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.

Predictive value of Type D personality for impaired endothelial function in patients with coronary artery disease.

BACKGROUND: Type D personality (high negative affectivity and social inhibition) is associated with cardiovascular events and coronary plaque severity. Whether Type D is also related to functional vasomotion abnormalities is unknown. We examined concurrent and predictive associations of Type D with endothelial dysfunction in patients with coronary artery disease (CAD). METHODS: At baseline, 180 CAD patients (90% men; M = 58.0 years) completed Type D (DS14) and depression scales, and entered a 12-week exercise program. Flow-mediated dilation (FMD) of the brachial artery and circulating CD34+/KDR+/CD45+dim endothelial progenitor cells (EPCs) were assessed at baseline, 3 months, and 12 months. Logistic regression and linear mixed models were used to analyze endothelial function. RESULTS: Type D personality was associated with decreased FMD across baseline, 3 months, and 12 months (mixed model analysis, p = 0.04), after adjustment for clinical characteristics, exercise training and depression. There was no significant association between Type D and decreased EPCs (p = 0.07). Age and smoking were other significant correlates of FMD and EPCs. Using a FMD <5.5% cut-off, Type D patients more often had endothelial dysfunction at baseline (24/37 = 65%) than non-Type Ds (63/143 = 44%); OR = 3.03, 95% CI 1.04-8.80. This significant Type D effect was confirmed in prospective analyses of endothelial dysfunction at 12 months (OR = 3.43, 95% CI 1.01-11.64), and in subgroup analyses of male patients. CONCLUSIONS: Type D personality was associated with impaired endothelial function in men with CAD. This association was robust across time, independent from depressive symptoms, and supports the notion that Type D has an adverse effect on cardiovascular health in patients with CAD.

A maximal exercise bout increases the number of circulating CD34+/KDR+ endothelial progenitor cells in healthy subjects. Relation with lipid profile.

Mobilization of bone marrow-derived endothelial progenitor cells (EPC) might explain exercise-induced improvement of endothelial function. We assessed whether a maximal exercise bout could alter the number of circulating EPC in healthy subjects and whether this effect is related to their cardiovascular risk profile. Additionally, we investigated possible mediators of this effect, namely nitric oxide (NO) bioavailability and vascular endothelial growth factor (VEGF) release. Healthy subjects (group 1, n = 11; group 2, n = 14) performed a symptom-limited cardiopulmonary exercise test on a bicycle ergometer. Numbers of CD34+/kinase insert domain receptor (KDR)+ cells were determined by flow-cytometric analysis, either after magnetic separation of CD34+ cells (group 1) or starting from whole blood (group 2). Serum concentrations of VEGF and NO metabolites were measured by using ELISA. Following exercise, EPC increased by 76% (15.4 +/- 10.7 cells/ml vs. 27.2 +/- 13.7 cells/ml; P = 0.01) in group 1 and by 69% in group 2 (30.9 +/- 14.6 cells/ml vs. 52.5 +/- 42.6 cells/ml; P = 0.03). The increase in EPC correlated positively with LDL and total cholesterol/HDL ratio and negatively with peak oxygen consumption and oxygen consumption at anaerobic threshold. VEGF levels increased with exercise, with a strong trend toward significance (P = 0.055). NO levels remained unchanged. The present study demonstrates that a maximal bout of exercise induces a significant shift in CD34+ cells toward CD34+/KDR+ cells. This response was larger in subjects with a less favorable lipid profile.

Intracellular monocyte cytokine production and CD 14 expression are up-regulated in severe vs mild chronic heart failure.

BACKGROUND: The role of circulating monocytes in the process of low-grade inflammation, characteristic of chronic heart failure (CHF), has recently been questioned. Lipopolysaccharide (LPS) desensitization has been proposed to mediate reduced monocyte cytokine elaboration in patients with severe CHF. METHODS: Intracellular monocyte production of interleukin-1 beta (IL-1 beta), interleukin-6 (IL-6) and tumor necrosis factor (TNF)-alpha, and monocyte CD 14 expression were measured flow-cytometrically without and after 8-hour LPS stimulation in 46 patients with CHF and in a healthy control group. RESULTS: Basal cytokine concentrations were similar for the control and the mild CHF groups (New York Heart Association [NYHA] Class I or II). After LPS stimulation, IL-6 (p=0.002) and TNF-alpha levels (p=0.001) were lower in the latter group, whereas IL-1 beta production was comparable. For the moderate-severe CHF patients, unstimulated IL-1 beta (p=0.04) was higher, whereas IL-6 (p=0.2) and TNF-alpha (p=0.1) levels were not different from the controls. Measurement of LPS-stimulated cytokine production showed no differences between the control group and patients with moderate-severe CHF (all p= 0.5). Upon comparing mild vs moderate-severe CHF patients, higher levels of unstimulated cytokine production (IL-1 beta, p=0.002; IL-6, p=0.01; TNF-alpha, p=0.003), stimulated IL-1 beta (p=0.002) and IL-6 (p=0.008) were found in the latter patients. CD 14 expression in the moderate-severe CHF group was higher than in the mild-CHF group (p = 0.03) and was strongly related to stimulated IL-1 beta (r=0.62, p<0.0001), IL-6 (r=0.56, p=0.0002) and TNF-alpha (r=0.41, p=0.006) production. CONCLUSIONS: CD 14 expression and monocyte cytokine production, both unstimulated and after LPS stimulation, are increased in moderate-severe CHF when compared with mild CHF. These data suggest that circulating monocytes, possibly via increased CD 14 expression, may play a significant role in the immunologic dysbalance observed in advanced CHF.