Biomarkers associated with cardiovascular disease in women with spontaneous preterm birth: A case-control study.

INTRODUCTION: Women with spontaneous preterm birth have an increased risk of cardiovascular disease later in life. Studies suggest potential pathophysiological mechanisms in common, but whether these could be identified by measurement of soluble circulating protein biomarkers in women with spontaneous preterm birth is unknown. The aim of this study was to determine if protein biomarkers associated with cardiovascular disease distinguish women with spontaneous preterm birth from healthy controls, both at pregnancy and at follow up. MATERIAL AND METHODS: Study participants were identified in the population-based Uppsala biobank of pregnant women in Sweden, where plasma samples were collected in mid-pregnancy. In a first screening phase, we identified participants who subsequently experienced spontaneous preterm birth (<37 weeks) in the index pregnancy (N = 13) and controls (N = 6). In these samples, differences in protein expression were examined by comparative mass spectrometry. In a second validation phase, we invited 100 cases with previous spontaneous preterm birth in the index pregnancy and 100 controls (matched for age, body mass index, and year of delivery) from the same source population, to a follow-up visit 4-15 years after pregnancy. At follow up, we collected plasma samples and data on cardiovascular risk factors. We measured concentrations of selected biomarkers identified in the screening phase, as well as lipid profiles in samples both from pregnancy (biobank) and follow up. CLINICALTRIALS: gov registration NCT05693285. RESULTS: In the screening phase, fibrinogen, cadherin-5, complement C5, factor XII, plasma kallikrein, apolipoprotein M, and vitamin D-binding protein differed significantly at pregnancy. In the validation phase, 65 women agreed to participate (35 cases and 30 controls), with a median follow-up time of 11.8 years since pregnancy. The concentration of fibrinogen (p = 0.02) and triglycerides (p = 0.03) were slightly higher in cases compared with matched controls at follow up. CONCLUSIONS: Compared with women without preterm birth, those with spontaneous preterm birth had slightly higher concentrations of fibrinogen, both at mid-pregnancy and a decade after pregnancy. Additionally, we found slightly higher concentration of triglycerides at follow up in women with previous spontaneous preterm birth. The relevance of this finding is uncertain but might indicate potential pathophysiological mechanisms in common between spontaneous preterm birth and cardiovascular disease.

Symptoms during pregnancy in primiparous women with congenital heart disease.

Background: As more women with congenital heart disease (CHD) are reaching childbearing age, it becomes more common for their symptoms to be evaluated during pregnancy. However, pregnancy-related symptoms are similar to those caused by heart disease. This study investigated the prevalence of factors associated with symptoms during pregnancy in women with CHD. Methods: The national birth register was searched for primiparous women with CHD who were registered in the national quality register for patients with CHD. Results: Symptoms during the third trimester were reported in 104 of 465 evaluated women. The most common symptom was palpitations followed by dyspnea. Factors associated with symptoms were tested in a univariable model; higher NYHA classification (>1) (OR 11.3, 95%CI 5.5-23.2), low physical activity (≤3 h/week) (OR 2.1 95%CI 1.3-3.6) and educational level ≤ 12 years (OR 1.9 95%CI 1.2-3.0) were associated with having symptoms. In multivariable analysis, low physical activity level (OR 2.4 95%CI 1.2-5.0) and higher NYHA class (OR 11.3 95%CI 5.0-25.6) remained associated with symptoms during pregnancy. There were no cases with new onset of impaired systemic ventricular function during pregnancy. Conclusion: Symptoms during pregnancy are common in women with CHD but are often already present before pregnancy. Because ordinary symptoms during pregnancy often overlap with symptoms of heart disease, it is important to know if symptoms were present before pregnancy and if they became worse during pregnancy. These results should be included in pre-pregnancy counselling and considered in the monitoring during pregnancy.

Self-rated health in primiparous women with congenital heart disease before, during and after pregnancy - A register study.

Background. Poor maternal self-rated health in healthy women is associated with adverse neonatal outcomes, but knowledge about self-rated health in pregnant women with congenital heart disease (CHD) is sparse. This study, therefore, investigated self-rated health before, during, and after pregnancy in women with CHD and factors associated with poor self-rated health. Methods. The Swedish national registers for CHD and pregnancy were merged and searched for primiparous women with data on self-rated health; 600 primiparous women with CHD and 3062 women in matched controls. Analysis was performed using descriptive statistics, chi-square test and logistic regression. Results. Women with CHD equally often rated their health as poor as the controls before (15.5% vs. 15.8%, p = .88), during (29.8% vs. 26.8% p = .13), and after pregnancy (18.8% vs. 17.6% p = .46). None of the factors related to heart disease were associated with poor self-rated health. Instead, factors associated with poor self-rated health during pregnancy in women with CHD were ≤12 years of education (OR 1.7, 95%CI 1.2-2.4) and self-reported history of psychiatric illness (OR 12.6, 95%CI 1.4-3.4). After pregnancy, solely self-reported history of psychiatric illness (OR 5.2, 95%CI 1.1-3.0) was associated with poor self-rated health. Conclusion. Women with CHD reported poor self-rated health comparable to controls before, during, and after pregnancy, and factors related to heart disease were not associated with poor self-rated health. Knowledge about self-rated health may guide professionals in reproductive counselling for women with CHD. Further research is required on how pregnancy affects self-rated health for the group in a long-term perspective.

Management of patients on antithrombotic therapy with severe infections: a joint clinical consensus statement of the ESC Working Group on Thrombosis, the ESC Working Group on Atherosclerosis and Vascular Biology, and the International Society on Thrombosis and Haemostasis.

