Appropriateness of antithrombotics in geriatric inpatients with atrial fibrillation: a retrospective, cross-sectional study.

BACKGROUND: Atrial fibrillation occurs in nearly half of geriatric inpatients and is a major cause of morbidity and mortality. Suboptimal anticoagulation use is an important concern in this population. This study aimed to evaluate the appropriateness of antithrombotic therapies in this patient cohort. METHODS: A retrospective analysis was conducted on the geriatric wards of a teaching hospital in Belgium, on a background of clinical pharmacy services. The first 90 atrial fibrillation patients from 2020 to 2022 were included if they received an oral anticoagulant. We assessed utilisation and appropriateness of antithrombotics at discharge, examined reasons for guideline deviations, and explored factors associated with underdosing. Temporal associations for appropriateness and type of anticoagulant (vitamin K antagonist (VKA) vs direct oral anticoagulant (DOAC)) were assessed. RESULTS: The mean age of patients was 86.5 (±5.3) years and the median CHA2DS2-VASc score was 5 (interquartile range (IQR) 4-6). At discharge, 256 (94.8%) patients used a DOAC; nine (3.3%) used a VKA; one (0.4%) a DOAC-antiplatelet combination, and in four patients (1.5%) all antithrombotics were discontinued. The majority (64.4%) of patients received reduced DOAC doses with apixaban prescribed in 40.7%. In 39 (14.4%) patients, antithrombotic use was considered inappropriate, mostly without a rationale (23/39). Year 2022 (odds ratio (OR) 0.104; 95% confidence interval (CI), 0.012-0.878) was the sole determinant for underdosing. No significant differences were found with respect to appropriateness (p=0.533) or anticoagulant class (p=0.479) over time. CONCLUSION: Most geriatric inpatients received a justified reduced DOAC dose. A significant proportion was managed inappropriately with underdosing (= unjustified reduced dose) being most common. Frequently no rationale was provided for deviating from trial-tested doses.

Artificial intelligence electrocardiogram as a novel screening tool to detect a newly abnormal left ventricular ejection fraction after anthracycline-based cancer therapy.

AIMS: Cardiotoxicity is a serious side effect of anthracycline treatment, most commonly manifesting as a reduction in left ventricular ejection fraction (EF). Early recognition and treatment have been advocated, but robust, convenient, and cost-effective alternatives to cardiac imaging are missing. Recent developments in artificial intelligence (AI) techniques applied to electrocardiograms (ECGs) may fill this gap, but no study so far has demonstrated its merit for the detection of an abnormal EF after anthracycline therapy. METHODS AND RESULTS: Single centre consecutive cohort study of all breast cancer patients with ECG and transthoracic echocardiography (TTE) evaluation before and after (neo)adjuvant anthracycline chemotherapy. Patients with HER2-directed therapy, metastatic disease, second primary malignancy, or pre-existing cardiovascular disease were excluded from the analyses as were patients with EF decline for reasons other than anthracycline-induced cardiotoxicity. Primary readout was the diagnostic performance of AI-ECG by area under the curve (AUC) for EFs < 50%. Of 989 consecutive female breast cancer patients, 22 developed a decline in EF attributed to anthracycline therapy over a follow-up time of 9.8 ± 4.2 years. After exclusion of patients who did not have ECGs within 90 days of a TTE, 20 cases and 683 controls remained. The AI-ECG model detected an EF < 50% and ≤ 35% after anthracycline therapy with an AUC of 0.93 and 0.94, respectively. CONCLUSION: These data support the use of AI-ECG for cardiotoxicity screening after anthracycline-based chemotherapy. This technology could serve as a gatekeeper to more costly cardiac imaging and could enable patients to monitor themselves over long periods of time.

Artificial intelligence electrocardiogram can be used to screen for an abnormal heart function after anthracycline chemotherapy, opening the door to new ways of cost-effective screening of cancer survivors at risk of cardiotoxicity over long periods of time.

Guideline-Directed Medical Therapies for Heart Failure with a Reduced Ejection Fraction in Older Adults: A Narrative Review on Efficacy, Safety and Timeliness.

