Clonal hematopoiesis confers an increased mortality risk in orthotopic heart transplant recipients.

Novel risk stratification and non-invasive surveillance methods are needed in orthotopic heart transplant (OHT) to reduce morbidity and mortality post-transplant. Clonal hematopoiesis (CH) refers to the acquisition of specific gene mutations in hematopoietic stem cells linked to enhanced inflammation and worse cardiovascular outcomes. The purpose of this study was to investigate the association between CH and OHT. Blood samples were collected from 127 OHT recipients. Error-corrected sequencing was used to detect CH-associated mutations. We evaluated the association between CH and acute cellular rejection, CMV infection, cardiac allograft vasculopathy (CAV), malignancies, and survival. CH mutations were detected in 26 (20.5%) patients, mostly in DNMT3A, ASXL1, and TET2. Patients with CH showed a higher frequency of CAV grade 2 or 3 (0% vs. 18%, p < .001). Moreover, a higher mortality rate was observed in patients with CH (11 [42%] vs. 15 [15%], p = .008) with an adjusted hazard ratio of 2.9 (95% CI, 1.4-6.3; p = .003). CH was not associated with acute cellular rejection, CMV infection or malignancies. The prevalence of CH in OHT recipients is higher than previously reported for the general population of the same age group, with an associated higher prevalence of CAV and mortality.

Anthracycline-induced cardiomyopathy: cellular and molecular mechanisms.

Despite the known risk of cardiotoxicity, anthracyclines are widely prescribed chemotherapeutic agents. They are broadly characterized as being a robust effector of cellular apoptosis in rapidly proliferating cells through its actions in the nucleus and formation of reactive oxygen species (ROS). And, despite the early use of dexrazoxane, no effective treatment strategy has emerged to prevent the development of cardiomyopathy, despite decades of study, suggesting that much more insight into the underlying mechanism of the development of cardiomyopathy is needed. In this review, we detail the specific intracellular activities of anthracyclines, from the cell membrane to the sarcoplasmic reticulum, and highlight potential therapeutic windows that represent the forefront of research into the underlying causes of anthracycline-induced cardiomyopathy.

Evaluation of Risk Prediction Models to Identify Cancer Therapeutics Related Cardiac Dysfunction in Women with HER2+ Breast Cancer.

Cancer-therapeutics-related cardiac dysfunction (CTRCD) is an important concern in women receiving trastuzumab therapy for HER2+ breast cancer. However, the ability to assess CTRCD risk remains limited. In this retrospective cohort study, we apply three published risk prediction models (Ezaz et al., NSABP-31 cardiac risk scores (CRS), and HFA-ICOS trastuzumab proforma) to 629 women (mean age 52.4 ± 10.9 years) with Stage I-III HER2+ breast cancer treated with trastuzumab ± anthracyclines to assess their performance to identify CTRCD during or immediately post treatment. Using these models, patients were classified into CTRCD risk categories according to the pre-treatment characteristics. With NSABP-31 CRS and HFA-ICOS proformas, patients in the highest risk category had a 1.7-to-2.4-fold higher relative risk of CTRCD than the low-risk category (p = 0.010 and 0.005, respectively). However, with all three risk models, those in the low-risk category had a high absolute risk of CTRCD (15.5-25.5%). The discrimination of the models for CTRCD (AUC 0.51-0.60) and their calibration was limited. NSAP-31 CRS and HFA-ICOS proformas can identify relative differences in CTRCD risk between patients, but when considering absolute risk, they are only able to identify the highest risk patients. There remains an ongoing need for accurate CTRCD risk prediction models in women with HER2+ breast cancer.

Immune checkpoint inhibitor-related myocarditis: an illustrative case series of applying the updated Cardiovascular Magnetic Resonance Lake Louise Criteria.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have improved outcomes for many types of cancer. However, ICI therapies are associated with the development of myocarditis, an immune-mediated adverse event associated with a high mortality rate. Therefore, prompt diagnosis and early intervention are of outmost importance. There is limited data on the application of cardiovascular magnetic resonance (CMR)-based modified Lake Louise Criteria (mLLC) with the use of relaxometry techniques for the diagnosis of ICI myocarditis. CASE SUMMARY: Four cancer patients undergoing ICI treatment presented with various clinical symptoms and troponin elevation to emergency/ambulatory clinics within 10-21 days after ICI initiation. On the suspicion of possible ICI-related myocarditis all patients underwent CMR within a few days after admission. Applying mLLC including relaxometry techniques, all patients met 'non-ischaemic injury criteria', while 3/4 patients met 'oedema criteria'. In most patients, quantitative mapping revealed substantially increased T1 values, while T2 values were only mildly increased or normal. In two patients with follow-up, CMR demonstrated improvement in findings after immunosuppressive treatment. However, there was only limited agreement between the degree of high-sensitive troponin levels and T1/T2 levels. DISCUSSION: The application of mLLC with T1/T2 mapping appears useful in the CMR diagnosis of acute ICI myocarditis with non-ischaemic myocardial injury criteria being the most common finding. The sensitivity of native T1 appears higher than T2 mapping in the acute diagnosis as well as in the assessment of treatment response. As troponin elevations may persist for some time with ICI myocarditis, CMR may represent an alternate strategy to monitor treatment response.

