In 2015 there will be an estimated 11.3 million cancer survivors. With a growing population of cancer survivors, it is imperative to understand treatment options and outcomes for chemotherapy related cardiomyopathy. Anthracycline (AC) based chemotherapy causes heart failure (HF) in approximately 5% of patients. Orthotopic heart transplant (OHT) is an option for cancer survivors in complete remission who develop end-stage HF. We examined retrospective OHT data collected from United Network of Organ Sharing (UNOS) from 1987–2011. The primary aim to was characterize the survival in patients with either the primary diagnosis of “Dilated Cardiomyopathy: Adriamycin” (DCA) versus “all other” causes of cardiomyopathy. The secondary aim was to define the differences in primary cause of death and to describe the temporal relationship of DCA OHT. The UNOS database identified 453 OHT for the diagnosis of DCA and 51,312 OHT for all other causes of cardiomyopathy. DCA group was significantly younger with a higher percentage of females. After adjusting for age, gender, and previous history of malignancy, the 10-year survival curves show that DCA patients have an improved survival over all other causes cardiomyopathy (HR 1.28, p = 0.026). There was no difference in the primary cause of death between the 2 groups. There was a statistically significant increasing temporal trend in the number of OHT for the diagnosis DCA. In conclusion patients who undergo OHT for DCA have a favorable 10-year survival, making OHT a good therapeutic option for end-stage HF due to anthracyclines. Additionally there was no increased risk of cancer related deaths in the DCA, demonstrating that recurrent malignancy does not impact long-term survival. Temporal trends demonstrate that DCA remains a significant problem for cancer survivors.
Background
Breast cancer (BC) treatments can cause heart failure (HF) in a subset of patients. ACC/AHA guidelines classify patients receiving cardiotoxic medications as Stage A, a high-risk population for the development of HF. Circulating neuregulin (NRG) correlates with outcomes in Stage C and D HF. We examined the levels of NRG in a BC cohort receiving cardiotoxic chemotherapy and its relationship with adverse cardiac effects during the transition from Stage A to Stage B/C HF.
Methods
In an ongoing prospective study, a planned interim analysis of 78 BC women receiving either anthracycline (AC) or trastuzumab (Tsz) was performed. Biometric data, cardiac risk factors, and NRG levels, were collected pre-chemotherapy and after completion of AC therapy or three months into Tsz therapy. Cardiac function was measured by left ventricular ejection fraction (LVEF) by echocardiography at the above time points and longitudinally as standard of care.
Results
The interim cohort was predominately Caucasian with Stage II BC and a median age of 50 years. A reduction of > 10 absolute percentage points in LVEF was observed in 21.4% of the cohort, representing a transition from Stage A to Stage B or C HF. A statistically significant drop in plasma NRG was observed in women treated with either AC and/or Tsz (p < 0.001). Additionally, baseline NRG correlated with the maximal change in LVEF.
Conclusions
More than 20% of women experienced cardiac dysfunction, detected by decline in LVEF, and are reclassified as Stage B or C HF. Plasma NRG levels are reduced after exposure to cardiotoxic chemotherapy, suggesting a loss in a cardioprotective growth factor. Higher baseline NRG levels were observed in those with the greatest decline in LVEF, supporting the continued investigation of NRG as a potential prognostic marker in early Stage HF.
Endothelial progenitor cells (EPCs) are mobilized into the vascular space and home to damaged tissues, where they promote repair in part through a process of angiogenesis. Neuregulins (NRGs) are ligands in the epidermal growth factor family that signal through type I receptor tyrosine kinases in the erbB family (erbB2, erbB3, and erbB4) and regulate endothelial cell biology, promoting angiogenesis. Stimuli such as ischemia and exercise that promote EPC mobilization also induce cleavage and release of transmembrane NRG from cardiac microvascular endothelial cells (CMECs). We hypothesized that NRG/erbB signaling may regulate EPC biology. Using an embryonic (e)EPC cell line that homes to and repairs injured myocardium, we were able to detect erbB2 and erbB3 transcripts. Identical receptor expression was found in EPCs isolated from rat bone marrow and human whole blood. NRG treatment of eEPCs induces phosphorylation of kinases including Akt, GSK-3β, and Erk1/2 and the nuclear accumulation and transcriptional activation of β-catenin. NRG does not induce eEPC proliferation or migration but does protect eEPCs against serum deprivation-induced apoptosis. These results suggest a role for tissue-derived NRG in the regulation of EPC survival.
Circumferential type A aortic dissection and intimal intussusception of the aorta causing severe aortic regurgitation and obstruction of the left main coronary artery.
Hypertrophic cardiomyopathy (HCM) is an inherited cardiac disease with an autosomal dominant mode of transmission. Comprehensive genetic screening of several genes frequently found mutated in HCM is recommended for first-degree relatives of HCM patients. Genetic testing provides the means to identify those at risk of developing HCM and to institute measures to prevent sudden cardiac death (SCD). Here, we present an adoptee whose natural mother and maternal relatives were known be afflicted with HCM and SCD. The proband was followed closely from age 6 to 17 years, revealing a natural history of the progression of clinical findings associated with HCM. Genetic testing of the proband and her natural mother, who is affected by HCM, revealed that they were heterozygous for both the R719Q and T1513S variants in the cardiac beta-myosin heavy chain (MYH7) gene. The proband's ominous family history indicates that the combination of the R719Q and T1513S variants in cis may be a “malignant” variant that imparts a poor prognosis in terms of the disease progression and SCD risk.
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