Background: We evaluated the role of the aldosterone blocker spironolactone in attenuating long-term pressure overload-induced cardiac remodeling and heart failure (HF) in spontaneously hypertensive rats (SHR). Methods and Results: Thirteen month-old male SHR were assigned to control (SHR-C, n=20) or spironolactone (SHR-SPR, 20 mg/kg/day, n=24) groups for six months. Normotensive Wistar-Kyoto rats (WKY, n=15) were used as controls. Systolic blood pressure was higher in SHR groups and unchanged by spironolactone. Right ventricular hypertrophy, which characterizes HF in SHR, was less frequent in SHR-SPR than SHR-C. Echocardiographic parameters did not differ between SHR groups. Myocardial function was improved in SHR-SPR compared to SHR-C [developed tension: WKY 4.85±0.68; SHR-C 5.22±1.64; SHR-SPR 6.80±1.49 g/mm2; -dT/dt: WKY 18.0 (16.0-19.0); SHR-C 20.8 (18.4-25.1); SHR-SPR 28.9 (24.2-34.6) g/mm2/s]. Cardiomyocyte cross-sectional area and total collagen concentration (WKY 1.06±0.34; SHR-C 1.85±0.63; SHR-SPR 1.28±0.39 µg/mg wet tissue) were greater in SHR-C than WKY and SHR-SPR. Type 3 collagen expression was lower in SHR-C than WKY and unchanged by spironolactone. Soluble collagen, type I collagen, and lysyl oxidase did not differ between groups. Conclusion: Early spironolactone treatment decreases heart failure development frequency by improving myocardial systolic and diastolic function and attenuating hypertrophy and fibrosis in spontaneously hypertensive rats.
527 Background: The combined analysis of the Suppression of Ovarian Function Trial (SOFT) and Tamoxifen and Exemestane Trial (TEXT) trials have shown significant survival benefit of adding ovarian function suppression (OFS) with GnRH agonists (GnRHa) to aromatase inhibitors (AI) versus tamoxifen in high-risk premenopausal patients (pts) with estrogen receptor (ER)-positive breast cancer (BC). In both studies, GnRHa was administered every 4 weeks. However, the efficacy of 3-monthly GnRHa plus AI has not been well studied. We conducted a retrospective study designed to assess the efficacy of OFS with 3-montlhy compared with monthly goserelin, associated with AI, in premenopausal pts with ER-positive BC. Methods: Medical records of premenopausal pts with ER-positive BC who received OFS with 10.8mg 3-montlhy goserelin plus AI or 3.6mg monthly goserelin plus AI, between June/2013 and January/2023 were reviewed. Patient characteristics, such as age, body mass index (BMI) and prior chemotherapy were analyzed. Estradiol (E2) levels were measured by gas chromatography tandem mass spectrometry. Pts with at least one E2 level above 2.72 pg/ml were considered to have ineffective OFS. Analysis of E2 measurements was divided into periods: < 3, 3 to 6, 6 to 9, 9 to 12, 12 to 18, 18 to 24 and > 24 months. E2 levels greater than 2.72 pg/ml were evaluated at each timepoint. Results: A total of 88 pts were included. 27 (30.7%) received monthly goserelin and 61 (69.3%) 3-monthly goserelin. Patient characteristics were well balanced between the groups. Relevant demographic data are shown in table. For E2 analysis, 20 (22.7%) pts had at least one measurement greater than 2.72 pg/ml, 11 (40.7%) in the monthly group and 9 (14.8%) in the 3-monthly group (p = 0.007). The percentages of E2 measurements ≥ 2.72 pg/ml, in each time period, were 0%, 40%, 12.5%, 16.7%, 33.3%, 50% and 50% in monthly group versus 8%, 4.2%, 10%, 14.3%, 4.8%, 8.3% and 5.6%, in 3-monthly group, respectively. Conclusions: Our study demonstrated that more pts who underwent 3-monthly goserelin had E2 levels below the defined threshold of 2.72 pg/ml compared with monthly goserelin, when associated with AI, with statistical significance. These findings suggest that 3-monthly goserelin may result in better efficacy in OFS when comparing with monthly and provide greater convenience for pts. [Table: see text]
e13034 Background: Antibody-drug conjugates (ADC) are widely used in the treatment of breast cancer (BC). In our service, we observed that a significant number of patients (pts) with HER2-positive metastatic breast cancer (MBC) treated with T-DM1 had long-lasting response and survival rates, even after discontinuing T-DM1 due to limiting toxicity. However, data are scarce regarding its long-term benefit. We performed a retrospective study to evaluate the long-term efficacy of T-DM1 in the treatment of HER2-positive MBC. Methods: Medical records of pts with HER2-positive MBC treated with T-DM1 between September 2013 and January 2023 were reviewed. We analyzed data in the overall population and in the subgroup of pts who discontinued T-DM1 due to only limiting toxicity and did not have disease progression or death for at least 12 months, without receiving other subsequent lines of treatment. The primary endpoints were progression-free survival (PFS) and overall survival (OS) from the start of the treatment with T-DM1 to disease progression or death for the overall population, and from the time of T-DM1 discontinuation to disease progression or death for the aforementioned subgroup. Secondary endpoints were objective response rate (ORR) and toxicity. Results: A total of 73 pts were included. In the overall population, ORR was 82.6%, median PFS was 12.7 months (CI95% 8-16) and median OS was 53.9 months (CI95% 34-73). 