Cardiovascular Disease Among Patients With AML and CHIP-Related Mutations.

Background: Clonal hematopoiesis of indeterminate potential (CHIP) is a novel cardiovascular disease (CVD) risk factor in individuals without acute myeloid leukemia (AML). Objectives: The aim of this study was to examine the association between mutations associated with CHIP (CHIP-related mutations) identified in patients at AML diagnosis and the risk for cardiovascular events (CVEs). Methods: This was a retrospective cohort study of 623 patients with AML treated between 2015 and 2018 who underwent DNA analysis. Cause-specific hazard regression models were used to study the associations between pathogenic mutations in common CHIP-related genes (DNMT3A, TET2, ASXL1, JAK2, TP53, SRSF2, and SF3B1) and the rate of CVEs (heart failure hospitalization, acute coronary syndrome, coronary artery revascularization, ischemic stroke, venous thromboembolism, and CVD death) and between CVE development and all-cause mortality. Results: Patients were 64.6 ± 15.3 years of age, 265 (42.5%) were women, and 63% had at least 1 CHIP-related mutation. Those with CHIP-related mutations were older (69.2 ± 12.3 vs 56.6 ± 16.6 years; P < 0.001) and had a greater prevalence of CVD risk factors and CVD history. In adjusted analysis, the presence of any CHIP-related mutation was associated with a higher rate of CVEs (HR: 1.74; 95% CI: 1.03-2.93; P = 0.037) among intensively treated patients (anthracycline based) but not the whole cohort (HR: 1.26; 95% CI: 0.81-1.97; P = 0.31). TP53 (HR: 4.18; 95% CI: 2.07-8.47; P < 0.001) and ASXL1 (HR: 2.37; 95% CI: 1.21-4.63; P = 0.012) mutations were associated with CVEs among intensively treated patients. Interval development of CVEs was associated with all-cause mortality (HR: 1.99; 95% CI: 1.45-2.73; P < 0.001). Conclusions: Among patients with AML treated with intensive chemotherapy, mutations in CHIP-related genes were associated with an increased risk for developing incident CVEs after AML diagnosis.

Diagnostic and Prognostic Value of Myocardial Work Indices for Identification of Cancer Therapy-Related Cardiotoxicity.

BACKGROUND: Echocardiographic global longitudinal strain (GLS) is a useful measure for detection of cancer treatment-related cardiac dysfunction (CTRCD) but is influenced by blood pressure changes. This limitation may be overcome by assessment of myocardial work (MW), which incorporates blood pressure into the calculation. OBJECTIVES: This work aims to determine whether myocardial work indices (MWIs) can help diagnose or prognosticate CTRCD. METHODS: In this prospective cohort study, 136 women undergoing anthracycline and trastuzumab treatment for HER2+ breast cancer, underwent serial echocardiograms and cardiac magnetic resonance pre- and post-anthracycline and every 3 months during trastuzumab. GLS, global work index (GWI), global constructive work (GCW), global wasted work, and global work efficiency were measured. CTRCD was defined with cardiac magnetic resonance. Generalized estimating equations quantified the association between changes in GLS and MWIs and CTRCD at the current (diagnosis) and subsequent visit (prognosis). Regression tree analysis was used to explore the combined use of GLS and MW for the diagnostic/prognostic assessment of CTRCD. RESULTS: Baseline left ventricular ejection fraction (LVEF) was 63.2 ± 4.0%. Thirty-seven (27.2%) patients developed CTRCD. An absolute change in GLS (standardized odds ratio [sOR]: 1.97 [95% CI: 1.07-3.66]; P = 0.031) and GWI (sOR: 1.73 [95% CI: 1.04-2.85]; P = 0.033) were associated with concurrent CTRCD. An absolute change in GLS (sOR: 1.79 [95% CI: 1.22-2.62]; P = 0.003), GWI (sOR: 1.67 [95% CI: 1.20-2.32]; P = 0.003), and GCW (sOR: 1.65 [95% CI: 1.17-2.34]; P = 0.005) were associated with subsequent CTRCD. Change in GWI and GCW demonstrated incremental value over GLS and clinical factors for the diagnosis of concurrent CTRCD. In a small group with a GLS change <3.3% (absolute), and a >21 mm Hg reduction in systolic blood pressure, worsening of GWI identified patients with higher probability of concurrent CTRCD (24.0% vs 5.2%). MWIs did not improve identification of subsequent CTRCD beyond knowledge of GLS change. CONCLUSIONS: GLS can be used to diagnose and prognosticate cardiac magnetic resonance (CMR) defined CTRCD, with additional value from MWIs in selected cases. (Evaluation of Myocardial Changes During Breast Adenocarcinoma Therapy to Detect Cardiotoxicity Earlier With MRI [EMBRACE-MRI]; NCT02306538).