Heart failure is a prevalent syndrome among older adults, with a major impact on morbidity and mortality. Higher age is correlated with underuse of guideline-directed medical therapies which, in turn, has been linked to worse clinical outcomes. Importantly, most evidence so far has been collected in adults who were younger, less multi-morbid and polymedicated compared with those who are commonly treated in daily clinical practice. Hence, we aimed to assess and describe the evidence base for pharmacotherapy in older adults with heart failure with a reduced ejection. First, a narrative review was undertaken using Medline, from inception to January 2023. Four foundational therapies were selected based on the latest European Society of Cardiology clinical practice guideline: angiotensin-converting enzyme inhibitors/angiotensin receptor neprilysin inhibitors, beta blockers, mineralocorticoid receptor antagonists and sodium-glucose cotransporter-2 inhibitors. Post hoc analyses from landmark heart failure drug trials were searched and included if they contained data on the impact of age on efficacy, safety and/or timeliness of therapies in the management of heart failure with a reduced ejection fraction. Second, a proposal was developed to support and promote the use of evidence-based heart failure pharmacotherapy in complex, older adults. In total, 11 articles were selected: 4 meta-analyses, 6 post hoc analyses and 1 review paper. No attenuation of efficacy for any of the foundational agents was found in older adults. Regarding safety, dedicated analyses showed that beta blockers, mineraloid receptor antagonists, sacubitril-valsartan, dapagliflozin and empagliflozin retained their overall benefit-risk profile regardless of age. Time to benefit was short and occurred generally within 1 month. Consensus was achieved on a five-step proposal to manage complex medication regimens in older adults suffering from heart failure. In conclusion, older adults suffering from heart failure with a reduced ejection fraction should not be denied treatment based on their age.

Pharmacokinetic drug-drug interactions with direct anticoagulants in the management of cancer-associated thrombosis.

Drug-drug interactions (DDIs) are common in cancer management and complicate the choice of anticoagulation in cancer-associated thrombosis. Cancer confers an increased risk of thrombotic events. Also, more bleeding events are observed in those who receive anticoagulation compared to those without cancer. In the treatment of cancer-associated thrombosis, direct oral anticoagulants (DOACs) have been found to be at least as effective as low-molecular weight heparins, which became the standard of care after several trials demonstrated superiority over vitamin K antagonists. Non-inferiority compared to low-molecular weight heparins has been shown for rivaroxaban, edoxaban and apixaban with a signal of fewer recurrent thrombotic events, albeit with an increase in bleeding events. Yet, potentially major pharmacokinetic drug-drug interactions have been identified as a reason to withhold DOACs and to rather choose an alternative. Practical guidance on what constitutes a major pharmacokinetic interaction and/or how to deal with these interactions in clinical practice is limited. Hence, here we have provided a framework to allow clinicians to better deal with pharmacokinetic drug-drug interactions between DOACs and cancer therapies in the management of cancer-associated thrombosis. In this review we have discussed the current literature, how the pharmacokinetic profile links to the label information on DDI, and have provided a practical proposal, applied to a clinical case.

Mortality and Major Adverse Cardiac Events in Patients With Breast Cancer Receiving Radiotherapy: The First Decade.

Background Treatment for breast cancer (BC) frequently involves radiotherapy. Guidelines recommend screening for cardiac adverse events starting 10 years after radiotherapy. The rationale for this interval is unclear. Methods and Results We aimed to study cardiovascular event rates in the first decade following curative radiotherapy for BC. We compared mortality and cardiovascular event rates with an age- and risk factor-matched control population. We included 1095 patients with BC (mean age 56±12 years). Two hundred and eighteen (19.9%) women died. Cancer and cardiovascular mortality caused 107 (49.1%) and 22 (10.1%) deaths, respectively. A total of 904 cases were matched to female FLEMENGHO (Flemish Study on Environment, Genes and Health Outcomes) participants. Coronary artery disease incidence was similar (risk ratio [RR], 0.75 [95% CI, 0.48-1.18]), yet heart failure (RR, 1.97 [95% CI, 1.19-3.25]) and atrial fibrillation/flutter (RR, 1.82 [95% CI, 1.07-3.08]) occurred more often in patients with BC. Age (hazard ratio [HR], 1.033 [95% CI, 1.006-1.061], P=0.016), tumor grade (HR, 1.739 [95% CI, 1.166-2.591], P=0.007), and neoadjuvant treatment setting (HR, 2.782 [95% CI, 1.304-5.936], P=0.008) were risk factors for mortality. Risk factors for major adverse cardiac events were age (HR, 1.053 [95% CI, 1.013-1.093]; P=0.008), mean heart dose (HR, 1.093 [95% CI, 1.025-1.167]; P=0.007), history of cardiovascular disease (HR, 2.386 [95% CI, 1.096-6.197]; P=0.029) and Mayo Clinic Cardiotoxicity Risk Score (HR, 2.664 [95% CI, 1.625-4.367]; P<0.001). Conclusions Ten-year mortality following curative treatment for unilateral BC was mainly cancer related, but heart failure and atrial fibrillation/flutter were already common in the first decade following irradiation. Mean heart dose, pre-existing cardiovascular diseases, and Mayo Clinic Cardiotoxicity Risk Score were risk factors for cardiac adverse events. These results suggest a need for early dedicated cardio-oncological follow-up after radiotherapy.

