Beneficial impacts of physical activity on heart rate variability: A systematic review and meta-analysis.

BACKGROUND: Cardiovascular diseases (CVD) are the leading causes of morbidity and mortality. Heart rate variability (HRV) represents the modulatory capacity of the autonomous nervous system and influences mortality. By surveying this meta-analysis, we investigated the impact of physical activity on HRV. METHODS: Databases, online journal libraries and clinical trial registries were searched for publications of randomized controlled and non-randomized controlled trials concerning adults with coronary artery disease (CAD)/ischemic heart disease (IHD), congestive heart failure (CHF), peripheral arterial disease (PAD) or after acute coronary syndrome (ACS) joining an intervention group with physical activity or a control group with usual care or no intervention. Extracted time-domain and frequency-domain parameter of HRV were analyzed in a meta-analysis using a random effect model. Subgroup analyses concerning intervention type, study design and type of heart disease and sensitivity analysis were performed. RESULTS: Significant results were obtained for RR-Interval (p = 0.05) and standard deviation of Normal-to-Normal intervals (SDNN) (p = 0.01) for short-term assessment and for the ratio of low-frequency power (LF) to high-frequency power (HF) (p = 0.05) for 24-hour assessment. Subgroup analyses also resulted significant: root-mean-square difference of successive normal R-R intervals (RMSSD) (p = 0.01), SDNN (p = 0.02) and HF (p < 0.01) concerning CHF. CONCLUSION: We were able to demonstrate the positive impact of physical activity on HRV, especially in patients with CHF. Cardiac rehabilitation exercise programs need to be individualized to identify the most beneficial method of training for improving the prognosis of patients with CVD.

High neutrophil-to-lymphocyte ratio is associated with cancer therapy-related cardiovascular toxicity in high-risk cancer patients under immune checkpoint inhibitor therapy.

BACKGROUND: Cancer therapy-related cardiovascular toxicity (CTR-CVT) from immune checkpoint inhibitor (ICI) therapy is still incompletely characterized, and patients with pre-existing cardiovascular disease represent a particularly high-risk cohort. Valid parameters for risk stratification of these patients are missing. Neutrophil-to-lymphocyte ratio (NLR) has been shown to predict mortality and adverse events in other cardiovascular cohorts. The present study aims to examine the predictive capacity of NLR for risk stratification of patients particularly vulnerable for CTR-CVT under ICI therapy. METHODS: We performed an analysis of 88 cancer patients (69 ± 11 years, 25% female) with pre-existing cardiovascular disease under ICI therapy from the prospective Essen Cardio-Oncology Registry (ECoR). NLR was assessed at patient enrollment and the population was divided through receiver operator characteristic (ROC) curve analysis in patients with low (< 4.57) and high (≥ 4.57) NLR. Endpoint was the whole spectrum of CTR-CVT, according to the European guidelines on cardio-oncology. The median follow-up was 357 days (interquartile range (IQR): 150-509 days). RESULTS: We observed 4 cases of myocarditis, 17 cases of vascular toxicity, 3 cases of arterial hypertension, 22 cases of arrhythmia or QTc prolongation and 17 cases of cardiovascular dysfunction. NLR was associated with overall CTR-CVT by univariable Cox regression (hazard ratio (HR): 1.443; 95% confidence interval (CI) 1.082-1.925; p = 0.013). However, this association was attenuated after adjusting for further confounders. CONCLUSION: NLR is moderately associated with CTR-CVT in cancer patients with pre-existing cardiovascular disease under ICI therapy. Surveillance of NLR during ICI therapy might be an effective and economically biomarker for risk stratification in these high-risk patients.

The cardiorespiratory optimal point as a discriminator of lesion severity in adults with congenital heart disease.