Statin Exposure and Risk of Heart Failure After Anthracycline- or Trastuzumab-Based Chemotherapy for Early Breast Cancer: A Propensity Score‒Matched Cohort Study.

Background Statins are hypothesized to reduce the risk of cardiotoxicity associated with anthracyclines and trastuzumab. Our aim was to study the association of statin exposure with hospitalization or emergency department visits (hospital presentations) for heart failure (HF) after anthracycline- and/or trastuzumab-containing chemotherapy for early breast cancer. Methods and Results Using linked administrative databases, we conducted a retrospective cohort study of women aged ≥66 years without prior HF who received anthracyclines or trastuzumab for newly diagnosed early breast cancer in Ontario between 2007 to 2017. Statin-exposed and unexposed women were matched 1:1 using propensity scores. Trastuzumab-treated women were also matched on anthracycline exposure. We matched 666 statin-discordant pairs of anthracycline-treated women and 390 pairs of trastuzumab-treated women (median age, 69 and 71 years, respectively). The 5-year cumulative incidence of HF hospital presentations after anthracyclines was 1.2% (95% CI, 0.5%-2.6%) in statin-exposed women and 2.9% (95% CI, 1.7%-4.6%) in unexposed women (P value, 0.01). The cause-specific hazard ratio associated with statins in the anthracycline cohort was 0.45 (95% CI, 0.24-0.85; P value, 0.01). After trastuzumab, the 5-year cumulative incidence of HF hospital presentations was 2.7% (95% CI, 1.2%-5.2%) in statin-exposed women and 3.7% (95% CI, 2.0%-6.2%) in unexposed women (P value 0.09). The cause-specific hazard ratio associated with statins in the trastuzumab cohort was 0.46 (95% CI, 0.20-1.07; P value, 0.07). Conclusions Statin-exposed women had a lower risk of HF hospital presentations after early breast cancer chemotherapy involving anthracyclines, with non-significant trends towards lower risk following trastuzumab. These findings support the development of randomized controlled trials of statins for prevention of cardiotoxicity.

Characteristics and Outcomes of Women Developing Heart Failure After Early Stage Breast Cancer Chemotherapy: A Population-Based Matched Cohort Study.

BACKGROUND: The prognosis of heart failure (HF) after early stage breast cancer (EBC) treatment with anthracyclines or trastuzumab is not well-characterized. METHODS: Using administrative databases, women diagnosed with HF after receiving anthracyclines or trastuzumab for EBC in Ontario during 2007 to 2017 (the EBC-HF cohort) were categorized by cardiotoxic exposure (anthracycline alone, trastuzumab alone, sequential therapy with both agents) and matched on age with ≤3 cancer-free HF controls to compare baseline characteristics. To study prognosis after HF onset, we conducted a second match on age plus important HF prognostic factors. The cumulative incidence function was used to describe risk of hospitalization or emergency department visits (hospital presentations) for HF and cardiovascular death. RESULTS: A total of 804 women with EBC developed HF after anthracyclines (n=312), trastuzumab (n=112), or sequential therapy (n=380); they had significantly fewer comorbidities than 2411 age-matched HF controls. After the second match, the anthracycline-HF cohort had a similar 5-year incidence of HF hospital presentations (16.5% [95% CI, 12.0%-21.7%]) as controls (17.1% [95% CI, 14.4%-20.1%]); the 5-year incidence was lower than matched controls for the trastuzumab-HF (9.7% [95% CI, 4.7%-16.9%]; controls 16.4% [95% CI, 12.1%-21.3%]; P=0.03) and sequential-HF cohorts (2.7% [95% CI, 1.4%-4.8%]; controls 10.8% [95% CI, 8.9%-13.0%]; P<0.001). At 5 years, the incidence of cardiovascular death was 2.9% (95% CI, 1.2%-5.9%) in the anthracycline-HF cohort vs. 9.5% (95% CI, 6.9%-12.6%) in controls, and 1.7% (0.6%-3.7%) for women developing HF after trastuzumab vs. 4.3% (95% CI, 3.1-5.8%) for controls. CONCLUSIONS: Women developing HF after cardiotoxic EBC chemotherapy have fewer comorbidities than cancer-free women with HF; trastuzumab-treated women who develop HF have better prognosis than matched HF controls.

