac implantable electronic devices -CIED- and/or prosthetic heart valve -PHV-) and late-onset-BSI (>1 year after the CD implantation/last manipulation) were selected from the PROBAC project, a prospective, observational cohort study including adult patients with bacteraemia consecutively admitted to 26 Spanish hospitals from October 2016 to March 2017. Multivariate analyses using logistic regression were performed to identify the risk factors associated with CDRI. RESULTS: 317 BSI from patients carrying a CD were registered, 187 (56.2%) were late-onset-BSI. A total of 40 (21.4%) CDRI were identified during late-onset-BSI. The CDRI cumulative incidence in Gram-positive-BSI was 41.8% (38/91), with S. aureus, Enterococcus spp. and viridans streptococci showing the greatest percentages: 40% (12/30), 42% (11/26) and 75% (6/8), respectively. Independent predictors of CDRI were an unknown source of infection (OR: 2.88 [CI 95%:1.18-7.06], p = 0.02), Gram-positive-aetiology (23.1 [5.23-102.1], p < 0.001) and persistent bacteraemia (4.81 [1.21-19], p = 0.03). In an exploratory analysis, S. aureus (3.99 [1.37-11.65], p = 0.011), Enterococcus spp. (5.21 [1.76-15.4], p = 0.003) and viridans streptococci (28.7 [4.71-173.5], p < 0.001) aetiology were also found to be risk factors for CDRI. CONCLUSIONS: CDRI during late-onset-BSI is a frequent phenomenon. Risk of CDRI differs among species, happening in almost half of the Gram-positive-BSI. An unknown source of the primary infection, Gram-positive-aetiology -especially S. aureus, Enterococcus spp. and viridans streptococci-, and persistent bacteraemia were identified as risk factors for CDRI.

Impact of Successful Chronic Coronary Total Occlusion Recanalization on Recurrence of Ventricular Arrhythmias in Implantable Cardioverter-Defibrillator Recipients for Ischemic Cardiomyopathy (VACTO PCI Study).

BACKGROUND: Coronary chronic total occlusion lesions (CTOs) confer an increased risk of arrhythmic events among patients with ischemic cardiomyopathy (ICM) and implantable cardioverter-defibrillator (ICD) carriers, however the impact of CTO recanalization in this population remains unassessed. AIMS: Evaluate the impact of CTOs percutaneous coronary interventions (PCI) on arrhythmic events. METHODS: Patients with ICM and ICD from the VACTO I-II registries: patients with medically treated CTO (CTO-OMT group) and without CTO (no-CTO group) were compared after inverse-probability-weighting adjustment (IPWT) with a similar population of consecutive patients undergoing CTO-PCI. The primary endpoint was appropriate ICD therapy. The secondary endpoint was all-cause mortality. RESULTS: The total of 622 patients (mean age 67 ± 10 years, mean left ventricular ejection fraction 36 ± 11%) included in the analysis was composed by: CTO-PCI patients n = 113, CTO-OMT patients n = 286, no-CTO patients n = 223. In the CTO-PCI group, compared to the CTO-OMT group, 5-year Kaplan Meier estimates for appropriate ICD therapy (20.4% vs. 56.4%, IPW-adjusted HR: 0.45, 95% CI 0.29-0.71) and mortality (8.8% vs. 23%, IPW-adjusted HR: 0.43, 95% CI 0.22-0.85) were lower, driven by infarct related artery CTO (IRA-CTO) PCI, while similar to those occurring in the no-CTO group. CONCLUSIONS: In this large population, those with CTO receiving PCI had lower arrhythmic event rates and lower mortality compared to the CTO-OMT group, while showing an event rate similar to no-CTO patients. Sensitivity analyses suggest that the beneficial effect on the arrhythmic outcome was driven by IRA-CTO revascularization. CLASSIFICATION: Chronic total occlusion.

Improved prediction of electrical storm in patients with prior myocardial infarction and implantable cardioverter defibrillator.

AIMS: To evaluate predictors of electrical storm (ES), including chronic total occlusion in an infarct-related coronary artery (infarct-related artery CTO, IRACTO), in a cohort of patients with prior myocardial infarction (MI) and implantable cardioverter-defibrillators (ICD). METHODS: Multicenter observational cohort study including 643 consecutive patients with prior MI and a first ICD implanted between 2005 and 2018 at three tertiary hospitals. All the patients included in the study had undergone a diagnostic coronary angiography before ICD implantation. The variable prior ventricular arrhythmias (VA+) was positive in patients with secondary prevention ICDs and in those with at least one appropriate ICD therapy after primary prevention implantation. RESULTS: During a median follow-up of 42 months 59 patients (9%) suffered ES. The presence of at least one IRACTO not revascularized (IRACTO-NR) was associated with a significantly higher cumulative incidence of ES (14.5% vs 4.8%, p < 0.001). IRACTO-NR maintained a significant association with ES after adjustment for potential confounders (HR 2.3, p = 0.005) and was an independent predictor of ES together with VA+ and LVEF. The best cut-off of LVEF to predict ES was ≤38%. A risk-prediction model based on IRACTO-NR, VA+ and LVEF≤38% identified three categories of ES risk (low, intermediate and high), with progressively increasing cumulative incidence of ES (2.2%, 9% and 20%). CONCLUSION: In a cohort of patients with prior MI and ICD, IRACTO-NR is an independent predictor of ES. A new risk-prediction model allowed the identification of three categories of risk, with potentially important clinical implications.

Ventricular Arrhythmias and Sudden Death in Nonischemic Dilated Cardiomyopathy: Matter of Sex or Scar?

BACKGROUND: To evaluate the association between sex and ventricular arrhythmias (VA) or sudden death (SD) in nonischemic dilated cardiomyopathy, including analysis of potential confounders. METHODS AND RESULTS: Retrospective cohort study of consecutive patients with DCM referred for cardiac magnetic resonance at 2 tertiary hospitals. The primary combined end point encompassed sustained VA, appropriate implantable cardioverter defibrillator therapies, resuscitated cardiac arrest, and SD. We included 1165 patients with median follow-up of 36 months (interquartile range 20-58 months). The majority of patients (66%) were males. Males and females had similar left ventricular ejection fraction, but the prevalence of late gadolinium enhancement (LGE) at cardiac magnetic resonance was significantly higher among males (48% vs 30%, P < .001). Males had higher cumulative incidence of the primary end point (8% vs 4%, P = .02), and male sex was a significant predictor of the primary end point at univariate analysis (hazard ratio 1.93, P = .02). However, LGE had a major confounding effect in the association between sex and the primary outcome: the hazard ratio of male sex adjusted for LGE was 1.29 (P = .37). LGE+ females had significantly higher cumulative incidence of the primary end point than LGE- males (13% vs 1.8%, P < .001). CONCLUSIONS: In patients with DCM, the prevalence of LGE is significantly higher among males, implying a major confounding effect in the association between male sex and VA or SD. LGE+ females have significantly higher risk than LGE- males. These data do not support the inclusion of sex into risk stratification algorithms for VA or SD in DCM.