The benefits and risks of menopause hormone therapy for the cardiovascular system in postmenopausal women: a systematic review and meta-analysis.

BACKGROUND: Menopause hormone therapy (MHT), as an effective method to alleviate the menopause-related symptoms of women, its benefits, risks, and potential influencing factors for the cardiovascular system of postmenopausal women are not very clear. OBJECTIVES: To evaluate cardiovascular benefits and risks of MHT in postmenopausal women, and analyze the underlying factors that affect both. SEARCH STRATEGY: The EMBASE, MEDLINE, and CENTRAL databases were searched from 1975 to July 2022. SELECTION CRITERIA: Randomized Clinical Trials (RCTs) that met pre-specified inclusion criteria were included. DATA COLLECTION AND ANALYSIS: Two reviewers extracted data independently. A meta-analysis of random effects was used to analyze data. MAIN RESULTS: This systematic review identified 33 RCTs using MHT involving 44,639 postmenopausal women with a mean age of 60.3 (range 48 to 72 years). There was no significant difference between MHT and placebo (or no treatment) in all-cause death (RR = 0.96, 95%CI 0.85 to 1.09, I2 = 14%) and cardiovascular events (RR = 0.97, 95%CI 0.82 to 1.14, I2 = 38%) in the overall population of postmenopausal women. However, MHT would increase the risk of stroke (RR = 1.23, 95%CI 1.08 to 1.41,I2 = 0%) and venous thromboembolism (RR = 1.86, 95%CI 1.39 to 2.50, I2 = 24%). Compared with placebo, MHT could improve flow-mediated arterial dilation (FMD) (SMD = 1.46, 95%CI 0.86 to 2.07, I2 = 90%), but it did not improve nitroglycerin-mediated arterial dilation (NMD) (SMD = 0.27, 95%CI - 0.08 to 0.62, I2 = 76%). Compared with women started MHT more than 10 years after menopause, women started MHT within 10 years after menopause had lower frequency of all-cause death (P = 0.02) and cardiovascular events (P = 0.002), and more significant improvement in FMD (P = 0.0003). Compared to mono-estrogen therapy, the combination therapy of estrogen and progesterone would not alter the outcomes of endpoint event. (all-cause death P = 0.52, cardiovascular events P = 0.90, stroke P = 0.85, venous thromboembolism P = 0.33, FMD P = 0.46, NMD P = 0.27). CONCLUSIONS: MHT improves flow-mediated arterial dilation (FMD) but fails to lower the risk of all-cause death and cardiovascular events, and increases the risk of stroke and venous thrombosis in postmenopausal women. Early acceptance of MHT not only reduces the risk of all-cause death and cardiovascular events but also further improves FMD, although the risk of stroke and venous thrombosis is not reduced. There is no difference in the outcome of cardiovascular system endpoints between mono-estrogen therapy and combination therapy of estrogen and progesterone.

Smooth muscle ATP-sensitive potassium channels mediate migraine-relevant hypersensitivity in mouse models.

BACKGROUND: Opening of KATP channels by systemic levcromakalim treatment triggers attacks in migraine patients and hypersensitivity to von Frey stimulation in a mouse model. Blocking of these channels is effective in several preclinical migraine models. It is unknown in what tissue and cell type KATP-induced migraine attacks are initiated and which KATP channel subtype is targeted. METHODS: In mouse models, we administered levcromakalim intracerebroventricularly, intraperitoneally and intraplantarily and compared the nociceptive responses by von Frey and hotplate tests. Mice with a conditional loss-of-function mutation in the smooth muscle KATP channel subunit Kir6.1 were given levcromakalim and GTN and examined with von Frey filaments. Arteries were tested for their ability to dilate ex vivo. mRNA expression, western blotting and immunohistochemical stainings were made to identify relevant target tissue for migraine induced by KATP channel opening. RESULTS: Systemic administration of levcromakalim induced hypersensitivity but central and local administration provided antinociception respectively no effect. The Kir6.1 smooth muscle knockout mouse was protected from both GTN and levcromakalim induced hypersensitivity, and their arteries had impaired dilatory response to the latter. mRNA and protein expression studies showed that trigeminal ganglia did not have significant KATP channel expression of any subtype, whereas brain arteries and dura mater primarily expressed the Kir6.1 + SUR2B subtype. CONCLUSION: Hypersensitivity provoked by GTN and levcromakalim in mice is dependent on functional smooth muscle KATP channels of extracerebral origin. These results suggest a vascular contribution to hypersensitivity induced by migraine triggers.

