The association of hormone therapy with blood pressure control in postmenopausal women with hypertension: a secondary analysis of the Women's Health Initiative clinical trials.

OBJECTIVE: The objective of this study was to assess the effect of menopausal hormone therapy (HT) on blood pressure control in postmenopausal women with hypertension. METHODS: The Women's Health Initiative HT clinical trials were double-blinded, randomized, placebo-controlled studies of women aged 50 to 79 years testing the effects of HT (conjugated equine estrogens [CEE, 0.625 mg/d] or CEE + medroxyprogesterone acetate [MPA; 2.5 mg/d]) on risks for coronary heart disease and invasive breast cancer, the primary outcomes for efficacy and safety, respectively. This secondary analysis of the Women's Health Initiative HT trials examined a subsample of 9,332 women with hypertension (reported ever taking pills to treat hypertension or were taking antihypertensive medication) at baseline. Blood pressure was measured at baseline and up to 10 annual follow-up visits during the planned study phase. Antihypertensive medications were inventoried at baseline and years 1, 3, 6, and 9 during the study, and self-reported during extended follow-up: 2009-2010 and 2012-2013, which occurred median of 13 and 16 years after randomization, respectively. The intervention effect was estimated through year 6. Cumulative follow-up included all visits. RESULTS: Compared with placebo, CEE-alone had significantly ( P = 0.02) higher systolic blood pressure (SBP) by mean (95% confidene interval [CI]) = 0.9 (0.2-1.5) mm Hg during the intervention phase. For cumulative follow-up, the CEE arm was associated with increased SBP by mean (95% CI) = 0.8 (0.1-1.4) mm Hg ( P = 0.02). Furthermore, CEE + MPA relative to placebo was associated with increased SBP by mean (95% CI) = 1.8 (1.2-2.5) mm Hg during the intervention phase ( P < 0.001). For cumulative follow-up, the CEE + MPA arm was associated with increased SBP by mean (95% CI) = 1.6 (1.0-2.3) mm Hg ( P < 0.001). The mean number of antihypertensive medications taken at each follow-up visit did not differ between randomization groups during the intervention or long-term extended follow-up of 16 years. CONCLUSION: There was a small but statistically significant increase in SBP in both CEE-alone and CEE + MPA arms compared with placebo during both the intervention and cumulative follow-up phases among postmenopausal women with hypertension at baseline. However, this increase in SBP was not associated with an increased antihypertensive medication use over time among women randomized to HT compared with placebo.

Postoperative Myocardial Injury and Outcomes in Liver and Kidney Transplant Patients.

BACKGROUND/PURPOSE: Myocardial injury after noncardiac surgery (MINS) is associated with major adverse cardiac events (MACE), but its significance post-liver and post-kidney transplantation is not well-defined. METHODS/MATERIALS: We retrospectively studied consecutive patients undergoing single-organ liver or kidney transplantation at a large tertiary transplant center. Liver and kidney transplant patients with troponins drawn within 30 days of transplantation were included. The primary exposure was MINS, defined as troponin elevation above the 99th percentile of the upper reference limit within 30 days of transplantation. The primary outcome was MACE, defined as death, myocardial infarction, revascularization, stroke, or heart failure hospitalization. RESULTS: Overall, 112 patients were included: 58 (51.7%) were liver transplant recipients, and 54 (48.3%) were kidney transplant recipients. Patients with MINS were significantly older (mean age 59 vs. 54 years, p = 0.01) and more likely to have diabetes (35% vs. 17%, p = 0.03). Other baseline characteristics were similar. Sixteen patients (14.2%) developed MACE, including 11 (9.8%) with 1-year MACE. MINS patients were significantly more likely to develop 1-year MACE (adjusted hazard ratio, 10.4; 95% confidence interval, 1.8-198). Kaplan-Meier cumulative MACE was significantly higher in the MINS group (p = 0.03). CONCLUSIONS: Liver and kidney transplant recipients with MINS are significantly more likely to develop 1-year MACE compared to those without MINS. Future prospective studies are needed to further delineate the cardiac risk and outcomes in transplanted patients.

Association of Major Dietary Protein Sources With All-Cause and Cause-Specific Mortality: Prospective Cohort Study.

