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Aim: TransCon CNP is a novel prodrug designed to provide sustained release of C-type natriuretic peptide (CNP) for once-weekly therapy, addressing the pathology leading to aberrant skeletal development in achondroplasia. This phase 1 trial was initiated to assess the safety, tolerability, pharmacodynamics (PD) and pharmacokinetics (PK) of TransCon CNP., Methods: This randomized, placebo-controlled, single-ascending dose phase 1 trial was performed at two sites in Australia and enrolled 45 healthy adult males. Subjects received placebo or TransCon CNP (single-ascending dose cohorts [3, 10, 25, 75 or 150 μg CNP/kg]). The primary endpoint was frequency of adverse events and other safety outcomes. Other endpoints included PK and PD measured by cyclic guanosine-monophosphate (cGMP) and amino-terminal propeptide of CNP (NTproCNP)., Results: TransCon CNP provided continuous systemic exposure to CNP over at least 7 days post-dose. Plasma and urine levels of cGMP were significantly increased in subjects administered TransCon CNP at 75-150 μg CNP/kg, indicating target engagement of active CNP at the natriuretic peptide receptor-B (NPR-B) for at least 1 week post-dose. TransCon CNP was well-tolerated, with no serious treatment-emergent adverse events or discontinuations. Extensive cardiac safety assessments did not reveal any clinically relevant effects on electrocardiogram parameters, including heart rate, PR, QRS and QTcF intervals., Conclusions: Safety and PD data from this phase 1 trial support that TransCon CNP is well tolerated, with a PK profile compatible with a once-weekly dosing regimen. Further studies are ongoing to evaluate the potential of TransCon CNP to positively impact abnormal endochondral ossification in children with achondroplasia., (© 2022 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

There are no consensus guidelines on the management of catheter-related right atrial thrombus. We present the case of a 29-year-old female with end-stage renal disease who was found to have a large right atrial thrombus associated with her tunneled dialysis catheter during preoperative workup for renal transplant. She exhibited signs and symptoms of superior vena cava syndrome and NYHA class III congestive heart failure. She was successfully treated with surgical thrombectomy and demonstrated rapid resolution of her symptoms postoperatively., (© 2020 Wiley Periodicals, Inc.)

Hemophilia B is a rare X-linked recessive disorder that places surgical patients at an increased risk of bleeding. Patients with hemophilia are now achieving near-normal life expectancies and therefore the number of these patients requiring cardiac surgery due to the development of age-related cardiovascular disease may increase. We present the case of a young male with hemophilia B who was diagnosed with severe symptomatic mitral regurgitation and underwent successful robotic mitral valve repair. To our knowledge, this is the first report of a patient with hemophilia B who underwent robotic mitral valve repair., (© 2020 Wiley Periodicals, Inc.)

Background Heart fats (epicardial and paracardial adipose tissue [PAT]) are greater after menopause. Endogenous estrogen may regulate these fat depots. We evaluated the differential effects of hormone therapy formulations on heart fat accumulations and their associations with coronary artery calcification (CAC) progression in recently menopausal women from KEEPS (Kronos Early Estrogen Prevention Study). Methods and Results KEEPS was a multicenter, randomized, placebo-controlled trial of the effects of 0.45 mg/d oral conjugated equine estrogens and 50 µg/d transdermal 17β-estradiol, compared with placebo, on 48-month progression of subclinical atherosclerosis among 727 early menopausal women. CAC progression was defined if baseline CAC score was 0 and 48-month CAC score was >0 or if baseline CAC score was >0 and <100 and annualized change in CAC score was ≥10. Of 727 KEEPS participants, 474 (mean age: 52.7 [SD: 2.6]; 78.1% white) had computed tomography-based heart fat and CAC measures at both baseline and 48 months. Compared with women on placebo, women on oral conjugated equine estrogens were less likely to have any increase in epicardial adipose tissue (odds ratio for oral conjugated equine estrogens versus placebo: 0.62 [95% CI, 0.40-0.97]; P =0.03). PAT did not change in any group. Changes in epicardial adipose tissue and PAT did not differ by treatment group. CAC increased in 14% of participants. The assigned treatment modified the association between PAT changes and CAC progression ( P =0.02) such that PAT increases were associated with CAC increases only in the transdermal 17β-estradiol group. Conclusions In recently menopausal women, oral conjugated equine estrogens may slow epicardial adipose tissue accumulation, whereas transdermal 17β-estradiol may increase progression of CAC associated with PAT accumulation. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT00154180.