Cerebral Vasodilator Property of Poly(ADP-Ribose) Polymerase Inhibitor (PJ34) in the Neonatal and Adult Mouse Is Mediated by the Nitric Oxide Pathway.

The poly(ADP-ribose) polymerase (PARP) inhibitor PJ34 has been reported to improve endothelial dysfunction in the peripheral system. We addressed the role of PJ34 on the vascular tone and vasoreactivity during development in the mouse brain. Blood flows were measured in the basilar trunk using ultrasonography. Cerebral vasoreactivity or vasodilation reserve was estimated as a percentage increase in mean blood flow velocities (mBFV) recorded under normoxia-hypercapnia in control and after PJ34 administration. Non-selective and selective eNOS and nNOS inhibitors were used to evaluate the role of NO-pathway into the hemodynamic effects of PJ34. PJ34 increased mBFVs from 15.8 ± 1.6 to 19.1 ± 1.9 cm/s (p = 0.0043) in neonatal, from 14.6 ± 1.4 to 16.1 ± 0.9 cm/s (p = 0.0049) in adult, and from 15.7 ± 1.7 to 17.5 ± 2.0 cm/s (p = 0.0024) in aged mice 48 h after administration. These PJ34 values were similar to those measured in age-matched control mice under normoxia-hypercapnia. This recruitment was mediated through the activation of constitutive NO synthases in both the neonatal (38.2 ± 6.7 nmol/min/mg protein) and adult (31.5 ± 4.4 nmol/min/mg protein) brain, as compared to age-matched control brain (6.9 ± 0.4 and 6.3 ± 0.7 nmol/min/mg protein), respectively. In addition, quite selective eNOS inhibitor was able to inhibit the recruitment. PJ34 by itself is able to increase cerebral blood flow through the NO-pathway activation at least over 48 h after a single administration.

Investigation of sumatriptan and ketorolac trometamol in the human experimental model of headache.

BACKGROUND: Pituitary adenylate cyclase-activating polypeptide-38 (PACAP38) induces headache in healthy volunteers but the precise mechanisms by which PACAP38 leads to headache are unclear. We investigated the headache preventive effect of sumatriptan and ketorolac on PACAP38-induced headache in healthy volunteers. In addition, we explored contribution of vascular mechanisms to PACAP38-induced headache using high resolution magnetic resonance angiography. METHODS: Thirty-four healthy volunteers were divided in two groups (A and B) and received infusion of PACAP38 (10 picomol/kg/min) over 20 min. Group A was pretreated with intravenous sumatriptan (4 mg) or ketorolac (30 mg) 20 min before infusion of PACAP38. Group B received infusion of sumatriptan or ketorolac as post-treatment 90 min after infusion of PACAP38. In both experiments, we used a randomized, double-blind, cross-over design. We recorded headache characteristics and circumference of extra-intracerebral arteries. RESULTS: We found no difference in AUC (0-6 h) of PACAP38-induced headache in group A, pretreated with sumatriptan or ketorolac (p = 0.297). There was no difference between sumatriptan and ketorolac in PACAP38-induced circumference change (AUCBaseline-110 min) of MMA (p = 0.227), STA (p = 0.795) and MCA (p = 0.356). In group B, post-treatment with ketorolac reduced PACAP38-headache compared to sumatriptan (p < 0.001). Post-treatment with sumatriptan significantly reduced the circumference of STA (p = 0.039) and MMA (p = 0.015) but not of MCA (p = 0.981) compared to ketorolac. In an explorative analysis, we found that pre-treatment with sumatriptan reduced PACAP38-induced headache compared to no treatment (AUC0-90min). CONCLUSIONS: Post-treatment with ketorolac was more effective in attenuating PACAP38-induced headache compared to sumatriptan. Ketorolac exerted its effect without affecting PACAP38-induced arterial dilation, whereas sumatriptan post-treatment attenuated PACAP38-induced dilation of MMA and STA. Pre-treatment with sumatriptan attenuated PACAP38-induced headache without affecting PACAP38-induced arterial dilation. Our findings suggest that ketorolac and sumatriptan attenuated PACAP38-induced headache in healthy volunteers without vascular effects. TRIAL REGISTRATION: Clinicaltrials.gov (NCT03585894). Registered 13 July 2018.