Tools to differentiate between Filamin C and Titin truncating variant carriers: value of MRI.

Whereas truncating variants of the giant protein Titin (TTNtv) are the main cause of familial dilated cardiomyopathy (DCM), recently Filamin C truncating variants (FLNCtv) were identified as a cause of arrhythmogenic cardiomyopathy (ACM). Our aim was to characterize and compare clinical and MRI features of TTNtv and FLNCtv in the Belgian population. In index patients referred for genetic testing of ACM/DCM, FLNCtv and TTNtv were found in 17 (3.6%) and 33 (12.3%) subjects, respectively. Further family cascade screening yielded 24 and 19 additional truncating variant carriers in FLNC and TTN, respectively. The main phenotype was ACM in FLNCtv carriers whereas TTNtv carriers showed either an ACM or DCM phenotype. Non-sustained Ventricular Tachycardia was frequent in both populations. MRI data, available in 28/40 FLNCtv and 32/52 TTNtv patients, showed lower Left Ventricular (LV) ejection fraction and lower LV strain in TTNtv patients (p < 0.01). Conversely, both the frequency (68% vs 22%) and extent of non-ischemic myocardial late gadolinium enhancement (LGE) was significantly higher in FLNCtv patients (p < 0.01). Hereby, ring-like LGE was found in 16/19 (84%) FLNCtv versus 1/7 (14%) of TTNtv patients (p < 0.01). In conclusion, a large number of FLNCtv and TTNtv patients present with an ACM phenotype but can be separated by cardiac MRI. Whereas FLNCtv patients often have extensive myocardial fibrosis, typically following a ring-like pattern, LV dysfunction without or limited replacement fibrosis is the common TTNtv phenotype.

Case report: Myocarditis in congenital STAT1 gain-of function.

Autosomal dominant Signal transducer and activator of transcription 1 (STAT1) gain-of-function (GOF) mutations result in an inborn error of immunity characterized by chronic mucocutaneous candidiasis, recurrent viral and bacterial infections, and diverse autoimmune manifestations. Current treatment consists of chronic antifungal therapy, antibiotics for concomitant infections, and immunosuppressive therapy in case of autoimmune diseases. More recently, treatment with Janus kinases 1 and 2 (JAK1/2) inhibitors have shown promising yet variable results. We describe a STAT1 GOF patient with an incidental finding of elevated cardiac troponins, leading to a diagnosis of a longstanding, slowly progressive idiopathic myocarditis, attributed to STAT1 GOF. Treatment with a JAK-inhibitor (baricitinib) mitigated cardiac inflammation on MRI but was unable to alter fibrosis, possibly due to the diagnostic and therapeutic delay, which finally led to fatal arrhythmia. Our case illustrates that myocarditis could be part of the heterogeneous disease spectrum of STAT1 GOF. Given the insidious presentation in our case, a low threshold for cardiac evaluation in STAT1 GOF patients seems warranted.

Cardiovascular risk of metabolically healthy obesity in two european populations: Prevention potential from a metabolomic study.

