<div>Abstract<p>Protease-activated receptor 1 (PAR1) is a G protein–coupled receptor that is not expressed in normal breast epithelia but is up-regulated in invasive breast carcinomas. In the present study, we found that matrix metalloprotease-1 (MMP-1) robustly activates the PAR1-Akt survival pathway in breast carcinoma cells. This process is blocked by a cell-penetrating lipopeptide “pepducin,” P1pal-7, which is a potent inhibitor of cell viability in breast carcinoma cells expressing PAR1. Both a MMP-1 inhibitor and P1pal-7 significantly promote apoptosis in breast tumor xenografts and inhibit metastasis to the lungs by up to 88%. Dual therapy with P1pal-7 and Taxotere inhibits the growth of MDA-MB-231 xenografts by 95%. Consistently, biochemical analysis of xenograft tumors treated with P1pal-7 or MMP-1 inhibitor showed attenuated Akt activity. Ectopic expression of constitutively active Akt rescues breast cancer cells from the synergistic cytotoxicity of P1pal-7 and Taxotere, suggesting that Akt is a critical component of PAR1-dependent cancer cell viability. Together, these findings indicate that blockade of MMP1-PAR1 signaling may provide a benefit beyond treatment with Taxotere alone in advanced, metastatic breast cancer. [Cancer Res 2009;69(15):6223–31]</p></div>
Determination of a transvalvular pressure gradient for measurement of aortic valve area (AVA) by hemodynamic cardiac catheterization usually requires 2 catheters and 2 arterial access sites. We assessed the feasibility of using a single arterial puncture and a 0.014 inch pressure wire for evaluation of aortic stenosis.Eighteen patients (mean age, 76 years; 10 men) underwent hemodynamic catheterization for assessment of AVA. Cardiac output was determined by thermodilution (using a pulmonary artery catheter), and the transvalvular pressure gradient was obtained from simultaneous pressure recordings (using a pressure wire to measure left ventricular pressure and a 5 Fr catheter to measure ascending aortic pressure).This novel technique was technically feasible in all patients. Calibration of the pressure wire with the pressure of the fluid-filled catheter was possible and accurate in the left ventricle and aorta. The method required 36.4 +/- 9.6 minutes from injection of a local anesthetic to completion of AVA measurement; 53.3 +/- 18.6 minutes were required to finish all catheterization procedures, including coronary angiography. Measurements of AVA (mean, 1.01 +/- 0.43 cm2) and pressure gradients (mean, 27.5 +/- 10.5 mmHg) taken by a pressure wire were similar to measurements taken by Doppler echocardiography (1.07 +/- 0.58 cm2 and 32.9 +/- 12.1 mmHg, respectively); the correlation was significant (r = 0.856; p < 0.001, and r = 0.741; p < 0.001, respectively).Our findings suggest that a single arterial approach using a pressure wire is feasible, safe, accurate and rapid for the invasive assessment of aortic stenosis.
<div>AbstractPurpose:<p>Cardiac toxicity is a serious potential complication of HER2-directed therapies and anthracyclines. <i>HER2</i> codon 655 and <i>SLC28A3</i> gene polymorphisms have been reported to be associated with cardiac toxicity from anti-HER2 and anthracycline therapy, respectively. Association of the polymorphism at HER2 codon 655 with prognosis has also been reported.</p>Experimental Design:<p>Whole blood samples from patients treated on a randomized adjuvant breast cancer trial (BCIRG-006) that compared chemotherapy with or without trastuzumab plus either anthracycline or nonanthracycline chemotherapy were tested for genetic polymorphisms in <i>HER2</i> codon 655 and <i>SLC28A3</i>. Genotypes were correlated with cardiac function and disease-free survival (DFS) outcomes.</p>Results:<p>Of 3,222 patients enrolled in BCIRG-006, 662 patient samples were successfully genotyped for the rs1136201 allele in <i>HER2</i> (codon 655): 424 (64%) were AA, 30 (4.5%) were GG, and 208 (31%) were AG genotype. In addition, 665 patient samples were successfully genotyped for the rs7853758 allele in the <i>SLC28A3</i> gene: 19 (3%) were AA, 475 (71%) were GG, and 171 (26%) were AG genotype. Follow-up time was 10 years. No correlation between DFS, cardiac event rate, or mean left ventricular ejection fraction (LVEF) and rs1136201 genotype was seen in the trastuzumab-treated or non–trastuzumab-treated patients. Moreover, mean LVEF and cardiac event rates were similar in all rs7853758 genotype groups treated with anthracycline-based therapy.</p>Conclusions:<p>In the largest study to date to evaluate whether two polymorphisms are associated with DFS and/or cardiac toxicity in HER2-positive breast cancer treated with trastuzumab and/or anthracyclines, we observed no correlation.</p></div>
To evaluate the impact of age and COVID-19 variant time period on morbidity and mortality among those hospitalized with COVID-19.Patients from the American Heart Association's Get With The Guidelines COVID-19 cardiovascular disease registry (January 20, 2020-February 14, 2022) were divided into groups based on whether they presented during periods of wild type/alpha, delta, or omicron predominance. They were further subdivided by age (young: 18-40 years; older: more than 40 years), and characteristics and outcomes were compared.The cohort consisted of 45,421 hospitalized COVID-19 patients (wild type/alpha period: 41,426, delta period: 3349, and omicron period: 646). Among young patients (18-40 years), presentation during delta was associated with increased odds of severe COVID-19 (OR, 1.6; 95% CI, 1.3-2.1), major adverse cardiovascular events (MACE) (OR, 1.8; 95% CI, 1.3-2.5), and in-hospital mortality (OR, 2.2; 95% CI, 1.5-3.3) when compared with presentation during wild type/alpha. Among older patients (more than 40 years), presentation during delta was associated with increased odds of severe COVID-19 (OR, 1.2; 95% CI, 1.1-1.3), MACE (OR, 1.5; 95% CI, 1.4-1.7), and in-hospital mortality (OR, 1.4; 95% CI, 1.3-1.6) when compared with wild type/alpha. Among older patients (more than 40 years), presentation during omicron associated with decreased odds of severe COVID-19 (OR, 0.7; 95% CI, 0.5-0.9) and in-hospital mortality (OR, 0.6; 95% CI, 0.5-0.9) when compared with wild type/alpha.Among hospitalized adults with COVID-19, presentation during a time of delta predominance was associated with increased odds of severe COVID-19, MACE, and in-hospital mortality compared with presentation during wild type/alpha. Among older patients (aged more than 40 years), presentation during omicron was associated with decreased odds of severe COVID-19 and in-hospital mortality compared with wild type/alpha.
The presentation of a cardiac hamartoma, an exceedingly rare and histologically benign cardiac tumor, can be variable. We describe a case of refractory ventricular tachycardia in a patient with a cardiac mass failing multiple pharmacologic and procedural interventions, ultimately treated by cardiac transplantation and diagnosed with a mesenchymal cardiac hamartoma. (Level of Difficulty: Intermediate.)
