Combination anticoagulation strategy in pregnancy with mechanical valves: The KYBELE study.

BACKGROUND: Optimal first-trimester anticoagulation is still challenging in pregnant women with mechanical heart valves (MHVs) requiring high-dose warfarin. This multicenter prospective study aims to determine the optimal anticoagulation regimens for pregnant patients with MHVs. METHODS: All women were allocated to one of three treatment options during first trimester including lone low-molecular-weight heparin (LMWH), combination of LMWH + 2.5 mg warfarin, and LMWH+4 mg warfarin. Primary maternal outcome included a combination of death, thromboembolism, severe bleeding, and need for treatment of mechanical valve thrombosis (MVT). Any fetal loss was determined as primary fetal outcome. RESULTS: The study included 78 pregnancies in 65 women with MHVs. Primary maternal outcome rate was 44%, 12.5%, 3.5%, respectively. The rates of primary maternal outcome (44 vs 3.5%, P < .001), obstructive MVT (16 vs 0%, P = .04), MVT requiring treatment (28 vs 0%, P = .003), and cerebral embolism (24 vs 3.4%, P = .041) were found to be significantly higher in lone LMWH group compared to LMWH + 4 mg warfarin group. Moreover, the rates of primary maternal outcome (12.5 vs 44%, P = .015) and treatment for MHV thrombus (4.2 vs 28%, P = .049) were significantly lower in LMWH + 2.5 mg warfarin group compared to lone LMWH group. The incidences of fetal loss were 8 (32%) in the lone LMWH group, 8 (33.3%) in LMWH + 2.5 mg warfarin group, and 11 (37.9%) in LMWH + 4 mg warfarin group (P = .890 for 3-group).Warfarin related-embryopathy was not observed in any case. CONCLUSIONS: The combined anticoagulation strategy of LMWH plus low-dose warfarin during the first trimester of pregnancy may result in less maternal complications with comparable fetal outcomes in patients with MHVs. CONDENSED ABSTRACT: Low-molecular-weight heparin (LMWH) is thought to be safer for the fetus, however it is suspected to be less protective for the mother. To solve this dilemma, the authors suggested a novel anticoagulation strategy in pregnant women with prosthetic valves. Seventy-eight pregnancies of 65 women (median age 32 [27-35] years) were included in the study. A combination of LMWH and a reduced dose warfarin were associated with low rates of thrombus-related complications in pregnant patients with mechanical heart valves.

Recovery of left ventricular systolic function in peripartum cardiomyopathy: an observational study from rural Tanzania.

BACKGROUND: The aim of this study was to evaluate the recovery rate of the left ventricular systolic function of women diagnosed with peripartum cardiomyopathy receiving specialized care in rural Tanzania. METHODS: In this observational study, women diagnosed with peripartum cardiomyopathy at a referral center in rural Tanzania between December 2015 and September 2021 were included. Women diagnosed between February and September 2021 were followed prospectively, those diagnosed between December 2015 and January 2021 were tracked back for a follow-up echocardiography. All participants received a clinical examination, a comprehensive echocardiogram, and a prescription of guideline-directed medical therapy. The primary outcome was recovery of the left ventricular systolic function (left ventricular ejection fraction > 50%). RESULTS: Median age of the 110 participants was 28.5 years (range 17-45). At enrolment, 49 (45%) participants were already on cardiac medication, 50 (45%) had severe eccentric hypertrophy of the left ventricle, and the median left ventricular ejection fraction was 30% (range 15-46). After a median follow-up of 8.98 months (IQR 5.72-29.37), 61 (55%) participants were still on cardiac medication. Full recovery of the left ventricular systolic function was diagnosed in 76 (69%, 95% CI 59.6-77.6%) participants. In the multivariate analysis, a higher left ventricular ejection fraction at baseline was positively associated with full recovery (each 5% increase; OR 1.7, 95% CI 1.10-2.62, p = 0.012), while higher age was inversely associated (each 10 years increase; OR 0.40, 95% CI 0.19-0.82, p = 0.012). CONCLUSION: Left ventricular systolic function recovered completely in 69% of study participants with peripartum cardiomyopathy from rural Tanzania under specialized care.