BACKGROUND: Peak oxygen consumption (VO2peak), which depends on maximal exertion and is reduced in adults with congenital heart disease (ACHD), is associated with lesion severity. The lowest ventilatory equivalent for oxygen (the minimum value of VE/VO2) reflects the cardiorespiratory optimal point (COP) as best possible respiration-circulatory interaction and may discriminate between lesion types without the need for maximal exertion. However, data on COP in ACHD is scarce. METHODS: We retrospectively analyzed stable ACHD with moderate (N.=13) and severe lesions (N.=17) reporting to our outpatient clinic undergoing cardiopulmonary exercise testing. The primary outcome of the study was the difference of COP between moderate and severe lesions. Secondary outcomes were between group differences of the submaximal variable exercise oxygen uptake efficiency slope (OUES) and peak O2 pulse (O2pulsemax) as a surrogate for peripheral oxygen extraction and stroke volume increase during exercise. RESULTS: The group of severe lesions displayed higher COP (29.5±7.0 vs. 25.2±6.2, P=0.028) as well as lower O2pulsemax (13.3±8.4 vs. 14.9±3.4 mL/beat/kg 102, P=0.038). VO2peak (17.4±6.5 vs. 20.8±8.5 mL/kg/min, P=0.286) and OUES (1.5±0.7 vs. 1.8±0.9, P=0.613) showed a trend towards lower values in severe lesions. COP was a better between group discriminator than O2pulsemax (area under the curve 73.8% vs. 72.4%). CONCLUSIONS: As a submaximal variable, COP discriminated between moderate and severe lesions and may prove beneficial in a highly vulnerable population that is often unable to undergo exertional testing.

Phosphodiesterase-5 inhibitors for left ventricular assist device implantation complicated by right ventricular failure.

AIMS: Phosphodiesterase-5 inhibitors (PDE5I) are frequently implemented after left ventricular assist device (LVAD) implantation to improve haemodynamics in patients with early postoperative right ventricular (RV) failure. It is unknown if long-term PED5I therapy beyond the early post-operative period provides any clinical benefit in stable outpatients, who have recovered from post-operative RV failure under univentricular device support. This study aimed to investigate the impact of PDE5I discontinuation on RV function and cardiopulmonary exercise capacity in patients on durable LVAD support. METHODS AND RESULTS: We enrolled 31 clinically stable LVAD recipients on long-term oral PDE5I therapy. The mean age was 53 years, and 90% were male. Patients discontinued PDE5I and underwent cardiopulmonary exercise testing, echocardiography, LVAD interrogation, and biomarker analysis at baseline and 4 weeks after PDE5I withdrawal. At 4 weeks, no significant changes were observed in echocardiographic indices of RV morphology and function but an increase in peak tricuspid regurgitation velocity (2.1 vs. 2.4 m/s, P = 0.01). Peak oxygen consumption (11.4 vs. 11.8 mL/min/kg, P = 0.52), minute ventilation/carbon dioxide production slope (33 vs. 35, P = 0.56), N-terminal pro-brain natriuretic peptide (1455 vs. 1399 pg/mL, P = 0.55), flow and power readings of the device, and quality of life (Kansas City Cardiomyopathy Questionnaire score 78.3% vs. 77.5%, P = 0.62) exhibited no significant changes. We observed an increase in 6-min walking distance (346 vs. 364 m, P = 0.03). Two patients were hospitalized for non-cardiac reasons (subtherapeutic INR, driveline infection). No patient was hospitalized for cardiac decompensation. CONCLUSIONS: In LVAD patients with a history of early post-operative RV failure, discontinuation of long-term PDE5I therapy was not associated with deterioration of RV function, exercise capacity, and quality of life. PDE5I should be critically evaluated until more evidence regarding the net clinical benefit of this pharmacologic intervention becomes available.

Frequency and prognosis of CVD and myocardial injury in patients presenting with suspected COVID-19 - The CoV-COR registry.

Background: The COVID-19 pandemic led to an alteration of algorithms in emergency medicine, which may influence the management of patients with similar symptoms but underlying cardiovascular diseases. We evaluated key differential diagnoses to acute COVID-19 infection and the prevalence and the prognosis of myocardial injury in patients presenting for suspected COIVD-19 infection. Methods: This prospective observational study includes patients presenting with symptoms suggestive of COVID-19 infection during the pandemic. In patients without COVID-19, leading diagnoses was classified according to ICD-10. Myocardial injury was defined as elevated high-sensitivity Troponin I with at least one value above the 99th percentile upper reference limit and its prevalence together with 90-days mortality rate was compared in patients with vs without COVID-infection. Results: From 497 included patients (age 62.9 ± 17.2 years, 56 % male), 314 (63 %) were tested positive on COVID-19 based on PCR-testing, while another cause of symptom was detected in 183 patients (37 %). Cardiovascular diseases were the most frequent differential diagnoses (40 % of patients without COVID-19), followed by bacterial infection (24 %) and malignancies (16 %). Myocardial injury was present in 91 patients (COVID-19 positive: n = 34, COVID-19 negative: n = 57). 90-day mortality rate was higher in patients with myocardial injury (13.4 vs 4.6 %, p = 0.009). Conclusion: Cardiovascular diseases represent the most frequent differential diagnoses in patients presenting to a tertiary care emergency department with symptoms suggestive of an acute infection. Screening for cardiovascular disease is crucial in the initial evaluation of symptomatic patients during the COVID pandemic to identify patients at increased risk.Trial Registration:Clinicaltrials.gov Identifier: NCT04327479.