Effect of pituitary adenylate cyclase-activating polypeptide-27 on cerebral hemodynamics in healthy volunteers: A 3T MRI study.

Pituitary adenylate cyclase-activating polypeptide (PACAP) has emerged as an important signaling peptide in migraine pathogenesis. Recently, we have shown that the less-abundant PACAP isoform, PACAP27, induced migraine and headache in patients equipotently to PACAP38. The present study examined the effect of PACAP27 on cerebral hemodynamics in healthy volunteers using high resolution magnetic resonance angiography (MRA). Eighteen healthy volunteers received infusion of PACAP27 (10 pmol/kg/min) or placebo over 20 min and were scanned repeatedly in fixed intervals for 5 h in a double-blind, randomized, placebo-controlled study. The circumference of extra-intracerebral arteries was measured and compared with PACAP38 data. We found significant dilation of middle meningeal artery (MMA) (p = 0.019), superficial temporal artery (p = 0.001) and external carotid artery (p = 0.039) after PACAP27 infusion compared to placebo. Whereas the middle cerebral artery (MCA) (p = 0.011) and internal carotid artery (ICA) (pICAcervical = 0.015, pICAcerebral = 0.019) were constricted. No effects on basilar artery (p = 0.708) and cavernous portion of ICA were found. Post hoc analyses revealed significant larger area under the curve for MMA after PACAP38 compared to PACAP27 (p = 0.033). We also found that PACAP27 induced headache in nine out of twelve (75%) volunteers and one (17%) after placebo. In conclusion, PACAP27 induced headache and dilated extracerebral arteries (>5 h) and slightly constricted MCA in healthy volunteers. Post hoc analysis of PACAP38 data compared with PACAP27 showed that PACAP isoforms dilates MMA with significantly different magnitude.

Pulmonary arterial dilation with normal pulmonary artery pressure in sarcoidosis.

In this paper we present a clinical case that has improved on our knowledge and our curiosity about sarcoidosis. We report a case of a patient known to have pulmonary sarcoidosis, who presents with respiratory failure with severe hypercapnia. Following thorough investigations this patient was recognized to have three unique yet interrelated aspects of clinical manifestations. He was found to have severe bilateral diaphragmatic hypokinesis, dilated pulmonary vasculature with normal pulmonary pressure, and a state of high output right sided heart failure. We propose an explanation of such a presentation, while we attempted to discuss possible alternative mechanisms. In conclusion, we report this case as the first recognized case of sarcoidosis to be related to diffusely dilated pulmonary vasculature of normal vascular pressure.

Coronary atherosclerosis and dilation in hyper IgE syndrome patients: Depiction by magnetic resonance vessel wall imaging and pathological correlation.

BACKGROUND AND AIMS: Autosomal dominant hyper-IgE (AD-HIES) is a primary immunodeficiency caused by mutations in STAT3. Elevated levels of IgE, an ineffective immune response, connective tissue abnormalities, and coronary arterial dilation and tortuosity characterize AD-HIES. To date, coronary artery evaluation in AD-HIES patients has been limited to lumenography measurements. Direct in vivo coronary vessel wall (VW) imaging may allow for better interrogation of coronary vessel abnormalities. The goal of this prospective study was to evaluate the coronary VW of AD-HIES patients using Magnetic Resonance Imaging (MRI) and histology. VW image findings were compared in healthy subjects and subjects with coronary atherosclerotic disease (CAD). METHODS: A total of 28 subjects (10 with AD-HIES, 8 healthy, 10 with CAD) were studied by coronary VW MRI imaging. Additionally, a post-mortem coronary artery from one VW imaged AD-HIES patient was examined. RESULTS: Coronary VW in AD-HIES was thicker than in healthy controls but not significantly different from VW thickness in CAD subjects. AD-HIES coronaries showed increased VW area compared to healthy controls and CAD subjects. On histology, the AD-HIES coronary artery had findings consistent with atherosclerotic plaque, but had minimal luminal narrowing, deficient adventitia thickening and absence of both internal and external elastic laminae. CONCLUSIONS: This is the first study to demonstrate subclinical coronary atherosclerosis in AD-HIES patients on VW imaging by MRI. Histologic evaluation confirmed the presence of atherosclerosis with lack of supportive adventitial thickening and elastic components. These findings suggest mechanisms for coronary dilation in AD-HIES and thereby help direct clinical management.