Clinical Trials That Have Changed Obstetric Practice: The Chronic Hypertension and Pregnancy (CHAP) Trial.

We describe the evolution of treatment recommendations for chronic hypertension (CHTN) in pregnancy, the CHTN and pregnancy (CHAP) trial, and its impact on obstetric practice. The US multicenter CHAP trial showed that antihypertensive treatment for mild CHTN in pregnancy [blood pressures (BP)<160/105 mm Hg] to goal<140/90 mm Hg, primarily with labetalol or nifedipine compared with no treatment unless BP were severe reduced the composite risk of superimposed severe preeclampsia, indicated preterm birth <35 weeks, placental abruption, and fetal/neonatal death. As a result of this trial, professional societies in the United States recommended treatment of patients with CHTN in pregnancy to BP goal<140/90 mm Hg.

Overdose of angiotensin II receptor blocker in the third trimester of pregnancy: A case report.

Angiotensin II receptor blockers (ARBs) are contraindicated during pregnancy because of fetal toxicity. All previous reports on adverse fetal outcomes involved women who continued to take low-dose ARBs for hypertension and were unaware of the adverse effects. Herein, we report the case of a 23-year-old pregnant woman in her third trimester who experienced an ARB overdose after an argument with her partner. Pregnancy was complicated by transient oligohydramnios, and fetal magnetic resonance imaging suggested renal failure. Despite these concerns, the newborn had no morphological abnormalities or abnormal neurological findings. Renal impairment improved over time, and the infant grew well. A single overdose of ARBs in the third trimester can lead to fetal renal failure, similar to long-term low-dose ARB administration; however, favorable outcomes are possible. An overdose of ARBs may transiently cause renal failure, which may improve. The study findings may inform counseling for women who are unexpectedly exposed to an overdose of ARBs.

Risks associated with antidepressants in patients with hypertension during pregnancy: a retrospective cohort study.

PURPOSE: In a cohort of pregnant women using antihypertensive drugs, we compared exposure to antidepressants versus no exposure and the possible association with birth weight, APGAR scores, NICU admission, and maternal admission to an obstetrical intensive care unit (OHC). It was hypothesized that pregnant women with hypertensive disorders using antidepressants are at greater risk of complications. METHODS: A retrospective cohort study in a general teaching hospital in Zwolle, in the Middle-Northern part of The Netherlands. Finally, 58 pregnancies in the exposed group and 273 pregnancies in the reference group met all inclusion and exclusion criteria. We compared the neonate's birthweight between the exposed to antidepressants group and the reference group as the primary outcome. Secondary outcomes were the APGAR score at 1 and 5 min and obstetric high care (OHC) admission of the mother and neonatal intensive care unit (NICU) admission of the child. RESULTS: We found no differences in birth weight in neonates of mothers with hypertensive disorders and whether or not to use antidepressants. Besides a possible higher risk of admission to an OHC in women with hypertension-complicated pregnancies using antidepressants, we found no other maternal or neonatal risks in this population. CONCLUSION: We found no additional maternal or neonatal risks of using antidepressants prescribed to women with hypertension disorders during pregnancy.

How I treat venous thromboembolism in pregnancy.

One to 2 pregnant women in 1000 will experience venous thromboembolism (VTE) during pregnancy or postpartum. Pulmonary embolism (PE) is a leading cause of maternal mortality, and deep vein thrombosis leads to maternal morbidity, with postthrombotic syndrome potentially diminishing quality of life for a woman's lifetime. However, the evidence base for pregnancy-related VTE management remains weak. Evidence-based guideline recommendations are often extrapolated from nonpregnant women and thus weak or conditional, resulting in wide variation of practice. In women with suspected PE, the pregnancy-adapted YEARS algorithm is safe and efficient, rendering computed tomographic pulmonary angiography to rule out PE unnecessary in 39%. Low molecular weight heparin (LMWH) in therapeutic doses is the treatment of choice during pregnancy, and anticoagulation (LMWH or vitamin K antagonists [VKAs]) should be continued until 6 weeks after delivery, with a 3-month minimum total duration. LMWH or VKA use does not preclude breastfeeding. Postpartum, direct oral anticoagulants are an option if a woman does not breastfeed and long-term use is intended. Management of delivery, including type of analgesia, requires a multidisciplinary approach and depends on local preferences and patient-specific conditions. Several options are possible, including waiting for spontaneous delivery with temporary LMWH interruption. Prophylaxis for recurrent VTE prevention in subsequent pregnancies is indicated in most women with a history of VTE.