10 (13.6%) pts had T-DM1 discontinued due to only limiting toxicity and had no disease progression or death for at least 12 months. In this specific subgroup, 2 pts received T-DM1 as first line, 6 pts as second line, and 2 as third or more lines. At the start of T-DM1, 5 pts had visceral metastasis (3 liver, 2 lung), and 2 had only leptomeningeal involvement. Median age was 57 years (IQR 49-70) and median T-DM1 duration was 30 months (IQR 12-45). At the time of T-DM1 discontinuation, 9 pts presented complete response (CR) and 1 presented partial response (PR). 5 pts maintained CR, with no evidence of disease progression or death throughout the analyzed period. The PFS of these 5 pts, from the time of T-DM1 discontinuation to the last evaluation, was 35.6, 37.9, 40.5, 42.7 and 68.5 months. In the entire subgroup, median PFS was 22.5 months, 5-year OS was 66.7% and median OS was not reached. The adverse events that led to the T-DM1 discontinuation were thrombocytopenia (10%), nausea, vomiting and fatigue (10%), pneumonitis (20%), hepatic pseudocirrhosis (20%) and peripheral neuropathy (40%). Conclusions: Our experience suggests that pts with HER2-positive MBC who had T-DM1 discontinued due to limiting toxicity may derive long-term benefit. Further prospective studies are warranted to evaluate our findings, also including other ADC.
The purpose of this study was to compare the effect of early and late aldosterone blockade with spironolactone (SPR) on ventricular remodeling in spontaneously hypertensive rats (SHR) without HF.MethodsSHR were divided into four groups: control: CTL13 (n=20) 13 month‐old and CTL16 (n=72) 16 month‐old; SPR: SPR13 (n=24) 13 month‐old and SPR16 (n=34) 16 month‐old. SPR groups were treated with SPR for six months (20 mg/kg/day). Systolic blood pressure (BP) was measured. Echocardiogram (ECHO) was performed to evaluate cardiac structures and left ventricular (LV) function. Myocardial function was analyzed in LV papillary muscle preparations. Statistics: two way ANOVA and Student‐Newman‐Keuls. Significance: p<0.05.ResultsBP was not different between groups (CTL13: 184±24; SPR13: 197±22; CTL16: 199±43; SPR16: 200±35 mmHg; p>0.05). ECHO did not show differences between groups. In vitro evaluated myocardial function was improved in SPR13 vs. CTL13 group (developed tension (dT): 7.00±1.68 vs. 5.22±1.64 g/mm2; maximum rate of dT: 61.0±17.4 vs. 46.8±5.00 g/mm2/s; maximum rate of tension decline: 28.9±7.06 vs. 21.6±5.40 g/mm2/s; p<0.05). Mortality rate was significantly lower in SPR16 than CTL16 (38% vs. 71%; p<0.05).ConclusionAldosterone blockade initiated at 13 months but not at 16 months induces beneficial effects on myocardial function and collagen accumulation in SHR without heart failure.
The purpose of this study was to evaluate the effects of spironolactone (SPR), started before clinical evidence of heart failure, on cardiac remodeling in spontaneously hypertensive rats (SHR).MethodsThirty six 13 month old SHR were divided into control and SPR (20 mg/kg/day for six months) groups. Systolic blood pressure (BP) was measured by tail‐cuff method. Echocardiogram (ECHO) was performed to evaluate in vivo cardiac structures and left ventricular (LV) function. Myocardial function was analyzed in LV papillary muscle during isometric contractions at 1.25 mM calcium concentration. Right ventricle, LV, and atria were weighed. Statistics: Student's t test and Fisher exact test.ResultsBP was not different between groups at the end of the experiment (control: 184±24; SPR: 197±22 mmHg; p>0.05). Mortality rate was lower in SPR group but without statistical difference (12.5% vs 25%, p>0.05). ECHO did not show differences in cardiac structures or LV systolic and diastolic function between groups. Myocardial function evaluated in vitro showed better functional performance in SPR group. Right ventricular and atrial weights were lower in SPR versus control groups.ConclusionAldosterone blockade started before clinical evidence of heart failure shows benefitial effects on myocardial performance and right ventricular and atrial weights in spontaneously hypertensive rats. Support: FAPESP and CNPq.
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