Right ventricular and atrial strain in patients with advanced melanoma undergoing immune checkpoint inhibitor therapy.

AIMS: While immune checkpoint inhibitor (ICI) therapy significantly improves survival rates in advanced melanoma, ICI can evoke severe immune-related cardiovascular adverse events. Right ventricular (RV) dysfunction negatively impacts the outcomes in cardiovascular diseases and may be an early sign for overall cardiotoxicity. We aimed to assess RV function in melanoma patients undergoing ICI therapy using conventional echocardiographic and strain imaging techniques. METHODS AND RESULTS: We retrospectively examined 30 patients (40% women, age 59 ± 13 years) with advanced melanoma (stage III/IV) before and 4 weeks after the start of ICI therapy (follow-up at 39 ± 15 days); n = 15 of the patients received nivolumab, and n = 15 received the combination therapy nivolumab/ipilimumab. Two-dimensional echocardiography with assessment of RV longitudinal strain of the free wall (RV-LSFW) and assessment of right atrial (RA) strain from speckle tracking was performed at baseline and after the start of ICI therapy. Short-term ICI therapy caused a reduction of RV-LSFW (-25.5 ± 6.4% vs. -22.4 ± 4.3%, P = 0.002) and of RA strain during contraction phase (-10.6 ± 3.5% vs. -7.7 ± 3.1%, P = 0.001). Conventional parameters including tricuspid annular plane systolic excursion (TAPSE), fractional area change (FAC), and pulmonary artery systolic pressure were not different between the two time points (TAPSE 26 ± 5 vs. 25 ± 5 mm, P = 0.125; FAC 38 ± 13% vs. 38 ± 14%, P = 0.750; and pulmonary artery systolic pressure 27 ± 10 vs. 25 ± 8 mmHg, P = 0.268). CONCLUSIONS: Analysis of RV and RA strain shows alterations even in a short-term follow-up, while changes in RV function are not visible by conventional RV parameters. Alterations in RV and RA strain could be early signs of cardiotoxicity and therefore should be assessed in patients undergoing ICI therapy.

Targeting early stages of cardiotoxicity from anti-PD1 immune checkpoint inhibitor therapy.

AIMS: Cardiac immune-related adverse events (irAEs) from immune checkpoint inhibition (ICI) targeting programmed death 1 (PD1) are of growing concern. Once cardiac irAEs become clinically manifest, fatality rates are high. Cardio-oncology aims to prevent detrimental effects before manifestation of severe complications by targeting early pathological changes. We therefore aimed to investigate early consequences of PD1 inhibition for cardiac integrity to prevent the development of overt cardiac disease. METHODS AND RESULTS: We investigated cardiac-specific consequences from anti-PD1 therapy in a combined biochemical and in vivo phenotyping approach. Mouse hearts showed broad expression of the ligand PDL1 on cardiac endothelial cells as a main mediator of immune-crosstalk. Using a novel melanoma mouse model, we assessed that anti-PD1 therapy promoted myocardial infiltration with CD4+ and CD8+ T cells, the latter being markedly activated. Left ventricular (LV) function was impaired during pharmacological stress, as shown by pressure-volume catheterization. This was associated with a dysregulated myocardial metabolism, including the proteome and the lipidome. Analogous to the experimental approach, in patients with metastatic melanoma (n = 7) receiving anti-PD1 therapy, LV function in response to stress was impaired under therapy. Finally, we identified that blockade of tumour necrosis factor alpha (TNFα) preserved LV function without attenuating the anti-cancer efficacy of anti-PD1 therapy. CONCLUSIONS: Anti-PD1 therapy induces a disruption of cardiac immune homeostasis leading to early impairment of myocardial functional integrity, with potential prognostic effects on the growing number of treated patients. Blockade of TNFα may serve as an approach to prevent the manifestation of ICI-related cardiotoxicity.

Left Ventricular Diastolic Function Following Anthracycline-Based Chemotherapy in Patients with Breast Cancer without Previous Cardiac Disease-A Meta-Analysis.

