Variants in structural cardiac genes in patients with cancer therapy-related cardiac dysfunction after anthracycline chemotherapy: a case control study.

BACKGROUND: Variants in cardiomyopathy genes have been identified in patients with cancer therapy-related cardiac dysfunction (CTRCD), suggesting a genetic predisposition for the development of CTRCD. The diagnostic yield of genetic testing in a CTRCD population compared to a cardiomyopathy patient cohort is not yet known and information on which genes should be assessed in this population is lacking. METHODS: We retrospectively included 46 cancer patients with a history of anthracycline induced CTRCD (defined as a decrease in left ventricular ejection fraction (LVEF) to < 50% and a ≥ 10% reduction from baseline by echocardiography). Genetic testing was performed for 59 established cardiomyopathy genes. Only variants of uncertain significance and (likely) pathogenic variants were included. Diagnostic yield of genetic testing was compared with a matched cohort of patients with dilated cardiomyopathy (DCM, n = 46) and a matched cohort of patients without cardiac disease (n = 111). RESULTS: Average LVEF at time of CTRCD diagnosis was 30.1 ± 11.0%. Patients were 52.9 ± 14.6 years old at time of diagnosis and 30 (65.2%) were female. Most patients were treated for breast cancer or lymphoma, with a median doxorubicin equivalent dose of 300 mg/m2 [112.5-540.0]. A genetic variant, either pathogenic, likely pathogenic or of uncertain significance, was identified in 29/46 (63.0%) of patients with CTRCD, which is similar to the DCM cohort (34/46, 73.9%, p = 0.262), but significantly higher than in the negative control cohort (47/111, 39.6%, p = 0.018). Variants in TTN were the most prevalent in the CTRCD cohort (43% of all variants). All (likely) pathogenic variants identified in the CTRCD cohort were truncating variants in TTN. There were no significant differences in severity of CTRCD and in recovery rate in variant-harbouring individuals versus non-variant harbouring individuals. CONCLUSIONS: In this case-control study, cancer patients with anthracycline-induced CTRCD have an increased burden of genetic variants in cardiomyopathy genes, similar to a DCM cohort. If validated in larger prospective studies, integration of genetic data in risk prediction models for CTRCD may guide cancer treatment. Moreover, genetic results have important clinical impact, both for the patient in the setting of precision medicine, as for the family members that will receive genetic counselling.

The deleterious effects of smoking resumption after heart transplantation.

AIMS: Smoking is linked to disease and survival in the general and transplant population. We studied the smoking history, disease and survival of patients after heart transplantation. METHODS: A total of 130 patients who underwent heart transplantation between 1995 and 2019 received a questionnaire to document their smoking history. We assessed patient characteristics, comorbidities and survival. RESULTS: Sixty-five per cent of patients were active or former smokers prior to heart transplantation. All patients stopped smoking; 26% of the former smokers resumed smoking after transplantation. Patients who resumed smoking were younger at the time of transplantation, used fewer statins and were more likely to be treated with azathioprine after transplantation. The mean follow-up for all patients was 11 ± 5.5 years. Patients who resumed smoking were more likely to develop solid organ cancers (45%) compared to those who remained abstinent (23%) and those who never smoked (13%) (p 0.014). A Cox proportional hazards regression analysis identified smoking resumption, with a RR of 2.31 (1.14-4.68, p 0.02), and age at transplantation, with a RR of 1.03 (1-1.06, p 0.034), as significant for survival. Patients resuming smoking after transplantation had a significantly higher risk of dying from solid organ cancer, with a RR of 2.54 (1.03, 6.28; p 0.04) with a short median survival time (25th-75th percentile) of (1 (0-5) months, p 0.007). CONCLUSION: Patients who resume smoking after heart transplantation have worse survival and are at higher risk of dying from solid organ cancer. Implementing a smoking cessation plan throughout the post-transplant period is important.

Biomarkers and Donor Selection in Heart Transplantation.

BACKGROUND: Previously, we showed that B-type natriuretic peptide (BNP) measured in the donor was related to cardiac performance after cardiac transplantation. The present study assesses the value of 3 biomarkers in the selection of donor hearts in a larger cohort. METHODS: Blood samples were prospectively obtained in 105 brain-dead patients scheduled for heart donation. BNP, soluble suppressor of tumorigenicity 2 (ST2), and troponin of heart donors were correlated with hemodynamic parameters early after transplantation as well as with the mortality of the recipients. RESULTS: A significant inverse relationship was found between donor BNP measured at the time of donation and recipient cardiac index and cardiac output at day 13 post-transplantation (r = -0.31, P = .005, and r = -0.34, P = .0016, respectively). Logistic regression analysis-including BNP, ST2, and troponin-showed that donor BNP was a predictor of a poor cardiac index (< 2.2 L/min/m2) in the recipient (P = .04). A donor BNP > 132 pg/mL has a sensitivity of 56% (95% confidence interval 21-86) and a specificity of 86% (95% confidence interval 77-93) to predict poor cardiac performance in the recipient. When the donor BNP is ≤ 132 pg/mL, the risk of a poor cardiac function in the recipient is very low (negative predictive value 94%). Mortality at 30 days was also correlated to donor BNP (r = 0.29, P = .0029). Long-term survival of the recipient was not correlated to the biomarkers measured in the donor. CONCLUSION: Donor BNP, but not donor ST2 or high-sensitivity troponin, provides information on the donor heart and early post-transplant performance, including 1-month mortality.