Background Dietary recommendations regarding protein intake have been focused on the amount of protein. However, such recommendations without considering specific protein sources may be simplistic and insufficient. Methods and Results We included 102 521 postmenopausal women enrolled in the Women's Health Initiative between 1993 and 1998, and followed them through February 2017. During 1 876 205 person-years of follow-up, 25 976 deaths occurred. Comparing the highest with the lowest quintile, plant protein intake was inversely associated with all-cause mortality (hazard ratio [HR], 0.91 [0.86, 0.96]), cardiovascular disease mortality (HR, 0.88 [0.79, 0.97]), and dementia mortality (HR, 0.79 [0.67, 0.94]). Among major protein sources, comparing the highest with the lowest quintile of consumption, processed red meat (HR, 1.06 [1.01, 1.10]) or eggs (HR, 1.14 [1.10, 1.19]) was associated with higher risk of all-cause mortality. Unprocessed red meat (HR, 1.12 [1.02, 1.23]), eggs (HR, 1.24 [1.14, 1.34]), or dairy products (HR, 1.11 [1.02, 1.22]) was associated with higher risk of cardiovascular disease mortality. Egg consumption was associated with higher risk of cancer mortality (HR, 1.10 [1.02, 1.19]). Processed red meat consumption was associated with higher risk of dementia mortality (HR, 1.20 [1.05, 1.32]), while consumption of poultry (HR, 0.85 [0.75, 0.97]) or eggs (HR, 0.86 [0.75, 0.98]) was associated with lower risk of dementia mortality. In substitution analysis, substituting of animal protein with plant protein was associated with a lower risk of all-cause mortality, cardiovascular disease mortality, and dementia mortality, and substitution of total red meat, eggs, or dairy products with nuts was associated with a lower risk of all-cause mortality. Conclusions Different dietary protein sources have varying associations with all-cause mortality, cardiovascular disease mortality, and dementia mortality. Our findings support the need for consideration of protein sources in future dietary guidelines.

Macrophages transmit potent proangiogenic effects of oxLDL in vitro and in vivo involving HIF-1α activation: a novel aspect of angiogenesis in atherosclerosis.

Neovascularization has been linked to the progression and vulnerability of atherosclerotic lesions. Angiogenesis is increased in lipid-rich plaque. Hypoxia-inducible factor alpha (HIF-1α) is a key transcriptional regulator responding to hypoxia and activating genes, which promote angiogenesis, among them vascular endothelial growth factor (VEGF). Oxidized low-density lipoprotein (oxLDL) is generated in lipid-rich plaque by oxidative stress. It triggers an inflammatory response and was traditionally thought to inhibit endothelial cells. New data, however, suggest that oxLDL can activate HIF-1α in monocytes in a hypoxia-independent fashion. We hypothesized that HIF-1α activation in monocyte-macrophages could transmit proangiogenic effects of oxLDL linking hyperlipidemia, inflammation, and angiogenesis in atherosclerosis. First, we examined the effect of oxLDL on HIF-1α and VEGF expression in monocyte-macrophages and on their proangiogenic effect on endothelial cells in vitro in a monocyte-macrophage/endothelial co-culture model. OxLDL strongly induced HIF-1α and VEGF in monocyte-macrophages and significantly increased tube formation in co-cultured endothelial cells. HIF-1α inhibition reversed this effect. Second, we demonstrated a direct proangiogenic effect of oxLDL in an in vivo angiogenesis assay. Again, HIF-1α inhibition abrogated the proangiogenic effect of oxLDL. Third, in a rabbit atherosclerosis model, we studied the effect of dietary lipid lowering on arterial HIF-1α and VEGF expression. The administration of low-lipid diet significantly reduced the expression of both HIF-1α and VEGF, resulting in decreased plaque neovascularization. Our data point to oxLDL as a proangiogenic agent linking hyperlipidemia, inflammation, and angiogenesis in atherosclerosis. This effect is dependent on macrophages and, at least in part, on the induction of the HIF-1α pathway.

An update on menopausal hormone replacement therapy in women and cardiovascular disease.