BACKGROUND: Anthracycline-based chemotherapy (ANT) remains among the most effective therapies for breast cancer. Cardiotoxicity from ANT represents a severe adverse event and may predominantly manifest as heart failure. While it is well-recognised that left ventricular systolic heart failure assessment is key in ANT-treated patients, less is known about the relevance of LV diastolic functional impairment and its characterisation. METHODS: Studies reporting on echocardiographic diastolic function parameters before and after ANT in breast cancer patients without cardiac disease were included. We evaluated pulsed wave (E/A ratio and mitral E-wave deceleration time (EDT)) and tissue Doppler (mean velocities of the mitral ring in the early diastole (e') and E/e' ratio) echocardiographic parameters. RESULTS: A total of 892 patients from 13 studies were included. E/A ratio was significantly reduced at the end of ANT while EDT was not influenced by ANT. Additionally, e' and E/e' ratio showed no significant change after ANT. A modest reduction in LV ejection fraction and global longitudinal strain was observed at the end of ANT therapy. CONCLUSIONS: ANT had a modest early impact on E/A ratio, without changing EDT, e', or E/e' in patients with breast cancer without cardiac disease. Randomised studies on larger populations, using new parameters are required to define the role of diastolic dysfunction in the early diagnosis of ANT-induced cardiotoxicity.

ECG Scoring for the Evaluation of Therapy-Naïve Cancer Patients to Predict Cardiotoxicity.

OBJECTIVE: To evaluate a new electrocardiographic (ECG) score reflecting domains of electrical and structural alterations in therapy-naïve cancer patients to assess their risk of cardiotoxicity. METHODS: We performed a retrospective analysis of 134 therapy-naïve consecutive cancer patients in our two university hospitals concerning four ECG score parameters: Contiguous Q-waves, markers of left ventricular (LV) hypertrophy, QRS duration and JTc prolongation. Cardiotoxicity was assessed after a short-term follow-up (up to 12 months). RESULTS: Of all the patients (n = 25), 19% reached 0 points, 50% (n = 67) reached 1 point, 25% (n = 33) reached 2 points, 5% (n = 7) reached 3 points and 0.7% reached 4 or 5 points (n = 1 respectively). The incidence of cardiotoxicity (n = 28 [21%]) increased with the ECG score, with 0 points at 0%, 1 point 7.5%, 2 points 55%, 3 points 71% and ≥3 points 50%. In the ROC (Receiver operating curves) analysis, the best cut-off for predicting cardiotoxicity was an ECG score of ≥2 points (sensitivity 82%, specificity 82%, AUC 0.84, 95% CI 0.77-0.92, p < 0.0001) which was then defined as a high-risk score. High-risk patients did not differ concerning their age, LV ejection fraction, classical cardiovascular risk factors or cardiac biomarkers compared to those with a low-risk ECG score. CONCLUSION: ECG scoring prior to the start of anti-cancer therapies may help to identify therapy-naïve cancer patients at a higher risk for the development of cardiotoxicity.

Assessment of coronary artery disease during hospitalization for cancer treatment.

BACKGROUND: With improvement of cancer-specific survival, comorbidities and treatment-related side effects, particularly cardiovascular toxicities, need close attention. The aim of the present study was to evaluate clinical characteristics and outcomes of cancer patients requiring coronary angiography during inpatient care. METHODS: We performed a retrospective analysis of patients hospitalized between 02/2011 and 02/2018 in our two university hospital cancer centers. From a cohort of 60,676 cancer patients, we identified 153 patients (65.7 ± 11.6 years, 73.2% male), who underwent coronary angiography and were eligible for analysis. These were compared to a control group of 153 non-cancer patients pair-matched with respect to age, sex, and indication for catheterization. RESULTS: Cancer patients presented in 66% with an acute coronary syndrome (ACS). The most prevalent cancer entities were lymphoma (19%) and lung cancer (18.3%). The rate of primary percutaneous coronary interventions (PCI) was significantly lower in the cancer cohort (40.5% vs. 53.6%, p = 0.029), although manifestation of coronary artery disease (CAD) and PCI results were comparable (SYNergy between PCI with TAXus and cardiac surgery (SYNTAX)-score, delta pre- and post-PCI - 9.8 vs. - 8.0, p = 0.2). Mortality was remarkably high in cancer patients (1-year mortality 46% vs. 8% in non-cancer patients, p < 0.001), particularly with troponin-positive ACS (5-year mortality 71%). CONCLUSION: Strategies to effectively control cardiovascular risks in cancer patients are needed. Additionally, suspected CAD in cancer patients should not prevent prompt diagnostic clarification and optimal revascularization as PCI results in cancer patients are comparable to non-cancer patients and occurrence of troponin-positive ACS leads to a significantly increased risk of mortality.