BACKGROUND: A new definition of metabolically healthy obesity (MHO) has recently been proposed to stratify the heterogeneous mortality risk of obesity. Metabolomic profiling provides clues to metabolic alterations beyond clinical definition. We aimed to evaluate the association between MHO and cardiovascular events and assess its metabolomic pattern. METHODS: This prospective study included Europeans from two population-based studies, the FLEMENGHO and the Hortega study. A total of 2339 participants with follow-up were analyzed, including 2218 with metabolomic profiling. Metabolic health was developed from the third National Health and Nutrition Examination Survey and the UK biobank cohorts and defined as systolic blood pressure < 130 mmHg, no antihypertensive drugs, waist-to-hip ratio < 0.95 for women or 1.03 for men, and the absence of diabetes. BMI categories included normal weight, overweight, and obesity (BMI < 25, 25-30, ≥ 30 kg/m2). Participants were classified into six subgroups according to BMI category and metabolic healthy status. Outcomes were fatal and nonfatal composited cardiovascular events. RESULTS: Of 2339 participants, the mean age was 51 years, 1161 (49.6%) were women, 434 (18.6%) had obesity, 117 (5.0%) were classified as MHO, and both cohorts had similar characteristics. Over a median of 9.2-year (3.7-13.0) follow-up, 245 cardiovascular events occurred. Compared to those with metabolically healthy normal weight, individuals with metabolic unhealthy status had a higher risk of cardiovascular events, regardless of BMI category (adjusted HR: 3.30 [95% CI: 1.73-6.28] for normal weight, 2.50 [95% CI: 1.34-4.66] for overweight, and 3.42 [95% CI: 1.81-6.44] for obesity), whereas those with MHO were not at increased risk of cardiovascular events (HR: 1.11 [95% CI: 0.36-3.45]). Factor analysis identified a metabolomic factor mainly associated with glucose regulation, which was associated with cardiovascular events (HR: 1.22 [95% CI: 1.10-1.36]). Individuals with MHO tended to present a higher metabolomic factor score than those with metabolically healthy normal weight (0.175 vs. -0.057, P = 0.019), and the score was comparable to metabolically unhealthy obesity (0.175 vs. -0.080, P = 0.91). CONCLUSIONS: Individuals with MHO may not present higher short-term cardiovascular risk but tend to have a metabolomic pattern associated with higher cardiovascular risk, emphasizing a need for early intervention.

Prediction of coronary artery disease using urinary proteomics.

AIMS: Coronary artery disease (CAD) is multifactorial, caused by complex pathophysiology, and contributes to a high burden of mortality worldwide. Urinary proteomic analyses may help to identify predictive biomarkers and provide insights into the pathogenesis of CAD. METHODS AND RESULTS: Urinary proteome was analysed in 965 participants using capillary electrophoresis coupled with mass spectrometry. A proteomic classifier was developed in a discovery cohort with 36 individuals with CAD and 36 matched controls using the support vector machine. The classifier was tested in a validation cohort with 115 individuals who progressed to CAD and 778 controls and compared with two previously developed CAD-associated classifiers, CAD238 and ACSP75. The Framingham and SCORE2 risk scores were available in 737 participants. Bioinformatic analysis was performed based on the CAD-associated peptides. The novel proteomic classifier was comprised of 160 urinary peptides, mainly related to collagen turnover, lipid metabolism, and inflammation. In the validation cohort, the classifier provided an area under the receiver operating characteristic curve (AUC) of 0.82 [95% confidence interval (CI): 0.78-0.87] for the CAD prediction in 8 years, superior to CAD238 (AUC: 0.71, 95% CI: 0.66-0.77) and ACSP75 (AUC: 0.53 and 95% CI: 0.47-0.60). On top of CAD238 and ACSP75, the addition of the novel classifier improved the AUC to 0.84 (95% CI: 0.80-0.89). In a multivariable Cox model, a 1-SD increment in the novel classifier was associated with a higher risk of CAD (HR: 1.54, 95% CI: 1.26-1.89, P < 0.0001). The new classifier further improved the risk reclassification of CAD on top of the Framingham or SCORE2 risk scores (net reclassification index: 0.61, 95% CI: 0.25-0.95, P = 0.001; 0.64, 95% CI: 0.28-0.98, P = 0.001, correspondingly). CONCLUSION: A novel urinary proteomic classifier related to collagen metabolism, lipids, and inflammation showed potential for the risk prediction of CAD. Urinary proteome provides an alternative approach to personalized prevention.