Cardiovascular Risk Associated With Ibrutinib Use in Chronic Lymphocytic Leukemia: A Population-Based Cohort Study.

PURPOSE: Ibrutinib reduces mortality in chronic lymphocytic leukemia (CLL). It increases the risk of atrial fibrillation (AF) and bleeding and there are concerns about heart failure (HF) and central nervous system ischemic events. The magnitude of these risks remains poorly quantified. METHODS: Using linked administrative databases, we conducted a population-based cohort study of Ontario patients who were treated for CLL diagnosed between 2007 and 2019. We matched ibrutinib-treated patients with controls treated with chemotherapy but unexposed to ibrutinib on prior AF, age ≥ 66 years, anticoagulant exposure, and propensity for receiving ibrutinib. Study outcomes were AF-related health care contact, hospital-diagnosed bleeding, new diagnoses of HF, and hospitalizations for stroke and acute myocardial infarction (AMI). The cumulative incidence function was used to estimate absolute risks. We used cause-specific regression to study the association of ibrutinib with bleeding rates, while adjusting for anticoagulation as a time-varying covariate. RESULTS: We matched 778 pairs of ibrutinib-treated and unexposed patients with CLL (N = 1,556). The 3-year incidence of AF-related health care contact was 22.7% (95% CI, 19.0 to 26.6) in ibrutinib-treated patients and 11.7% (95% CI, 9.0 to 14.8) in controls. The 3-year risk of hospital-diagnosed bleeding was 8.8% (95% CI, 6.5 to 11.7) in ibrutinib-treated patients and 3.1% (95% CI, 1.9 to 4.6) in controls. Ibrutinib-treated patients were more likely to start anticoagulation after the index date. After adjusting for anticoagulation as a time-varying covariate, ibrutinib remained positively associated with bleeding (HR, 2.58; 95% CI, 1.76 to 3.78). The 3-year risk of HF was 7.7% (95% CI, 5.4 to 10.6%) in ibrutinib-treated patients and 3.6% (95% CI, 2.2 to 5.4) in controls. There was no significant difference in the risk of ischemic stroke or AMI. CONCLUSION: Ibrutinib is associated with higher risk of AF, bleeding, and HF, but not AMI or stroke.

Myocardial T1 and T2 Mapping by Magnetic Resonance in Patients With Immune Checkpoint Inhibitor-Associated Myocarditis.

BACKGROUND: Myocarditis is a potentially fatal complication of immune checkpoint inhibitor (ICI) therapy. Data on the utility of cardiovascular magnetic resonance (CMR) T1 and T2 mapping in ICI myocarditis are limited. OBJECTIVES: This study sought to assess the value of CMR T1 and T2 mapping in patients with ICI myocarditis. METHODS: In this retrospective study from an international registry of patients with ICI myocarditis, clinical and CMR findings (including T1 and T2 maps) were collected. Abnormal T1 and T2 were defined as 2 SD above site (vendor/field strength specific) reference values and a z-score was calculated for each patient. Major adverse cardiovascular events (MACE) were a composite of cardiovascular death, cardiogenic shock, cardiac arrest, and complete heart block. RESULTS: Of 136 patients with ICI myocarditis with a CMR, 86 (63%) had T1 maps and 79 (58%) also had T2 maps. Among the 86 patients (66.3 ± 13.1 years of age), 36 (41.9%) had a left ventricular ejection fraction <55%. Across all patients, mean z-scores for T1 and T2 values were 2.9 ± 1.9 (p < 0.001) and 2.2 ± 2.1 (p < 0.001), respectively. On Siemens 1.5-T scanner (n = 67), native T1 (1,079.0 ± 55.5 ms vs. 1,000.3 ± 22.1 ms; p < 0.001) and T2 (56.2 ± 4.9 ms vs. 49.8 ± 2.2 ms; p < 0.001) values were elevated compared with reference values. Abnormal T1 and T2 values were seen in 78% and 43% of the patients, respectively. Applying the modified Lake Louise Criteria, 95% met the nonischemic myocardial injury criteria and 53% met the myocardial edema criteria. Native T1 values had excellent discriminatory value for subsequent MACE, with an area under the curve of 0.91 (95% confidence interval: 0.84 to 0.98). Native T1 values (for every 1-unit increase in z-score, hazard ratio: 1.44; 95% confidence interval: 1.12 to 1.84; p = 0.004) but not T2 values were independently associated with subsequent MACE. CONCLUSIONS: The use of T1 mapping and application of the modified Lake Louise Criteria provides important diagnostic value, and T1 mapping provides prognostic value in patients with ICI myocarditis.