ECG Changes in Melanoma Patients Undergoing Cancer Therapy-Data From the ECoR Registry.

We aimed to evaluate whether therapy with immune checkpoint inhibitors (ICI) leads to changes in electrocardiogram (ECG) parameters in melanoma patients. We retrospectively examined 41 patients (46% women, age 61 ± 12years) with advanced melanoma (stage III/IV) before and during ICI treatment from our "Essen Cardio-oncology Registry" (ECoR). ECGs were analyzed before and 4-12 weeks after therapy started (follow-up, 90 ± 51 days). Heart rate, PR time, QRS duration and duration of the corrected QT (QTc) interval were recorded. QT dispersion (QTd) was calculated. Heart rate, PR time, QRS and QTc did not differ when comparing values before and after therapy started. QTd was prolonged after therapy started (32 ± 16 ms vs. 47 ± 19 ms, n = 41, p < 0.0001). Subgroup analyses revealed prolonged QTd in patients that received a combination immunotherapy with ipilimumab and nivolumab (31 ± 14 ms vs. 50 ± 14 ms, n = 21, p < 0.0001), while QTd in patients with anti-programmed death 1 (PD-1) inhibitor monotherapy did not change after therapy started. QTd is prolonged in patients under ICI combination therapy, potentially signaling an increased susceptibility to ventricular arrhythmias.

Global longitudinal strain is associated with better outcomes in transcatheter aortic valve replacement.

BACKGROUND: Parameters that mark the timing of left ventricular (LV) reverse remodeling following transcatheter aortic valve replacement (TAVR) are incompletely defined. This study aims to identify the dynamics of LV strain derived from speckle tracking echocardiography in a cohort of patients with severe aortic stenosis (AS) who underwent TAVR and its correlation with postprocedural outcomes. METHODS: We selected 150 consecutive patients (82 ± 4 years old, STS score 6.4 ± 6.2) who underwent transfemoral TAVR between 07/2016 and 12/2017 at our tertiary care center. All patients were evaluated at baseline, 1 week after TAVR, and 3 months following TAVR. RESULTS: The global longitudinal strain (GLS) 1 week following TAVR was comparable to that at baseline (- 15,9 ± 4.3 vs - 16.8 ± 4.1; p = NS) but significantly improved at 3 months following TAVR (- 15.9 ± 4.3% vs. -19.5 ± 3.5%; p < 0.001). No significant changes in global circumferential strain (GCS) and global radial strain (GRS) were detectable. The ejection fraction was significantly improved 1 week after the TAVR procedure. The baseline GLS correlated directly with the complication rate (R = 0.36, p = 0.005). The linear regression analysis showed that the main predictors of the improvement in the GLS at 3 months in our cohort were baseline GRS and GCS. CONCLUSION: GLS improves at 3 months after TAVR, while LV ejection fraction does not show a substantial change, signaling an early recovery of LV longitudinal function after the intervention. Additionally, GLS has a direct correlation with the postprocedural outcomes. GLS improvement might emerge as a valuable parameter for a tailored follow-up in TAVR patients.

Troponins and Natriuretic Peptides in Cardio-Oncology Patients-Data From the ECoR Registry.

BACKGROUND: The long-term survival of cancer patients has significantly improved over the past years. Despite their therapeutic efficacy, various cancer therapies are associated with cardiotoxicity. Therefore, timely detection of cardiotoxic adverse events is crucial. However, the clinical assessment of myocardial damage caused by cancer therapy remains difficult. METHODS: This retrospective study was performed to evaluate the diagnostic value of cardiac troponin I (cTnI) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) for monitoring cancer therapy-induced cardiomyopathy. A total of 485 cancer patients referred to our cardio-oncology unit between July 2018 and January 2020 were selected from our Essen Cardio-oncology Registry (ECoR). We included patients with all types of cancer. Plasma concentrations of cTnI and NT-proBNP were measured by radioimmunoassay, and two-dimensional left ventricular ejection fraction (2D-LVEF), diastolic function, and global longitudinal strain (GLS) were measured by transthoracic echocardiography. In 116 patients, assessment was conducted before the induction of cancer therapy and during a short-term follow-up period; n = 42 of these were treated for malignant melanoma, and n = 42 with serial measurements were under treatment for breast cancer. RESULTS: In cross-sectional data, elevated NT-proBNP was associated with reduced LVEF and pathological GLS in the total cohort. A total of 116 patients had serial LVEF and biomarker measurements, and changes in NT-proBNP and troponin correlated with changes in LVEF during follow-up investigations. Similar to the total cohort, a subgroup of patients treated for malignant melanoma showed a correlation between the change in cTnI and the change in LVEF. In a subgroup analysis of patients undergoing breast cancer therapy, a correlation between the change in NT-proBNP and the change in LVEF could be detected. Thirty patients presented with chemotherapy-induced cardiomyopathy, defined as a significant LVEF decrease (> 10%) to a value below 50%. The number of patients with increased cTnI and NT-proBNP was significantly higher in patients with chemotherapy-induced cardiomyopathy than in patients without cardiotoxicity. Patients with positive cTnI and NT-proBNP were more likely to have a history of coronary heart disease, atrial fibrillation, and arterial hypertension. CONCLUSION: Our data suggest that cardiac biomarkers play an important role in the detection of cancer therapy-induced cardiotoxicity. Larger systematic assessment in prospective cohorts is mandatory.