Effects of bromocriptine in peripartum cardiomyopathy: a systematic review and meta-analysis.

Peripartum cardiomyopathy (PPCM) is a rare but potentially life-threatening form of heart failure (HF). Bromocriptine, a dopamine D2 agonist, has been used as an adjunctive treatment for PPCM with controversial benefits. A comprehensive literature search was conducted through June 2021. We included studies comparing the outcomes of PPCM with or without bromocriptine use. Pooled risk ratio (RR) with 95% confidence intervals (CI) and I2 statistics were calculated. Composite major adverse outcomes were defined by a composite of death, need for advanced HF therapies, persistent New York Heart Association (NYHA) functional class III/V, or left ventricular ejection fraction (LVEF) ≤ 35% at 6-month follow-up. LVEF recovery was defined by improvement of LVEF to more than 50%. Eight studies (two randomized-controlled, six observational) involving 593 PPCM patients were included. Bromocriptine use was associated with significantly higher survival (91.6% vs. 83.9%, RR 1.11 p = 0.02). Baseline LVEF was not significantly different between the groups. LVEF at follow-up was significantly higher in the bromocriptine group (53.3% vs. 41.8%, p < 0.001). There was no significant association between bromocriptine use and lower composite major adverse outcomes (13.7% vs. 33.3%, RR 0.60 p = 0.54) or LVEF recovery (46.9% vs. 46.8%, RR 0.94 p = 0.74). In conclusion, the addition of bromocriptine to standard HF treatment in PPCM was associated with significantly higher survival and higher LVEF improvement. No association with lower composite adverse clinical outcomes or LVEF recovery was seen. The findings, although encouraging, warrant larger randomized-controlled studies.

Society for Maternal-Fetal Medicine Consult Series #61: Anticoagulation in pregnant patients with cardiac disease.

Pregnancy in individuals with a mechanical heart valve has been classified as very high risk because of a substantially increased risk of maternal mortality or severe morbidity. Lifelong therapeutic anticoagulation is a principal component of the medical management of mechanical heart valves to prevent valve thrombosis. Anticoagulation regimens indicated outside of pregnancy for patients with mechanical valves should be continued during pregnancy with the possibility of modifications based on the type of valve, the trimester of pregnancy, individual risk tolerance, and circumstances around the time of delivery. The purpose of this document is to provide recommendations regarding the management of anticoagulation for common cardiac conditions complicating pregnancy, including mechanical heart valves, atrial fibrillation, systolic heart failure, and congenital heart disease.

Society for Maternal-Fetal Medicine Statement: Antihypertensive therapy for mild chronic hypertension in pregnancy-The Chronic Hypertension and Pregnancy trial.

The recently published Chronic Hypertension and Pregnancy study provides important data to inform the management of mild chronic hypertension in pregnancy. The purpose of this statement is to review the results of this trial and provide guidance for the implementation of the study findings. Based on the available evidence, SMFM recommends treatment with antihypertensive therapy for mild chronic hypertension in pregnancy to a goal blood pressure of <140/90 mm Hg. Patients with treated chronic hypertension should continue established antihypertensive therapy during pregnancy or change to a regimen compatible with pregnancy to achieve this treatment goal.

Changes in ophthalmic artery Doppler during acute blood-pressure control in hypertensive pregnant women.