Cardiovascular Collapse in COVID-19 Infection: The Role of Venoarterial Extracorporeal Membrane Oxygenation (VA-ECMO).

Coronavirus Disease 2019 (COVID-19) has been associated with cardiovascular complications, including acute cardiac injury, heart failure, and cardiogenic shock (CS). The role of venoarterial extracorporeal membrane oxygenation (VA-ECMO) in the event of COVID-19-associated cardiovascular collapse has not been established. We reviewed the existing literature surrounding the role of VA-ECMO in the treatment of coronavirus-related cardiovascular collapse. COVID-19 is associated with a higher incidence of cardiovascular complications compared with previous coronavirus outbreaks (Severe Acute Respiratory Syndrome Coronavirus and Middle East Respiratory Syndrome Coronavirus). We found only 1 case report from China in which COVID-19-associated fulminant myocarditis and CS were successfully rescued using VA-ECMO as a bridge to recovery. We identified potential clinical scenarios (cardiac injury, myocardial infarction with and without obstructive coronary artery disease, viral myocarditis, and decompensated heart failure) leading to CS and risk factors for poor/uncertain benefit (age, sepsis, mixed/predominantly vasodilatory shock, prothrombotic state or coagulopathy, severe acute respiratory distress syndrome, multiorgan failure, or high-risk prognostic scores) specific to using VA-ECMO as a bridge to recovery in COVID-19 infection. Additional considerations and proposed recommendations specific to the COVID-19 pandemic were formulated with guidance from published data and expert consensus. A small subset of patients with cardiovascular complications from COVID-19 infection may progress to refractory CS. While accepting that resource scarcity may be the overwhelming concern for healthcare systems during this pandemic, VA-ECMO can be considered in highly selected cases of refractory CS and echocardiographic evidence of biventricular failure. The decision to initiate this therapy should take into consideration the availability of resources, perceived benefit, and risks of transmitting disease.

La maladie à coronavirus 2019 (COVID-19) est associée à des complications cardiovasculaires, y compris des lésions cardiaques aiguës, l'insuffisance cardiaque et le choc cardiogénique (CC). Le rôle de l'oxygénation par membrane extracorporelle (ECMO pour extracorporeal membrane oxygenation) veino-artérielle dans les cas de collapsus cardiovasculaire associé à la COVID-19 n'a pas été établi. Nous avons passé en revue la documentation existante abordant le rôle de l'ECMO veino-artérielle dans le traitement du collapsus cardiovasculaire lié au coronavirus. La COVID-19 est associée à une incidence plus élevée de complications cardiovasculaires comparativement aux éclosions antérieures d'infections à coronavirus (syndrome respiratoire aigu sévère et syndrome respiratoire du Moyen-Orient). Nous n'avons trouvé qu'un seul cas (signalé en Chine) de myocardite fulminante et de CC associés à la COVID-19 où l'ECMO veino-artérielle a permis d'assurer la survie du patient dans l'attente d'une récupération de la fonction cardiaque. Nous avons ciblé divers scénarios cliniques (lésion cardiaque, infarctus du myocarde avec ou sans coronaropathie obstructive, myocardite virale et insuffisance cardiaque décompensée) susceptibles d'aboutir à un CC et cerné des facteurs de risque de bienfaits faibles ou incertains (âge, septicémie, choc vasodilatateur mixte ou prédominant, état prothrombotique ou coagulopathie, syndrome de détresse respiratoire aiguë sévère, défaillance multiviscérale ou scores pronostiques à haut risque) cadrant spécifiquement avec l'utilisation de l'ECMO veino-artérielle dans l'attente d'une récupération de la fonction cardiaque chez le patient atteint de COVID-19. D'autres considérations et recommandations visant spécifiquement la pandémie de COVID-19 ont été énoncées à la lumière des données publiées et d'un consensus d'experts. Au sein d'un petit sous-groupe de patients atteints de COVID-19, les complications cardiovasculaires de l'infection peuvent évoluer vers un CC réfractaire. Tout en acceptant que la pénurie de ressources puisse être la principale préoccupation des systèmes de santé pendant cette pandémie, on peut envisager de recourir à l'ECMO veino-artérielle dans des cas soigneusement sélectionnés de CC réfractaire et en présence de preuves échocardiographiques d'insuffisance biventriculaire. La décision d'instaurer ce traitement doit tenir compte de la disponibilité des ressources, des avantages perçus et des risques de transmission de la maladie.