A biomarker that can predict coronary artery disease (CAD) is urgently in need. We developed and validated a urinary proteomic classifier for the prediction of CAD. The proteomic classifier involved in atherosclerosis improved the risk reclassification on top of the clinical risk score.

Combination prophylaxis in CMV high risk heart transplant recipients: A single center experience.

INTRODUCTION: Cytomegalovirus (CMV) is the most clinically relevant infectious agent following heart transplantation (HTX). Data on the beneficial effects of prophylactic use of CMV immunoglobulins (CMVIG) are scarce. METHODS: In this single-center, retrospective study, we reported patient outcomes following cardiac transplantation using prophylactic CMV treatment, including CMVIG. Distinct clinically relevant outcomes were compared across different CMV risk groups (CMV D-/R-, CMV D-/R+, CMV D+/R+, and CMV D+/R- or CMV high risk group). RESULTS: We included 272 heart transplant procedures, performed between 1/1/2009 and 1/11/2020. Sixty-one (22%) procedures belonged to the CMV high risk group, while 96 (35%), 50 (18%), and 65 (24%) were CMV D-/R-, CMV D-/R+, and CMV D+/R+, respectively. Baseline donor and recipient characteristics (sex, age, body mass index, cause of death, indication for HTX), ischemia times and baseline immunosuppressive regimens were similar across the different CMV risk groups, yet fewer patients were bridged with a mechanical circulatory support in the CMV D+/R- group. CMV disease following cardiac transplantation was more common in the CMV D+/R- risk group (n = 40 or 66.7%; p < .001), yet mortality and re-transplantation rates, cardiac allograft vasculopathy (CAV) severity, rejection episodes, and development of donor-specific antibodies (DSA), post-transplant lymphoproliferative diseases (PTLD), and EBV infections were similar across all four CMV risk groups. CONCLUSION: High risk CMV D+/R- patients had a similar survival compared to low and intermediate CMV risk groups using a prophylactic strategy combining CMVIG and viral DNA polymerase inhibitors. This may be related to a number of factors unrelated to prophylaxis strategy as two out of three CMV D+/R- recipients developed CMV primary infection after prophylaxis was discontinued.

Should vericiguat be initiated in geriatric inpatients with heart failure with reduced ejection fraction and a worsening heart failure event prior to discharge?

Heart failure (HF) occurs predominantly in older adults. HF patients have an increased risk for an acute exacerbation, which commonly requires hospitalisation. Such a worsening HF (WHF) event has an impact on prognosis. Vericiguat is a novel agent which has been shown to reduce the HF hospitalisation risk in patients with a recent WHF event. It is not fully clear how to position this novel agent in geriatric HF inpatients.

Estimating the Time to Benefit for Therapies in Heart Failure with Reduced Ejection Fraction: A Case Study of Sacubitril-Valsartan Using Reconstructed Data from a Randomized Controlled Trial.

BACKGROUND: Foundational therapies in heart failure improve clinical outcomes in heart failure with a reduced ejection fraction (HFrEF). Underuse of these life-prolonging heart failure therapies, such as sacubitril-valsartan, is common in older adults and has been associated with worse clinical outcomes. Characterizing the early benefits seen with these therapies might help increase their uptake in older adults. OBJECTIVE: We applied several methods to estimate the time to benefit of an HFrEF therapy, using sacubitril-valsartan as a case study. METHODS: PARADIGM-HF was a randomized controlled study on sacubitril-valsartan versus enalapril in stable, ambulatory HFrEF patients (n = 8399). The primary endpoint, a composite of death from cardiovascular causes or a first hospitalization for heart failure, was significantly reduced (sacubitril-valsartan (21.8%) versus enalapril (26.5%), hazard ratio (HR) 0.80 (95% confidence interval [CI] 0.73-0.87). We extracted and tabulated the Kaplan-Meier (KM) curves of the primary endpoint. An individual patient dataset was then reconstructed. The following methods were applied to explore the time to benefit of sacubitril-valsartan versus enalapril: visual estimation of the point of divergence of the KM curves, statistical process control (SPC), unadjusted landmark analyses using Cox proportional hazards analysis with 30-day increments until significance was persistently achieved, and comparing the survival probabilities of the extracted life tables. RESULTS: Six raters visually estimated the time to benefit at a median of 60 days (interquartile range 38-10 days). Using SPC we found an early benefit from 28 days on, using the longest predefined control period of 28 days. An absolute risk reduction of 1 and 2% was found after 59 and 250 days, respectively. The reconstructed dataset provided a similar HR of 0.8004 (95% CI 0.7331-0.8739). Landmark analyses persistently showed statistical significance from 390 days and later. Survival probabilities differed from 35 days onward. CONCLUSION: Using multiple approaches, the earliest benefit of sacubitril-valsartan compared to enalapril in stable HFrEF was found at about 1 month after initiation.