Impact of Bioprosthetic Choice on Mortality After Transfemoral Transcatheter Aortic Valve Implantation in Patients With Reduced Versus Preserved Left-Ventricular Ejection Fraction.

The outcome of transfemoral transcatheter aortic valve implantation (TF-TAVI) with a self-expanding (SEP) versus a balloon-expandable prosthesis (BEP) in patients with a reduced ejection fraction (rEF, ≤40%) has not been previously investigated. Patients with rEF have an increased risk of death after TF-TAVI compared to patients with a preserved ejection fraction (pEF), and prosthesis choice might influence the outcome of these patients. We, therefore, sought to compare all-cause mortality of patients with rEF using a SEP versus a BEP. We retrospectively analyzed data of 679 single-center TF-TAVI patients. Patients were censored at death or completion of 1-year follow-up, whichever occurred first. Patients with rEF (n = 141, 21%) had an increased 1-year mortality compared to patients with pEF (28% vs 19%, p = 0.007). SEP were implanted in 149 patients (49 with rEF, 33%), while BEP were implanted in 530 patients (92 with rEF, 17%). In patients with pEF, 1-year mortality was similar after SEP- and BEP-implantation (16% vs 19%, p = 0.516). In patients with rEF, however, 1-year mortality was higher after SEP- than after BEP-implantation (43% vs 21%, p = 0.004). These patients had a higher incidence of new permanent pacemaker implantation (26.5% vs 13%, p = 0.046) and paravalvular leak ≥II° (21% vs 10%, p = 0.07), but both factors could not explain the excess mortality after SEP-implantation in the multivariate analysis. In patients with rEF, the use of a SEP was an independent predictor of 1-year mortality (HR 2.44, 95% CI 1.27 to 4.27, p = 0.007). In conclusion, patients with rEF had a higher 1-year mortality after TF-TAVI when a SEP instead of a BEP was used.

Cardiac biomarkers for the detection of cardiotoxicity in childhood cancer-a meta-analysis.

AIMS: Childhood cancer therapy is associated with a significant risk of therapy-related cardiotoxicity. This meta-analysis aims to evaluate cardiac biomarkers for the detection of cancer therapy-related left ventricular (LV) dysfunction in childhood cancer patients. METHODS AND RESULTS: PubMed, Cochrane Library, Wiley Library, and Web of Science were screened for studies investigating brain natriuretic peptide (BNP)/N-terminal proBNP (NT-proBNP) or cardiac troponin in childhood cancer patients. The odds ratios (OR) for elevation of cardiac biomarkers and association with LV dysfunction were calculated using a random-effects model. Data from 27 studies with 1651 subjects were included. BNP/NT-proBNP levels were higher post-treatment compared with controls or pre-treatment values [standardized mean difference = 1.0; 95% confidence interval (CI) = 0.6-1.4; n = 320; P < 0.001]. LV dysfunction was present in 11.76% of included patients, and risk for LV dysfunction was increased in patients with elevated BNP/NT-proBNP (OR = 7.1; 95% CI = 2.0-25.5; n = 350; P = 0.003). The sensitivity of BNP/NT-proBNP for the detection of LV dysfunction was 33.3%, and the specificity was 91.5%. Sensitivity increased when selecting for studies that assessed patients < 5 years after anthracycline exposure and for studies including high cumulative anthracycline doses. Anthracycline chemotherapy was associated with an increased frequency of elevated troponin (OR = 3.7; 95% CI = 2.1-6.5; n = 348; P < 0.001). The available evidence on the association between elevated troponin and LV dysfunction was insufficient for an adequate analysis. In five included studies, the frequency of LV dysfunction was not increased in patients with elevated troponin (OR = 2.5; 95% CI = 0.5-13.2; n = 179; P = 0.53). CONCLUSIONS: BNP/NT-proBNP is associated with cardiotoxicity in paediatric cancer patients receiving anthracycline therapy, but owing to low sensitivity, BNP/NT-proBNP has to be evaluated in the context of further parameters including clinical assessment and echocardiography. Future studies are needed to determine whether troponin serves as a marker for cardiotoxicity in children. Standardized recommendations for the application of cardiac biomarkers in children undergoing cardiotoxic cancer therapy may benefit management and clinical outcome.