Trastuzumab-Related Cardiotoxicity and Cardiac Care in Patients With HER2 Positive Metastatic Breast Cancer.

Prolonged trastuzumab therapy is the standard of care for women with metastatic HER2 positive (HER2+) breast cancer. There are limited data on the incidence of cardiotoxicity, its treatment implication, and cardiac care in these patients. We retrospectively identified consecutive women who received >12 months of trastuzumab treatment at Princess Margaret Cancer Centre (Toronto, ON) from 2007 to 2012 for metastatic HER2 positive breast cancer and followed them until death or August 2018. Patients were included if a pretherapy multigated acquisition scan and ≥2 subsequent follow-up scans were available. The Cardiac Review and Evaluation Committee Criteria were used to identify cardiotoxicity. Baseline characteristics and outcomes (final left ventricular ejection fraction, change in LVEF, trastuzumab interruption) were compared in patients with and without cardiotoxicity. Cardiac care and treatment received were recorded. Sixty patients (mean age 52 ± 10.4 years) were included. The median trastuzumab exposure was 37 cycles (interquartile range 23 to 56) over 28 months (interquartile range 19 to 49) and 48% received previous anthracycline therapy. The cumulative incidence of cardiotoxicity was 35% (95% CI 23 to 48) at 3 years. Patients who developed cardiotoxicity were more likely to receive third-line cancer treatments and had lower final LVEF than patients without (54.9% ± 6.3% vs 64% ± 4.9%, p <0.001). Of the 23 patients with cardiotoxicity, 10 (43%) had trastuzumab interrupted for at least 1 cycle, only 7 (30%) patients were seen by a cardiologist and 4 (17%) received cardiac medications. In conclusion, patients with metastatic breast cancer receiving prolonged trastuzumab therapy appear to have high rates of cardiotoxicity. This was associated with high rates of trastuzumab interruption, but low rates of cardiology referral and cardiac treatment, reflecting a potential cardiac care gap.

The Yield of Routine Cardiac Imaging in Breast Cancer Patients Receiving Trastuzumab-Based Treatment: A Retrospective Cohort Study.

BACKGROUND: There are limited data on the yield of routine cardiac imaging for trastuzumab-treated patients with breast cancer. METHODS: We conducted a retrospective cohort study of patients with breast cancer treated with adjuvant trastuzumab between 2007 and 2012 at Princess Margaret Cancer Centre (Toronto, Canada). We classified imaging tests as clinically prompted or routinely ordered and determined whether each test led to changes in patient care. A generalized estimating equation model was used to determine if patient characteristics predicted routine studies more likely to change care. We analysed routine tests that were exclusively preceded by consecutive tests that did not change care to determine if their yield differed by time since trastuzumab start and the number of prior tests that did not change care. RESULTS: We identified 448 patients who received 1735 cardiac imaging studies after trastuzumab initiation. Of 1555 routine tests, 44 led to changes in care (2.8%) for 43 patients, whereas 50 of 180 clinically prompted tests (27.8%) altered care in 29 patients (P-value < 0.001). Earlier stage cancer, diabetes, prior anthracyclines, and prior cardiovascular disease were associated with a higher likelihood of changes in care following routine tests (P-value < 0.05). Among routine tests that were exclusively preceded by consecutive tests that did not change care, tests ordered outside months 3-9 and those that followed ≥ 3 tests were even less likely to change care. CONCLUSIONS: Routine cardiac imaging tests rarely changed care for trastuzumab-treated patients with breast cancer, particularly among lower risk anthracycline-naïve women who had multiple prior tests that did not change care.

Integrating the STOP-BANG Score and Clinical Data to Predict Cardiovascular Events After Infarction: A Machine Learning Study.