Endothelial Small- and Intermediate-Conductance K Channels and Endothelium-Dependent Hyperpolarization as Drug Targets in Cardiovascular Disease.

Endothelial calcium/calmodulin-gated K channels of small (KCa2.3) and intermediate conductance (KCa3.1) produce membrane hyperpolarization and endothelium-dependent hyperpolarization (EDH)-mediated vasodilation. Dysfunctions of the two channels and ensuing EDH impairments are found in several cardiovascular pathologies such as diabetes, atherosclerosis, postangioplastic neointima formation, but also inflammatory disease, cancer, and organ fibrosis. Moreover, KCa3.1 plays an important role in endothelial barrier dysfunction, edema formation in cardiac and pulmonary disease, and in ischemic stroke. Concerning KCa2.3, genome-wide association studies revealed an association of KCa2.3 channels with atrial fibrillation in humans. Accordingly, both channels are considered potential drug targets for cardio- and cerebrovascular disease states. In this chapter, we briefly review the function of the two channels in EDH-type vasodilation and systemic circulatory regulation and then highlight their pathophysiological roles in ischemic stroke as well as in pulmonary and brain edema. Finally, the authors summarize recent advances in the pharmacology of the channels and explore potential therapeutic utilities of novel channel modulators.

Effect of endurance exercise training on endothelial function and arterial stiffness in older patients with heart failure and preserved ejection fraction: a randomized, controlled, single-blind trial.

OBJECTIVES: The study sought to evaluate the effects of endurance exercise training (ET) on endothelial-dependent flow-mediated arterial dilation (FMD) and carotid artery stiffness, and their potential contributions to the training-related increase in peak exercise oxygen consumption (Vo2) in older patients with heart failure with preserved ejection fraction (HFPEF). BACKGROUND: Elderly HFPEF patients have severely reduced peak Vo2, which improves with ET, however, the mechanisms of this improvement are unclear. FMD and arterial distensibility are critical components of the exercise response and are reduced with aging. However, it is unknown whether these improve with ET in elderly HFPEF or contribute to the training-related improvement in peak Vo2. METHODS: A total of 63 HFPEF patients (age 70 ± 7 years) were randomized to 16 weeks of ET (walking, arm and leg ergometry, n = 32) or attention control (CT) (n = 31). Peak Vo2, brachial artery FMD in response to cuff ischemia, carotid artery distensibility by high-resolution ultrasound, left ventricular function, and quality of life were measured at baseline and follow-up. RESULTS: ET increased peak Vo2 (ET: 15.8 ± 3.3 ml/kg/min vs. CT: 13.8 ± 3.1 ml/kg/min, p = 0.0001) and quality of life. However, brachial artery FMD (ET: 3.8 ± 3.0% vs. CT: 4.3 ± 3.5%, p = 0.88), and carotid arterial distensibility (ET: 0.97 ± 0.56 vs. CT: 1.07 ± 0.34 × 10(-3) mm·mm Hg(-2); p = 0.65) were unchanged. Resting left ventricular systolic and diastolic function were unchanged by ET. CONCLUSIONS: In elderly HFPEF patients, 16 weeks of ET improved peak Vo2 without altering endothelial function or arterial stiffness. This suggests that other mechanisms, such as enhanced skeletal muscle perfusion and/or oxygen utilization, may be responsible for the ET-mediated increase in peak Vo2 in older HFPEF patients. (Prospective Aerobic Reconditioning Intervention Study [PARIS]; NCT01113840).