Background: Atrial fibrillation/flutter (AF) produces significant morbidity in women and is typically attributed to cardiac remodeling from multiple causes, particularly hypertension. Hypertensive pregnancy disorders (HPDs) are associated with future hypertension and adverse cardiac remodeling. We evaluated whether women with AF were more likely to have experienced a HPD compared with those without., Methods and Results: A nested case-control study was conducted within a cohort of 7566 women who had a live or stillbirth delivery in Olmsted County, Minnesota between 1976 and 1982. AF cases were matched (1:1) to controls based on date of birth, age at first pregnancy, and parity. AF and pregnancy history were confirmed by chart review. We identified 105 AF cases: mean age 57±8 (mean±SD) years, (controls 56±8 years), 32±8 years (controls 31±8 years) after the first pregnancy. Cases were more likely to have obesity during childbearing years, and hypertension, diabetes mellitus, dyslipidemia, coronary disease, valvular disease, and heart failure at the time of AF diagnosis. Cases were more likely to have a history of HPDs, compared with controls: 28/105 (26.7%) cases versus 12/105 (11.4%) controls, odds ratio: 2.60 (95% confidence interval, 1.21-6.04). After adjustment for hypertension and obesity, the association was attenuated and no longer statistically significant; odds ratio (95% confidence interval, 2.12 (0.92-5.23)., Conclusions: Women with AF are more likely to have had a HPD, a relationship at least partially mediated by associated obesity and hypertension. Given the high morbidity of AF, studies evaluating the benefit of screening for and management of cardiovascular risk factors in women with a history of HPD should be performed., (© 2018 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)

Incidence and rate of cardiovascular disease differ between men and women across the life span. Although hypertension is more prominent in men than women, there is a group of vasomotor disorders [i.e. Raynaud's disease, postural orthostatic tachycardia syndrome and vasomotor symptoms (hot flashes) of menopause and migraine] with a female predominance. Both sex and hormones interact to modulate neuroeffector mechanisms including integrated regulation of the Sry gene and direct effect of sex steroid hormones on synthesis, release and disposition of monoamine neurotransmitters, and distribution and sensitivity of their receptors in brain areas associated with autonomic control. The interaction of the sex chromosomes and steroids also modulates these effector tissues, that is, the heart, vascular smooth muscle and endothelium. Although involvement of central serotonergic centres has been studied in regard to mood disorders such as depression, their contribution to cardiovascular risk is gaining attention. Studies are needed to further evaluate how hormonal treatments and drugs used to modulate adrenergic and serotonergic activity affect progression and risk for cardiovascular disease in men and women., (© 2010 Mayo Clinic. Acta Physiologica © 2010 Scandinavian Physiological Society.)

1. Adverse thrombotic cardiovascular events increase in women coincident with the onset of menopause. 2. Age past menopause may be an important variable in defining the benefit/risk of hormone treatments. 3. Few studies have examined hormonal status as a variable of ageing using a polygenomic approach of both humoral and cellular components of the coagulation system. 4. Longitudinal studies of a global set of platelet functions that define procoagulant activity (i.e. adhesion, aggregation, secretion and thrombin production) in individuals with documented hormonal status are needed to better understand how hormonal changes associated with ageing impact thrombotic risk.

1. Experiments were designed to determine whether or not interactions of platelets with coronary arteries are affected by gender or oestrogen-status. 2. Platelets and right coronary arteries were isolated from sexually mature male, female and ovariectomized pigs. Arteries were suspended in organ chambers for the measurement of isometric force. Responses of rings, with and without endothelium, were evaluated to aggregating platelets and the platelet products 5-hydroxytryptamine (5-HT) and adenosine diphosphate (ADP). 3. Release of 5-HT, thromboxane A2 (TXA2) and prostacyclin were measured from platelets. 4. Platelets caused relaxations of rings with endothelium from all pigs. However, in rings without endothelium, consistent contractions were observed only in rings from male pigs. 5. The release of 5-HT and prostacyclin was greatest from platelets of ovariectomized pigs compared with male and female pigs. Release of TXA2 was greatest from platelets of male pigs. 6. Endothelium-dependent relaxations to ADP and contractions to 5-HT were similar among the three groups. 7. These results suggest that there may be gender-specific differences in vasomotor responses to autogenous platelets but not to the platelet-derived products 5-HT and ADP. Furthermore, there are gender differences in platelets in the release of cyclo-oxygenase metabolites of arachidonic acid and 5-HT. These products could contribute to gender differences in response to injury in the coronary circulation.

1. Experiments were designed to determine how sex hormonal status may influence production and response to endothelins. 2. Circulating concentrations of endothelin-1 were not different between sexually mature male and female pigs and did not differ between females of low- and high-oestrogen status. 3. Expression of messenger RNA for preproendothelin was not different in aortic endothelial cells derived from sexually mature male and female pigs. 4. Endothelin-1, endothelin-3 and sarafotoxin S6c caused concentration-dependent contractions of rings of coronary arteries suspended for the measurement of isometric force. Only in response to endothelin-1 were contractions greater in arteries from female than in male pigs. This difference was not related to oestrogen levels in females. 5. The intrinsic force-calcium relationship defined in smooth muscle cells permeabilized with either triton-X or beta-escine was not different in coronary arteries from male and female pigs. The calcium sensitivity was increased to the same extent by endothelin-1 in smooth muscle from male and female pigs. 6. Competitive inhibition of radiolabelled endothelin-1 by unlabelled endothelin-1 was not different in membranes prepared from coronary arteries from male and female pigs. However, competitive inhibition of radiolabelled endothelin-1 by unlabelled endothelin-3 showed two binding sites. The affinity of the high affinity binding site was increased only in females with high oestrogen levels. 7. These results suggest that there are gender differences in contractions of porcine coronary arteries to endothelin-1. These differences may not relate to transcriptional regulation for the production of the peptide in endothelial cells, to the regulation of the number or affinity of endothelin receptors or to intrinsic calcium-sensitivity of the contractile proteins. Rather they are probably due to differences in the regulation of intracellular calcium.