Evolution of Functional Mitral Regurgitation and Prognosis in Medically Managed Heart Failure Patients With Reduced Ejection Fraction.

OBJECTIVES: The purpose of this study was to assess whether medical management may alter the severity of functional mitral regurgitation (FMR) and its prognosis in patients who have heart failure with reduced ejection fraction (HFrEF). BACKGROUND: FMR in patients who have HFrEF is associated with a worse prognosis. It is uncertain to what extent medical management may alter the severity of FMR and its prognosis. METHODS: The extent of FMR was assessed at baseline and after a median follow-up period of 50 months in 163 consecutive HFrEF patients (left ventricular ejection fraction <40%). Severe FMR was defined as mitral regurgitation (MR) grade 3-4. All of the patients received the maximal tolerable doses of their heart failure (HF) medications. Major adverse cardiac events were defined as a composite of all-cause death and the need for heart transplantation or hospitalization for HF and/or malignant arrhythmias. RESULTS: A total of 50 (31%) patients had severe MR at baseline. During the follow-up period, 38% of the severe FMR patients showed an improvement to nonsevere FMR (MR grade <3), whereas 18% of the nonsevere FMR patients developed severe FMR despite optimal HF treatment. Cox regression analysis revealed that the presence of sustained severe FMR or worsening of FMR was the most important independent prognostic determinant with an adjusted odds ratio of 2.5 (95% confidence interval: 1.5 to 4.3, major adverse cardiac events 83% vs. 43%). In addition, those patients showed a 13% increase in left ventricular end-diastolic volume index (LVEDVI), whereas the patients with improvement in their severe MR showed a 2% decrease in LVEDVI (p = 0.01). CONCLUSIONS: Severe FMR was successfully treated with medication in almost 40% and was associated with prevention of left ventricular adverse remodeling and with an improved long-term prognosis.

Effect of intracoronary adenosine infusion during coronary intervention on myocardial reperfusion injury in patients with acute myocardial infarction.

Despite early recanalization of an occluded infarct artery, up to 33% of patients with acute myocardial infarction do not obtain complete myocardial reperfusion due to a process of reperfusion injury. This study assessed whether adjunctive therapy with adenosine might prevent or attenuate the phenomenon of myocardial reperfusion injury. Myocardial reperfusion was assessed in 79 consecutive patients receiving a 20-minute intracoronary infusion of adenosine during percutaneous coronary intervention (PCI) and in a historical cohort of 200 patients with acute myocardial infarction who were treated with PCI (controls). Myocardial reperfusion injury was defined as persistent (> or =50% of initial value) ST-segment elevation after successful recanalization. Its effect on infarct size was evaluated by calculating the Selvester QRS score before intervention and at follow-up. Myocardial reperfusion injury was present in 19% of patients receiving adenosine versus 35% of control patients (p = 0.004). Evaluation of infarct expansion over time showed almost no change in the QRS score in patients receiving adenosine (3.4 +/- 3.0 before PCI; 3.5 +/- 3.1 at follow-up). In contrast, infarct QRS score in the control group worsened from 3.1 +/- 2.7 before PCI to 4.5 +/- 3.2 at follow-up (p = 0.003 treatment with adenosine vs control). Multivariate analysis identified adjunctive therapy with adenosine as an independent protective determinant of myocardial reperfusion injury and of infarct expansion. The rate of major adverse cardiac events (death and myocardial infarction) at 1 month tended to be lower in patients receiving adenosine (4% vs 6.5%, p = 0.7) and was mainly observed in patients with evidence of myocardial reperfusion injury (cardiac event rate 2% in patients with ST-segment elevation of <50% vs 14% in patients with ST-segment elevation > or =50%, p = 0.003). Thus, impaired myocardial reperfusion is the most important determinant of clinical outcome in patients with acute myocardial infarction treated with PCI. Adjunctive therapy with intracoronary infusion of adenosine during PCI prevents the occurrence of severe myocardial reperfusion injury and is associated with less infarct expansion.