Lipoprotein profiles of fat distribution and its association with insulin sensitivity.

Background: Fat deposition is associated with adverse outcomes. Waist-to-hip (WHR) ratio is a simple feasible index to assess fat distribution. Lipoprotein particle composition in relation to WHR and to what extent their association is mediated by insulin sensitivity are less investigated. Methods: In 504 randomly recruited Flemish (mean age: 48.9 years; women: 51.6%), we analyzed the lipoprotein particle constitutions using nuclear magnetic resonance spectroscopy. WHR obesity described a WHR of ≥ 0.85 for women or 0.9 for men. Insulin sensitivity was evaluated by the homeostasis model assessment-estimated insulin resistance (HOMA-IR). SCORE-2 risk algorithm was applied to estimate 10-year cardiovascular risk. Statistical methods included multivariable-adjusted linear regression analysis, logistic regression analysis, and mediation analysis. Results: The prevalence of WHR obesity was 54.6%, approximately 3 times of BMI-determined obesity (19.1%). Individuals with WHR obesity had significantly higher metabolic complications, such as hypertension (57.1%), dyslipidemia (61.8%), and insulin resistance (14.2%). WHR and WHR obesity were positively associated with total very-low-density lipoprotein (VLDL) particle concentration, remnant cholesterol, and triglycerides, but were negatively associated with VLDL particle size (P ≤ 0.027), independent of body mass index and other covariates. WHR was inversely associated with total high-density lipoprotein (HDL) particle concentration, whereas WHR obesity was inversely associated with HDL cholesterol (P ≤ 0.039). Neither WHR nor WHR obesity was associated with the concentration of total low-density lipoprotein (LDL) particles, LDL particle size, and LDL cholesterol (P ≥ 0.089). In the mediation analysis, insulin sensitivity significantly mediated the effect of WHR on total VLDL particle concentration (mediation percentage: 37.0%), remnant cholesterol (47.7%), and HDL cholesterol (41.1%). Individuals with WHR obesity were at increased cardiovascular risk, regardless of LDL cholesterol (P ≤0.028). In WHR obesity, higher total VLDL particle concent36ration and remnant cholesterol, and lower HDL cholesterol were associated with an increased cardiovascular risk (P≤ 0.002). Conclusions: Upper-body fat deposition was independently associated with an unfavorable lipoprotein profile, and insulin sensitivity significantly mediated this association. LDL cholesterol might underestimate lipid abnormality for people with upper-body obesity and lowering VLDL particles and remnant cholesterol might potentially reduce the residual cardiovascular risk.

Consensus validation of a screening tool for cardiovascular pharmacotherapy in geriatric patients: the RASP_CARDIO list (Rationalization of Home Medication by an Adjusted STOPP list in Older Patients).