OBJECTIVE: To examine the changes in ophthalmic artery Doppler indices and their association with changes in mean arterial blood pressure (MAP) and systolic (SBP) and diastolic (DBP) blood pressure, following acute antihypertensive treatment in women with hypertensive disorders of pregnancy presenting with high blood pressure. METHODS: This was a prospective cohort study of 31 pregnant women presenting at 30 + 0 to 39 + 6 weeks' gestation for management of their hypertension. Paired maternal blood-pressure and ophthalmic-artery-Doppler measurements were performed prior to and at 30 min and 60 min after starting antihypertensive medication. In patients who did not achieve blood-pressure control (i.e. when blood pressure was < 140/90 mmHg) by 60 min, paired readings were continued up to 120 min. If blood-pressure control was still not achieved at that point, patients were admitted to hospital. Univariate linear regression was performed to determine the association of ophthalmic artery peak systolic velocity (PSV) ratio with SBP, DBP and MAP before treatment and after blood-pressure control. The longitudinal changes in MAP, SBP, DBP and PSV ratio from pretreatment to 30 min and 60 min after commencement of antihypertensives were examined by repeated measure, multilevel, linear mixed-effects analysis. RESULTS: Antihypertensive treatment was associated with a decrease in SBP, DBP, MAP and PSV ratio. At 60 min following antihypertensive treatment, the decrease in SBP, DBP, MAP and PSV ratio was 12.1 mmHg (95% CI, 9.0-15.1 mmHg; P < 0.0001), 9.1 mmHg (95% CI, 6.5-11.5 mmHg; P < 0.0001), 10.0 mmHg (95% CI, 7.6-12.4 mmHg; P < 0.0001) and 0.07 (95% CI, 0.03-0.11 mmHg; P < 0.001), respectively. From the total cohort, 20 (64.5%) women had achieved blood-pressure control at 60 min and another seven (22.6%) by 120 min from commencement of antihypertensive treatment. Four (12.9%) women did not achieve blood-pressure control during this period and were admitted to hospital. The relationship between PSV ratio and SBP, DBP and MAP was assessed before treatment (n = 31) and at the point of blood-pressure control in women in whom this was achieved by 120 min (n = 27). Prior to treatment, there was a significant association between PSV ratio and MAP (P < 0.0001, R2 = 0.39). This was primarily due to the association of PSV ratio with DBP (P < 0.0001, R2 = 0.39) and less so due to its association with SBP (P = 0.02, R2 = 0.16). At the point of achieving blood-pressure control, there was no significant association between PSV ratio and MAP (P = 0.7), DBP (P = 0.5) or SBP (P = 0.7). CONCLUSIONS: Acute blood-pressure control in pregnancy is associated with a concomitant reduction in blood pressure and ophthalmic artery PSV ratio. In hypertensive pregnant women, there is a significant association of PSV ratio with MAP, SBP and DBP, which disappears after blood pressure is reduced to < 140/90 mmHg following antihypertensive treatment. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

Pharmacokinetics of the most commonly used antihypertensive drugs throughout pregnancy methyldopa, labetalol, and nifedipine: a systematic review.

PURPOSE: Antihypertensive drugs are among the most prescribed drugs during pregnancy. Methyldopa, labetalol, and nifedipine have been perceived safe to use during pregnancy and are therefore recommended in international guidelines for treatment of hypertension. In this review, we provide a complete overview of what is known on the pharmacokinetics (PK) of the antihypertensive drugs methyldopa, labetalol, and nifedipine throughout pregnancy. METHODS: A systematic search was performed to retrieve studies on the PK of methyldopa, labetalol, and nifedipine used throughout pregnancy. The search was restricted to English and original studies. The systematic search was conducted on July 27, 2021, in Embase, Medline Ovid, Web of Science, Cochrane Library, and Google Scholar. Keywords were methyldopa, labetalol, nifedipine, pharmacokinetics, pregnancy, and placenta. RESULTS: A total of 1459 unique references were identified of which title and abstract were screened. Based on this screening, 67 full-text papers were assessed, to retain 30 PK studies of which 2 described methyldopa, 12 labetalol, and 16 nifedipine. No fetal accumulation is found for any of the antihypertensive drugs studied. CONCLUSION: We conclude that despite decades of prescribing methyldopa, labetalol, and nifedipine throughout pregnancy, descriptions of their PK during pregnancy are hampered by a large heterogeneity in the low number of available studies. Aiming for evidence-based and personalized dosing of antihypertensive medication in the future, further studies on the relationship of both PK and pharmacodynamics (including the optimal blood pressure targeting) during pregnancy and pregnancy-related pathology are urgently needed to prevent undertreatment, overtreatment, and side effects.