Troponins and brain natriuretic peptides for the prediction of cardiotoxicity in cancer patients: a meta-analysis.

AIMS: Cardiac biomarkers are a mainstay in diagnosis of cardiovascular disease but their role in cardio-oncology has not yet been systematically evaluated. This meta-analysis aims to determine whether cardiac troponins and (N-terminal pro) brain natriuretic peptide (BNP/NT-proBNP) predict cancer therapy-related left ventricular (LV) dysfunction. METHODS AND RESULTS: Scientific databases were searched for studies that assessed troponins or BNP/NT-proBNP in adult patients undergoing cancer therapy. Data from 61 trials with 5691 patients were included. Cancer therapy was associated with an increase in troponin levels [odds ratio (OR) 14.3, 95% confidence interval (CI) 6.0-34.1; n = 3049]. Patients with elevated troponins receiving chemotherapy or human epidermal growth factor receptor 2 inhibitor therapy were at higher risk for LV dysfunction (OR 11.9, 95% CI 4.4-32.1; n = 2163). Troponin had a negative predictive value of 93%. Mean BNP/NT-proBNP levels were increased in patients post-treatment (standardized mean difference 0.6, 95% CI 0.3-0.9; n = 912), but the available evidence did not consistently indicate prediction of LV dysfunction (OR 1.7, 95% CI 0.7-4.2; n = 197). ß-blocker and angiotensin-converting enzyme inhibitor therapy to mitigate cardiotoxicity during cancer therapy was associated with a decline in serum troponins (OR 4.1, 95% CI 1.7-9.8; n = 466). CONCLUSION: Elevated troponin levels predict LV dysfunction in patients receiving cancer therapy. Assessment of troponin levels may qualify as a screening test to identify patients who require referral to cardio-oncology units and benefit from preventive strategies. Further evidence is required for both biomarkers.

Impact of Cancer in Patients Undergoing Transcatheter Aortic Valve Replacement: A Single-Center Study.

BACKGROUND: The use of transcatheter aortic valve replacement (TAVR) in cancer survivors and patients with active cancer (AC) in cancer survivors and patients with active cancer (AC) is expanding, suggesting a need to adjust the indications and risk assessment pre-TAVR. OBJECTIVES: The purpose of this study was to determine the impact of cancer on peri-procedural complications and survival in a long-term, single-center cohort of patients treated with TAVR. METHODS: Patients treated with TAVR between January 2006 and December 2018 were grouped as follows: controls (patients without cancer), stable cancer (SC), and AC. The primary endpoints were peri-procedural complications and 30-day survival. A secondary endpoint was 10-year survival. RESULTS: A total of 1,088 patients (age 81 ± 5 years, 46.6% men) treated with transfemoral TAVR were selected: 839 controls, 196 SC, and 53 AC. Predominant malignancies were breast, gastrointestinal, and prostate cancer. No differences were observed between patients with cancer and controls regarding peri-procedural complications. Patients with AC had similar 30-day survival compared with controls and SC (94.3% vs. 93.3% vs. 96.9%, p = 0.161), but as expected, reduced 10-year survival. AC was associated with a 1.47 (95% CI 1.16 to 1.87) fold increased risk of all-cause 10-year mortality in multivariable adjusted models. CONCLUSIONS: TAVR should be performed in patients with cancer when indicated, considering that patients with cancer have similar periprocedural complications and short-term survival compared with control patients. However, patients with AC have worse 10-year survival. Future studies are needed to define cancer-specific determinants of worse long-term survival.

Cardiovascular Adverse Events Associated With BRAF and MEK Inhibitors: A Systematic Review and Meta-analysis.