PURPOSE: Cardiovascular agents commonly used in geriatric patients, are linked to potentially avoidable harm and might hence be a suitable substrate for medication review practices. Therefore, we sought to update and validate the content of the cardiovascular segment of the previously published Rationalization of Home Medication by an Adjusted STOPP list in Older Patients (RASP) List. METHODS: A three-step study was conducted by the pharmacy department in collaboration with the geriatric medicine and cardiology department at the University Hospitals Leuven, Belgium. First, the cardiovascular segment of the RASP list version 2014 was updated taking into account published research, other screening tools and the input of end-users. Secondly, this draft was reviewed during three panel discussions with five expert cardiologists and three clinical pharmacists, all of whom had relevant expertise in geriatric pharmacotherapy. Thirdly, the content was validated using a modified Delphi Technique by a panel of European hospital pharmacists, cardiologists, geriatricians and an internal medicine physician. RESULTS: After the first and second step, the RASP_CARDIO list comprised 94 statements. Consensus (≥ 80% agreement) of all statements and one new statement about gliflozins in heart failure was achieved by a panel of seventeen experts across four European countries after two validation rounds. The final construct comprised a list of 95 statements related to potentially inappropriate prescribing of cardiovascular agents. CONCLUSION: The RASP_CARDIO list is an updated and validated explicit screening tool to optimize cardiovascular pharmacotherapy in geriatric patients.

Urinary matrix Gla protein is associated with mortality risk in Flemish population: A prospective study.

Background: Vascular calcification is strongly related to the risk of mortality and cardiovascular (CV) diseases. In vascular calcification, matrix Gla protein (MGP), a small vitamin K-dependent protein, is an important mineralization inhibitor. Recent studies showed that circulating MGP is associated with mortality risk. However, the longitudinal association between urinary excretion of MGP and all-cause mortality was not established. Materials and methods: Urinary MGP was measured in 776 randomly recruited Flemish population (mean age: 51.2 years; 50.9% women) at baseline (during 2005-2010) using capillary electrophoresis coupled with mass spectrometry. Plasma inactive MGP [desphospho-uncarboxylated MGP (dp-ucMGP)] levels were quantified in 646 individuals by ELISA kits. Mortality status was ascertained through the Belgian Population Registry until 2016. The longitudinal association with mortality was determined by the multivariate-adjusted Cox proportional hazards regression models. The multivariate linear regression models were used to identify determinants of urinary MGP level. Results: Over the 9.2 years, 47 (6.06%) participants died, including 15 CV deaths. For a doubling of urinary MGP, the hazard ratios (HRs) were 1.31 (95% CI: 1.01-1.69, P = 0.040) for all-cause mortality and 2.05 (95% CI: 1.11-3.79, P = 0.023) for CV mortality with adjustment for covariates, including estimated glomerular filtration rate and urine microalbumin. The addition of urinary MGP to the basic models improved the reclassification as suggested by the increased net reclassification improvement [64.01% (95% CI: 32.64-98.63)] and integrated discrimination improvement [2.33% (95% CI: 0.24-4.71)]. Circulating inactive MGP, total cholesterol, urine microalbumin, and smoking were significantly associated with urinary MGP levels (P ≤ 0.041), independent of sex and age. Conclusion: Elevated urinary MGP was associated with an increased risk of all-cause mortality and CV mortality and improved the risk reclassification for all-cause mortality. These findings suggested that urinary MGP might be useful in mortality risk assessment in the general population. However, these observations need to be replicated in larger studies with a longer follow-up time.

Predictability of cardiotoxicity: Experience of a Belgian cardio-oncology clinic.

BACKGROUND: New oncological treatments improved survival but also increased awareness of cardiovascular side-effects during and after cancer therapy. METHODS: We report the experience of the cardio-oncology clinic at a large Belgian tertiary care center and investigated the predictability of cardiotoxicity based on referring department, cardiovascular risk factors, cancer treatment and existing risk scores of the American Society of Clinical Oncologists (ASCO) and Mayo Clinic. Cardiotoxicity was defined as a 10% reduction in Left Ventricular Ejection Fraction (LVEF) compared to the baseline transthoracic echocardiography (TTE) in asymptomatic patients or 5% in symptomatic patients. RESULTS: Of the 324 patients included, 14.5% died during follow-up. Most deaths were oncological, yet 19% of deaths were attributable to cardiovascular diseases. Models based on cardiovascular risk factors alone and cardiovascular risk factors combined with cardiotoxic medication poorly predicted cardiotoxicity. Existing risk scores from ASCO and Mayo Clinic also poorly predicted cardiotoxicity. A weighed model based on the Mayo Clinic cardiotoxicity risk score was the best risk assessment tool with still a limited predictive value with an Area Under the Receiver Operating Characteristic curve of 0.654 (CI 95%: 0.601-0.715). CONCLUSION: Cardiovascular morbidity and mortality are common in cancer patients and survivors and stress the unmet need of adequate risk prediction tools for systematic screening and rigorous cardiovascular follow-up. In our outpatient cohort, cardiotoxicity risk could not be adequately predicted by cancer type, using classic cardiovascular risk factors, nor by the combination of cardiovascular risk factors and the proposed cancer treatment. Furthermore, we showed that existing cardiotoxicity risk scores are suboptimal and should thus be interpreted with caution.