Women's values and preferences on low-molecular-weight heparin and pregnancy: a mixed-methods systematic review.

BACKGROUND: Venous thromboembolism (VTE) in pregnancy is an important cause of maternal morbidity and mortality. Low-molecular-weight heparin (LMWH) is the cornerstone of prophylaxis and treatment of thrombotic events during pregnancy. LMWH has fewer adverse effects than other anticoagulants, does not cross the placenta, and is safe for the fetus. However, the use of LMWH during pregnancy is sensitive to womens' underlying preferences. The objective of this review is to systematically assess women's values and preferences research evidence on this topic. METHODS: We searched four electronic databases from inception to March 2022, and included studies examining values and preferences of using LMWH among pregnant women at risk of VTE. We followed a convergent integrated mixed-methods design to compare and contrast quantitative outcomes (utility and non-utility measures) and qualitative findings. We assessed the certainty of the values and preferences evidence with the GRADE approach for quantitative findings, and with GRADE-CERqual for qualitative evidence. Results were presented in a conjoint display. RESULTS: We screened 3,393 references and identified seven eligible studies. The mixed methods analysis resulted in four themes. Datasets confirmed each other in that: 1) the majority of women consider that benefits of treatment outweigh the inconveniences of daily injections; and 2) main concerns around medication are safety and injections administration. Quantitative outcomes expanded on the qualitative findings in that: 3) participants who perceived a higher risk of VTE were more willing to take LMWH. Finally, we found a discrepancy between the datasets around: 4) the amount of information preferred to make the decision; however, qualitative data expanded to clarify that women prefer making informed decisions and receive support from their clinician in their decision-making process. CONCLUSIONS: We are moderately confident that in the context of pregnancy, using LMWH is preferred by women given its net beneficial balance. Integrating data from different sources of evidence, and representing them in a jointly manner helps to identify patient's values and preferences. Our results may inform clinical practice guidelines and support shared decision-making process in the clinical encounter for the management of VTE in the context of pregnancy.

Extending the window for thrombolysis for treatment of acute ischaemic stroke during pregnancy: a review.

Historically, safety of intravenous recombinant tissue plasminogen activator (IV rt-PA) for the treatment of acute ischaemic stroke (AIS) is limited to use within 4.5 hours from symptom onset. Recent studies suggest the treatment window may be extended when patients have salvageable brain tissue on advanced neuroimaging. This paper describes a novel use of IV rt-PA for treatment of AIS in a pregnant patient within an extended-time window (>4.5 hours, and <9 hours) based on advanced neuroimaging with a favourable outcome. TWEETABLE ABSTRACT: Novel use of IV rt-PA for treatment of AIS in pregnancy within an extended-time window based on advanced imaging with a favourable outcome.

Impact of autoantibodies against the M2-muscarinic acetylcholine receptor on clinical outcomes in peripartum cardiomyopathy patients with standard treatment.

OBJECTIVES: To evaluate the impact of autoantibodies against the M2-muscarinic receptor (anti-M2-R) on the clinical outcomes of patients receiving the standard treatment for peripartum cardiomyopathy (PPCM). METHODS: A total of 107 PPCM patients who received standard heart failure (HF) treatment between January 1998 and June 2020 were enrolled in this study. According to anti-M2-R reactivity, they were classified into negative (n = 59) and positive (n = 48) groups, denoted as the anti-M2-R (-) and anti-M2-R (+) groups. Echocardiography, 6-min walk distance, serum digoxin concentration (SDC), and routine laboratory tests were performed regularly for 2 years. The all-cause mortality, cardiovascular mortality, and rehospitalisation rate for HF were compared between the two groups. RESULTS: A total of 103 patients were included in the final data analysis, with 46 in the anti-M2-R (+) group and 57 in the anti-M2-R (-) group. Heart rate was lower in the anti-M2-R (+) group than in the anti-M2-R (-) group at the baseline (102.7 ± 6.1 bpm vs. 96.0 ± 6.4 bpm, p < 0.001). The initial SDC was higher in the anti-M2-R (+) group than in the anti-M2-R (-) group with the same dosage of digoxin (1.25 ± 0.45 vs. 0.78 ± 0.24 ng/mL, p < 0.001). The dosages of metoprolol and digoxin were higher in the anti-M2-R (-) patients than in the anti-M2-R (+) patients (38.8 ± 4.6 mg b.i.d. vs. 27.8 ± 5.3 mg b.i.d., p < 0.0001, respectively, for metoprolol; 0.12 ± 0.02 mg/day vs. 0.08 ± 0.04 mg/day, p < 0.0001, respectively, for digoxin). Furthermore, there was a greater improvement in cardiac function in the anti-M2-R (-) patients than in the anti-M2-R (+) patients. Multivariate analysis identified negativity for anti-M2-R as the independent predictor for the improvement of cardiac function. Rehospitalisation for HF was lower in the anti-M2-R (-) group, but all-cause mortality and cardiovascular mortality were the same. CONCLUSIONS: There were no differences in all-cause mortality or cardiovascular mortality between the two groups. Rehospitalisation rate for HF decreased in the anti-M2-R (-) group. This difference may be related to the regulation of the autonomic nervous system by anti-M2-R.