BACKGROUND: OSA conveys worse clinical outcomes in patients with coronary artery disease. The STOP-BANG score is a simple tool that evaluates the risk of OSA and can be added to the large number of clinical variables and scores that are obtained during the management of patients with myocardial infarction (MI). Currently, machine learning (ML) is able to select and integrate numerous variables to optimize prediction tasks. RESEARCH QUESTION: Can the integration of STOP-BANG score with clinical data and scores through ML better identify patients who experienced an in-hospital cardiovascular event after acute MI? STUDY DESIGN AND METHODS: This is a prospective observational cohort study of 124 patients with acute MI of whom the STOP-BANG score classified 34 as low (27.4%), 30 as intermediate (24.2%), and 60 as high (48.4%) OSA-risk patients who were followed during hospitalization. ML implemented feature selection and integration across 47 variables (including STOP-BANG score, Killip class, GRACE score, and left ventricular ejection fraction) to identify those patients who experienced an in-hospital cardiovascular event (ie, death, ventricular arrhythmias, atrial fibrillation, recurrent angina, reinfarction, stroke, worsening heart failure, or cardiogenic shock) after definitive MI treatment. Receiver operating characteristic curves were used to compare ML performance against STOP-BANG score, Killip class, GRACE score, and left ventricular ejection fraction, independently. RESULTS: There were an increasing proportion of cardiovascular events across the low, intermediate, and high OSA risk groups (P = .005). ML selected 7 accessible variables (ie, Killip class, leukocytes, GRACE score, c reactive protein, oxygen saturation, STOP-BANG score, and N-terminal prohormone of B-type natriuretic peptide); their integration outperformed all comparators (area under the curve, 0.83 [95% CI, 0.74-0.90]; P < .01). INTERPRETATION: The integration of the STOP-BANG score into clinical evaluation (considering Killip class, GRACE score, and simple laboratory values) of subjects who were admitted for an acute MI because of ML can significantly optimize the identification of patients who will experience an in-hospital cardiovascular event.

Right ventricular free wall strain predicts functional capacity in patients with repaired Tetralogy of Fallot.

To investigate the role of right ventricular free wall strain (RVFWSL) to predict low functional capacity in repaired tetralogy of Fallot (rTOF). We prospectively enrolled 33 patients with rTOF with moderate to severe PR who underwent rest and peak exercise echocardiography on a semisupine cycloergometer. Conventional function and strain imaging parameters of both ventricles were measured. Patients performing < 7 METS were defined to have low functional capacity. Logistic regression was used to identify parameters associated with low functional capacity. Eleven patients (33.3%) had low functional capacity. These patients were shorter (height 155 ± 7 vs 163 ± 9 cm, p = 0.023), more frequently female (27.3 vs 72.7%, p = 0.024) and had history of Blalock-Taussig shunt (45.5 vs 9.1%, p = 0.027). On multivariate analysis RVFWSL was the only predictor of low functional capacity OR 1.39 (CI 95%, 1.06-1.83., p = 0.018) per % change. A RVFWSL < 17% (absolute value) had an AUC of 0.785, sensitivity of 81.8% and specificity of 77.3% to predict low functional capacity. Right ventricular free wall strain is an independent predictor of low functional capacity in repaired tetralogy of Fallot with moderate to severe PR. A value < 17% might be useful in deciding when to perform pulmonary valve replacement, when functional capacity cannot be objectively measured.

Connections Between Clonal Hematopoiesis, Cardiovascular Disease, and Cancer: A Review.

Importance: Clonal hematopoiesis (CH) has been recently described as a novel driver for cancer and cardiovascular disease (CVD). Clonal hematopoiesis is a common, age-associated disorder marked by expansion of hematopoietic clones carrying recurrent somatic mutations. Current literature suggests that patients with CH have a higher risk of subsequent hematological malignant conditions and mortality attributable to excess CVD. This review discusses the association of cancer with CVD with CH as a potential unifying factor. Observations: The prevalence of CH varies based on the sequencing depth, diagnostic criteria, and patient age and ranges from less than 1% in those younger than 40 years to more than 15% to 20% in those 90 years and older. Clonal hematopoiesis is associated with a 0.5% to 1.0% absolute annual risk of hematological malignant condition and a 2-fold to 4-fold higher risk of coronary artery disease, stroke, and CVD deaths, independent of traditional cardiovascular risk factors. In fact, CH appears to have a relative risk similar to that of traditional cardiovascular risk factors for CVD. Experimental studies suggest that the link between CVD and CH is causal, with inflammation as 1 potential mechanism. There may be also a link between CH and CVD in survivors of cancer; however, data to support this association are currently limited. Conclusions and Relevance: Clonal hematopoiesis represents a premalignant state, with carriers having an increased risk of hematological malignant conditions. Although most carriers will not develop a malignant condition, CH confers an increased risk of CVD, possibly via inflammation. Clonal hematopoiesis may also contribute to CVD in survivors of cancer, although this hypothesis requires validation. Clinically, as advanced sequencing techniques become available, CH may pave the way for precision medicine in the field of cardio-oncology.