Incidence of Cardiovascular Events in Patients Treated With Immune Checkpoint Inhibitors.

PURPOSE: In rare cases, immune checkpoint inhibitors (ICIs) cause immune-mediated myocarditis. However, true incidence of other major adverse cardiovascular events (MACEs) after ICI treatment remains unknown, mainly because late occurring side effects are rarely reported in prospective clinical trials. The aims of this study were (1) to identify incidence and risk factors of MACE in a real-life ICI-treated cancer cohort and (2) to compare incidence rates with patients with cancer who are not treated with ICIs and population controls. METHODS: In total, 672 patients treated with ICIs were included. The primary end point was MACE, a composite of acute coronary syndrome, heart failure (HF), stroke, and transient ischemic attack. Secondary outcomes were acute coronary syndrome and HF separately. Incidence rates were compared between groups after matching according to age, sex, cardiovascular history, and cancer type. RESULTS: The incidence of MACE was 10.3% during a median follow-up of 13 (interquartile range, 6-22) months. In multivariable analysis, a history of HF (hazard ratio 2.27; 95% CI, 1.03 to 5.04; P = .043) and valvular heart disease (hazard ratio 3.01; 95% CI, 1.05 to 8.66; P = .041) remained significantly associated with MACE. Cumulative incidence rates were significantly higher in the ICI group compared with the cancer cohort not exposed to ICI and the population controls, mainly driven by a higher risk of HF events. CONCLUSION: Cardiovascular events during and after ICI treatment are more common than currently appreciated. Patients at risk are those with a history of cardiovascular disease. Compared with matched cancer and population controls, MACE incidence rates are significantly higher, suggesting a potential harmful effect of ICI treatment besides the underlying risk.

Urinary Proteomic Profile of Arterial Stiffness Is Associated With Mortality and Cardiovascular Outcomes.

Background The underlying mechanisms of arterial stiffness remain not fully understood. This study aimed to identify a urinary proteomic profile to illuminate its pathogenesis and to determine the prognostic value of the profile for adverse outcomes. Methods and Results We measured aortic stiffness using pulse wave velocity (PWV) and analyzed urinary proteome using capillary electrophoresis coupled with mass spectrometry in 669 randomly recruited Flemish patients (mean age, 50.2 years; 51.1% women). We developed a PWV-derived urinary proteomic score (PWV-UP) by modeling PWV with proteomics data at baseline through orthogonal projections to latent structures. PWV-UP that consisted of 2336 peptides explained the 65% variance of PWV, higher than 36% explained by clinical risk factors. PWV-UP was significantly associated with PWV (adjusted ß=0.73 [95% CI, 0.67-0.79]; P<0.0001). Over 9.2 years (median), 36 participants died, and 75 experienced cardiovascular events. The adjusted hazard ratios (+1 SD) were 1.46 (95% CI, 1.08-1.97) for all-cause mortality, 2.04 (95% CI, 1.07-3.87) for cardiovascular mortality, and 1.39 (95% CI, 1.11-1.74) for cardiovascular events (P≤0.031). For PWV, the corresponding estimates were 1.25 (95% CI, 0.97-1.60), 1.35 (95% CI, 0.85-2.15), and 1.22 (95% CI, 1.02-1.47), respectively (P≥0.033). Pathway analysis revealed that the peptides in PWV-UP mostly involved multiple pathways, including collagen turnover, cell adhesion, inflammation, and lipid metabolism. Conclusions PWV-UP was highly associated with PWV and could be used as a biomarker of arterial stiffness. PWV-UP, but not PWV, was associated with all-cause mortality and cardiovascular mortality, implying that PWV-UP-associated peptides may be multifaceted and involved in diverse pathological processes beyond arterial stiffness.