Warfarin Anticoagulation and Fetal Central Nervous System Abnormalities: a Case Report.

BACKGROUND: Anticoagulation of pregnant woman with mechanical prosthetic heart valves is associated with significant maternal and fetal risks. METHODS: We describe a case of dorsal midline dysplasia in a fetus at 11 weeks' gestation. The mother was receiving warfarin therapy at a dose of 7.5 mg daily following a mechanical mitral valve replacement for rheumatic heart disease. RESULTS: Histological assessment revealed a meningocele with hemorrhage. No cerebellar or cerebral tissue was present in the skull confirming anencephaly. CONCLUSIONS: A multidisciplinary approach in pregnant women with mechanical prosthetic heart valves is essential in order to improve fetal outcomes.

Successful treatment of arrhythmia with ß-blocker and flecainide combination in pregnant patients with Andersen-Tawil syndrome: A case report and literature review.

Andersen-Tawil syndrome (ATS) is a rare disorder characterized by a triad of ventricular arrhythmia (VA), dysmorphic features, and periodic paralysis. Due to the rarity of this condition, less is known about physiologic effect of pregnancy to ATS and arrhythmia. There is no established guideline for peripartum or postpartum treatment and prevention of arrhythmia in ATS; thus, the clinical management is challenging. We reported two KCNJ2-associated ATS patients who got pregnant and underwent vaginal birth safely. Both individuals had VA, micrognathia without periodic paralysis. ß-blocker plus flecainide could be an effective treatment combination when monotherapy failed to control arrhythmia. VA of two pregnant patients with ATS could be controlled by either physiologic changes associated pregnancy or the combination treatment of ß-blocker and flecainide.

A first trimester pregnancy with cerebrovascular accident treated with thrombolytic therapy.

Pregnant patients are at increased risk of cerebrovascular accident due to the prothrombotic state of pregnancy. This risk is highest in those with pre-eclampsia and eclampsia as well as those of Asian descent. Despite this increased risk, pregnancy was an exclusion criterion for major stroke intervention trials. As a result, there are significant challenges concerning the management of this unique patient population. We describe a case of an early first trimester cerebrovascular accident treated with systemic thrombolysis.

Mechanical heart valve thrombosis during pregnancy under non-warfarin anticoagulation therapy: Two-case report and literature review. / å¦Šå¨ æœŸæœºæ¢°å¿ƒè„ç“£è†œç½®æ¢éžåŽæ³•æž—æŠ—å‡æ‚£è€ å‡ºçŽ°è¡€æ “å¡ç“£2ä¾‹å¹¶æ–‡çŒ®å¤ä¹ .

Anticoagulation drugs should be used for patients with mechanical heart valve (MHV) in case of potential risk of thrombosis. Pregnant women with MHV have to change therapies due to teratogenic effect of some anti-coagulation drugs. European Society of Cardiology clinical guidelines for the management of cardiovascular diseases during pregnancy gives specific suggestions for anticoagulation therapy.We have treated 2 patients with mechanical heart valve thrombosis (MVT) during pregnancy: One received low molecular weight heparin (LMWH) throughout the pregnancy and developed MVT at the third trimester of pregnancy; one developed MVT at the first trimester when replacing vitamin K antagonists (VKA) with LMWH. These patients raised secondary reflection on the balance between clinical guideline and personalized medicine. During LMWH therapy, we should dynamically monitor patients' anti-activated factor X (anti-Xa) level to evaluate coagulation function during pregnancy. When a pregnant woman with MHV develops symptoms of acute heart failure, stuck mechanical valve should be paid attention to and surgery should be promptly performed if necessary.