Cardioprotective Effect of Statins in Patients With HER2-Positive Breast Cancer Receiving Trastuzumab Therapy.

BACKGROUND: Statins can reduce the risk of anthracycline-induced cardiotoxicity. Whether such cardioprotective effects can be seen in trastuzumab-treated patients has not been explored. METHODS: Consecutive women with HER2+ breast cancer who received trastuzumab with or without anthracyclines were identified retrospectively. Patients receiving statins before and during cancer treatment were matched with 2 patients of the same age (± 2 years) and anthracycline exposure status but without statin treatment. The primary outcome was final left ventricular ejection fraction (LVEF). Analysis of covariance (ANCOVA) was used to assess the relationship between statin exposure and the final LVEF. A logistic regression model was constructed to assess the relationship between statin exposure and cardiotoxicity (secondary outcome). RESULTS: Included were 129 patients (62 ± 9 years). Forty-three received statins during cancer treatment. The median trastuzumab exposure time was 11.8 (interquartile range [IQR] 11 to 12) months. Seventy-two (56%) patients received anthracyclines. Compared with controls, patients treated with statins were more likely to have diabetes (37.2% vs 4.7%, P < 0.001), hypertension (58.1% vs 22.1%, P < 0.001), and coronary artery disease (11.6% vs 2.3%, P = 0.04). Within a median cardiac follow-up duration of 11 (IQR 9 to 18) months, the adjusted final LVEF was lower in the control group (61.2% vs 64.6%, P = 0.034). A significant change in LVEF was observed in the control group (median -6%, IQR -10% to -1% P < 0.001) but not in the statin group (median 0%, IQR -5% to +3%, P = 0.27). Upon adjusted analysis, statin treatment was independently associated with a lower risk of cardiotoxicity (odds ratio [OR] 0.32, 95% confidence interval [CI], 0.10-0.99, P = 0.049). CONCLUSIONS: In women with HER2+ breast cancer receiving trastuzumab-based therapy with or without anthracyclines, concomitant use of statins was associated with a lower risk of cardiotoxicity.

Added Value of 3- Versus 2-Dimensional Echocardiography Left Ventricular Ejection Fraction to Predict Arrhythmic Risk in Patients With Left Ventricular Dysfunction.

OBJECTIVES: This study sought to evaluate the potential clinical impact of using 3-dimensional echocardiography (3DE) to measure left ventricular ejection fraction (LVEF) in patients considered for implantable cardioverter-defibrillator (ICD) implantation and to assess the predictive value of 3DE LVEF for arrhythmic events. BACKGROUND: ICD therapy is currently recommended to prevent sudden cardiac death in patients with symptomatic heart failure and LVEF ≤35%, and in asymptomatic patients with ischemic heart disease and LVEF ≤30%. Two-dimensional echocardiography (2DE) is currently used to calculate LVEF. However, 3DE has been reported to be more reproducible and accurate than 2DE to measure LVEF. METHODS: The study prospectively enrolled 172 patients with LV dysfunction (71% ischemic). Both 2DE and 3DE LVEF were obtained during the same study. The outcome was the occurrence of major arrhythmic events (sudden cardiac death, aborted cardiac arrest, appropriate ICD therapy). RESULTS: After a median follow up of 56 (range 18 to 65) months, major arrhythmic events occurred in 30% of the patients. Compared with 2DE, 3DE changed the assignment above or below the LVEF thresholds for ICD implantation in 20% of patients, most of them having 2DE LVEFs within ± 10% from threshold. By cause-specific hazard model, 3DE LVEF was the only independent predictor of the occurrence of major arrhythmic events. CONCLUSIONS: LVEF by 3DE was an independent predictor of major arrhythmic events and improved arrhythmic risk prediction in patients with LV dysfunction. When compared with 2DE LVEF, 3DE measurement of LVEF may change the decision to implant an ICD in a sizable number of patients.