Importance: Cardiovascular adverse events (CVAEs) after treatment with BRAF and MEK inhibitors in patients with melanoma remain incompletely characterized. Objective: To determine the association of BRAF and MEK inhibitor treatment with CVAEs in patients with melanoma compared with BRAF inhibitor monotherapy. Data Sources: PubMed, Cochrane, and Web of Science were systematically searched for keywords vemurafenib, dabrafenib, encorafenib, trametinib, binimetinib, and cobinimetinib from database inception through November 30, 2018. Study Selection: Randomized clinical trials reporting on CVAEs in patients with melanoma being treated with BRAF and MEK inhibitors compared with patients with melanoma being treated with BRAF inhibitor monotherapy were selected. Data Extraction and Synthesis: Data assessment followed the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines. Pooled relative risks (RRs) and 95% CIs were determined using random-effects and fixed-effects analyses. Subgroup analyses were conducted to assess study-level characteristics associated with CVAEs. Main Outcomes and Measures: The selected end points were pulmonary embolism, a decrease in left ventricular ejection fraction, arterial hypertension, myocardial infarction, atrial fibrillation, and QTc interval prolongation. All-grade and high-grade (≥3) CVAEs were recorded. Results: Overall, 5 randomized clinical trials including 2317 patients with melanoma were selected. Treatment with BRAF and MEK inhibitors was associated with an increased risk of pulmonary embolism (RR, 4.36; 95% CI, 1.23-15.44; P = .02), a decrease in left ventricular ejection fraction (RR, 3.72; 95% CI, 1.74-7.94; P < .001), and arterial hypertension (RR, 1.49; 95% CI, 1.12-1.97; P = .005) compared with BRAF inhibitor monotherapy. The RRs for myocardial infarction, atrial fibrillation, and QTc prolongation were similar between the groups. These results were consistent when assessing high-grade CVAEs (left ventricular ejection fraction: RR, 2.79; 95% CI, 1.36-5.73; P = .005; I2 = 29%; high-grade arterial hypertension: RR, 1.54; 95% CI, 1.14-2.08; P = .005; I2 = 0%), but RRs for high-grade pulmonary embolism were similar between groups. A higher risk of a decrease in left ventricular ejection fraction was associated with patients with a mean age younger than 55 years (RR, 26.50; 95% CI, 3.58-196.10; P = .001), and the associated risk of pulmonary embolism was higher for patients with a mean follow-up time longer than 15 months (RR, 7.70; 95% CI, 1.40-42.12; P = .02). Conclusions and Relevance: Therapy with BRAF and MEK inhibitors was associated with a higher risk of CVAEs compared with BRAF inhibitor monotherapy. The findings may help to balance between beneficial melanoma treatment and cardiovascular morbidity and mortality.

Heart failure from cancer therapy: can we prevent it?

AIMS: Conventional cytotoxic chemotherapy is still among the most effective treatment options for many types of cancer. However, cardiotoxicity, notably the decrease in left ventricular function under these regimens, can impair prognosis. Thus, prevention and treatment of cardiotoxicity are crucial. The present meta-analysis aims to assess the efficacy of beta-blockers or angiotensin-converting enzyme (ACE) inhibitors/angiotensin II receptor blockers (ARBs) for prevention of cardiotoxicity. METHODS AND RESULTS: We systematically searched Pubmed, Cochrane, EMBASE, and Web of Science databases for randomized controlled trials published until February 2019. The analysis included randomized studies that reported on left ventricular ejection fraction (LVEF) after 6 months of chemotherapy in cancer patients who received beta-blockers or ACE inhibitors/ARBs for prevention of cardiotoxicity compared with controls. Studies on combination cardioprotective therapies were excluded from the analysis. The primary endpoint was prevention of a decrease in LVEF as defined by the individual study and as assessed by either transthoracic echocardiography or magnetic resonance imaging. We here show that patients under anthracycline-based chemotherapy have a moderate yet significant benefit in LVEF from beta-blockers or ACEs/ARBs. The beta-blocker analysis included 769 cancer patients, and the ACE inhibitors/ARBs analysis included a total of 581 cancer patients. The mean LVEF difference between the beta-blocker group and the control group was 2.57% (95% confidence interval 0.63-4.51, P = 0.009). The mean difference for ACE inhibitors/ARBs was 4.71% (95% confidence interval 0.38-9.03, P = 0.03). However, the beneficial effects throughout the studies were variable as documented by significant heterogeneity between the studies. CONCLUSIONS: Systematic evidence is needed to solidly found recommendations for cardioprotective prevention during chemotherapy. Likewise, trials on other neurohumoral drugs (spironolactone) and lipid-lowering approaches are required to improve protection for cardio-oncology patients.