PURPOSE OF REVIEW: This review presents the available evidence for effects of menopausal hormone replacement therapy (MHT), more specifically estrogen, and selective estrogen receptor modulators on the cardiovascular system with a focus on randomized controlled trials (RCTs) published since 2010. RECENT FINDINGS: In contrast to early observational studies, the Women's Health Initiative, the largest randomized controlled trial of MHT in generally healthy women, suggested harmful cardiovascular effects. Subsequent subanalyses of the Women's Health Initiative and other studies suggest the cardiovascular effects of MHT may vary by age and time since menopause, giving rise to a 'timing hypothesis'. Recent trials have looked at this issue by evaluating surrogate markers of cardiovascular disease (CVD) or CVD events adjudicated as secondary outcomes in RCTs and show a reduction in events with MHT. SUMMARY: Athough the data overall do not support the use of MHT or selective estrogen receptor modulator for primary prevention of CVD, evidence is accumulating that careful use of MHT for perimenopausal symptoms may not carry CVD harm. This review highlights some of the strengths and weaknesses of these recent reports. Ongoing studies of MHT will shed more light on the interaction between age or time after menopause and the vascular effects of MHT.

Potentiation of Doxorubicin cardiotoxicity by iron loading in a rodent model.

OBJECTIVES: The role of iron toward doxorubicin (DOX) cardiotoxicity was studied using a rodent model of dietary carbonyl iron loading. BACKGROUND: Doxorubicin, a commonly used anticancer drug, is known to cause serious and potentially life-threatening cardiotoxicity. Doxorubicin cardiotoxicity is thought to be mediated through free-radical injury. METHODS: Male Sprague Dawley rats fed iron-rich chow (n = 8) and regular chow (n = 8) were treated with DOX or saline (4 animals in each arm). Cardiotoxicity was assessed using mortality, weight changes, Tc-99m annexin-V imaging, histopathology, and immunohistochemistry. RESULTS: Animals fed iron-rich chow showed significantly higher DOX cardiotoxicity as evidenced by greater weight loss (107 +/- 14 g vs. 55 +/- 10 g weight loss, p < 0.05), higher annexin uptake (0.14 +/- 0.01% vs. 0.08 +/- 0.01% injected dose/g of myocardium, p < 0.05), more severe myocyte injury on electron microscopy, and significantly higher cleaved caspase-3 staining compared with regular chow fed rats given DOX. Feeding iron-rich chow alone did not result in any cardiotoxicity. CONCLUSIONS: Dietary iron loading resulted in a substantially increased DOX cardiotoxicity in rats. Body iron stores as well as its bioavailability in tissue may be important independent predictors of susceptibility to DOX cardiotoxicity in man. Further clinical studies are warranted.

Vascular endothelial growth factor regulates reendothelialization and neointima formation in a mouse model of arterial injury.

BACKGROUND: The rate of reendothelialization is critical in neointima formation after arterial injury. Vascular endothelial growth factor (VEGF), a potent endothelial mitogen, has been advocated for accelerating endothelial repair and preventing intimal hyperplasia after percutaneous coronary interventions. However, the precise mechanism of action of VEGF treatment and the physiologic role of endogenous VEGF after arterial injury are not well described. To better understand the role of VEGF in arterial repair, we overexpressed both VEGF and a soluble, chimeric VEGF receptor (VEGF-trap), which binds free VEGF with high affinity, in a mouse model of arterial injury. METHODS AND RESULTS: Four groups of C57BL/6 mice underwent denuding endothelial injury 1 day after systemic injection of recombinant adenovirus expressing (1) VEGF, (2) VEGF-trap, (3) VEGF plus VEGF-trap, or (4) control adenovirus. Circulating levels of adenovirus-encoded proteins were significantly elevated after gene transfer. VEGF overexpression accelerated reendothelialization and increased luminal endothelial cell proliferation 2 weeks after arterial injury (P<0.05), resulting in decreased neointima formation at 4 weeks compared with control (P<0.01). Cotreatment with VEGF-trap completely sequestered free VEGF and abrogated the beneficial effect of VEGF overexpression. Interestingly, sequestration of endogenous VEGF by VEGF-trap overexpression alone also led to delayed reendothelialization at 2 weeks (P<0.01) and increased neointima formation at 4 weeks (P<0.01). CONCLUSIONS: VEGF overexpression accelerated endothelial repair and inhibited neointima formation after arterial injury. Conversely, sequestration of exogenous and/or endogenous VEGF by VEGF-trap delayed reendothelialization and significantly increased neointima size. This demonstrates the therapeutic potential of VEGF but also emphasizes the important physiologic role of endogenous VEGF in vascular repair.