Prenatal hypoxia inhibited propionate-evoked BK channels of mesenteric artery smooth muscle cells in offspring.

As a common complication of pregnancy, gestational hypoxia has been shown to predispose offspring to vascular dysfunction. Propionate, one of short-chain fatty acids, exerts cardioprotective effects via reducing blood pressure. This study examined whether prenatal hypoxia impaired propionate-stimulated large-conductance Ca2+ -activated K+ (BK) channel activities in vascular smooth muscle cells (VSMCs) of offspring. Pregnant rats were exposed to hypoxia (10.5% oxygen) and normoxia (21% oxygen) from gestational day 7-21. At 6 weeks of age, VSMCs in mesenteric arteries of offspring were analysed for BK channel functions and gene expressions. It was shown firstly that propionate could open significantly BK single channel in VSMCs in a concentration-dependent manner. Antagonists of G protein ßγ subunits and inositol trisphosphate receptor could completely suppress the activation of BK by propionate, respectively. Gαi/o and ryanodine receptor were found to participate in the stimulation on BK. Compared to the control, vasodilation and increments of BK NPo (the open probability) evoked by propionate were weakened in the offspring by prenatal hypoxia with down-regulated Gßγ and PLCß. It was indicated that prenatal hypoxia inhibited propionate-stimulated BK activities in mesenteric VSMCs of offspring via reducing expressions of Gßγ and PLCß, in which endoplasmic reticulum calcium release might be involved.

The INVICTUS rheumatic heart disease research program: Rationale, design and baseline characteristics of a randomized trial of rivaroxaban compared to vitamin K antagonists in rheumatic valvular disease and atrial fibrillation.

BACKGROUND: Rheumatic heart disease (RHD) is a neglected disease affecting 33 million people, mainly in low and middle income countries. Yet very few large trials or registries have been conducted in this population. The INVICTUS program of research in RHD consists of a randomized-controlled trial (RCT) of 4500 patients comparing rivaroxaban with vitamin K antagonists (VKA) in patients with RHD and atrial fibrillation (AF), a registry of 17,000 patients to document the contemporary clinical course of patients with RHD, including a focused sub-study on pregnant women with RHD within the registry. This paper describes the rationale, design, organization and baseline characteristics of the RCT and a summary of the design of the registry and its sub-study. Patients with RHD and AF are considered to be at high risk of embolic strokes, and oral anticoagulation with VKAs is recommended for stroke prevention. But the quality of anticoagulation with VKA is poor in developing countries. A drug which does not require monitoring, and which is safe and effective for preventing stroke in patients with valvular AF, would fulfill a major unmet need. METHODS: The INVestIgation of rheumatiC AF Treatment Using VKAs, rivaroxaban or aspirin Studies (INVICTUS-VKA) trial is an international, multicentre, randomized, open-label, parallel group trial, testing whether rivaroxaban 20 mg given once daily is non-inferior (or superior) to VKA in patients with RHD, AF, and an elevated risk of stroke (mitral stenosis with valve area ≤2 cm2, left atrial spontaneous echo-contrast or thrombus, or a CHA2DS2VASc score ≥2). The primary efficacy outcome is a composite of stroke or systemic embolism and the primary safety outcome is the occurrence of major bleeding. The trial has enrolled 4565 patients from 138 sites in 23 countries from Africa, Asia and South America. The Registry plans to enroll an additional 17,000 patients with RHD and document their treatments, and their clinical course for at least 2 years. The pregnancy sub-study will document the clinical course of pregnant women with RHD. CONCLUSION: INVICTUS is the largest program of clinical research focused on a neglected cardiovascular disease and will provide new information on the clinical course of patients with RHD, and approaches to anticoagulation in those with concomitant AF.