Patients with severe infections and a pre-existing indication for antithrombotic therapy, i.e. antiplatelet agents, anticoagulant drugs, or their combinations, require integrated clinical counselling among coagulation, infectious disease, and cardiology specialists, due to sepsis-induced coagulopathy that frequently occurs. Bacterial and viral pathogens constitute an increasing threat to global public health, especially for patients with ongoing antithrombotic treatment who have a high risk of thrombotic recurrences and high susceptibility to severe infections with increased morbidity and mortality. Similarly, sepsis survivors are at increased risk for major vascular events. Coagulopathy, which often complicates severe infections, is associated with a high mortality and obligates clinicians to adjust antithrombotic drug type and dosing to avoid bleeding while preventing thrombotic complications. This clinical consensus statement reviews the best available evidence to provide expert opinion and statements on the management of patients hospitalized for severe bacterial or viral infections with a pre-existing indication for antithrombotic therapy (single or combined), in whom sepsis-induced coagulopathy is often observed. Balancing the risk of thrombosis and bleeding in these patients and preventing infections with vaccines, if available, are crucial to prevent events or improve outcomes and prognosis.

Plasma Neurofilament Light Chain Is Elevated after Transcatheter Aortic Valve Implantation.

INTRODUCTION: Transcatheter aortic valve implantation (TAVI) is associated with a high incidence of new silent brain infarcts (SBIs) on postprocedural neuroimaging. A venous blood sample reflecting neuronal damage following TAVI could help identify patients with potential SBIs. We aimed to investigate if a biochemical marker of neuronal injury, neurofilament light chain (NFL), is elevated after TAVI. METHODS: In this observational study, NFL was measured in plasma from 31 patients before and after TAVI. Multivariable regression analysis was performed to investigate any effect of clinical- and procedure-related factors on differences in NFL levels before and after TAVI. RESULTS: Samples were collected 41 (14-81) days before and 44 (35-59) days after TAVI, median (interquartile range). Median age was 81 (77-84) years, and 35% were female. No patient had any overt procedure-related neurological complications. The geometric mean (95% confidence interval) of the NFL concentration was 30 (25-36) pg/mL before TAVI and 48 (39-61) pg/mL, after TAVI, p <0.001. None of the included variables in the multiple linear regression model were statistically significantly associated with the difference in levels before and after TAVI. CONCLUSIONS: NFL levels in plasma were higher after TAVI as compared with levels before, with a mean increase of 60% (18 pg/mL). Further studies including neuroimaging and cognitive outcomes are needed to understand the potential value of measuring NFL in relation to TAVI.

Association Between History of Adverse Pregnancy Outcomes and Coronary Artery Disease Assessed by Coronary Computed Tomography Angiography.

Importance: Adverse pregnancy outcomes are recognized risk enhancers for cardiovascular disease, but the prevalence of subclinical coronary atherosclerosis after these conditions is unknown. Objective: To assess associations between history of adverse pregnancy outcomes and coronary artery disease assessed by coronary computed tomography angiography screening. Design, Setting, and Participants: Cross-sectional study of a population-based cohort of women in Sweden (n = 10 528) with 1 or more deliveries in 1973 or later, ascertained via the Swedish National Medical Birth Register, who subsequently participated in the Swedish Cardiopulmonary Bioimage Study at age 50 to 65 (median, 57.3) years in 2013-2018. Delivery data were prospectively collected. Exposures: Adverse pregnancy outcomes, including preeclampsia, gestational hypertension, preterm delivery, small-for-gestational-age infant, and gestational diabetes. The reference category included women with no history of these exposures. Main Outcomes and Measures: Coronary computed tomography angiography indexes, including any coronary atherosclerosis, significant stenosis, noncalcified plaque, segment involvement score of 4 or greater, and coronary artery calcium score greater than 100. Results: A median 29.6 (IQR, 25.0-34.9) years after first registered delivery, 18.9% of women had a history of adverse pregnancy outcomes, with specific pregnancy histories ranging from 1.4% (gestational diabetes) to 9.5% (preterm delivery). The prevalence of any coronary atherosclerosis in women with a history of any adverse pregnancy outcome was 32.1% (95% CI, 30.0%-34.2%), which was significantly higher (prevalence difference, 3.8% [95% CI, 1.6%-6.1%]; prevalence ratio, 1.14 [95% CI, 1.06-1.22]) compared with reference women. History of gestational hypertension and preeclampsia were both significantly associated with higher and similar prevalence of all outcome indexes. For preeclampsia, the highest prevalence difference was observed for any coronary atherosclerosis (prevalence difference, 8.0% [95% CI, 3.7%-12.3%]; prevalence ratio, 1.28 [95% CI, 1.14-1.45]), and the highest prevalence ratio was observed for significant stenosis (prevalence difference, 3.1% [95% CI, 1.1%-5.1%]; prevalence ratio, 2.46 [95% CI, 1.65-3.67]). In adjusted models, odds ratios for preeclampsia ranged from 1.31 (95% CI, 1.07-1.61) for any coronary atherosclerosis to 2.21 (95% CI, 1.42-3.44) for significant stenosis. Similar associations were observed for history of preeclampsia or gestational hypertension among women with low predicted cardiovascular risk. Conclusions and Relevance: Among Swedish women undergoing coronary computed tomography angiography screening, there was a statistically significant association between history of adverse pregnancy outcomes and image-identified coronary artery disease, including among women estimated to be at low cardiovascular disease risk. Further research is needed to understand the clinical importance of these associations.

Platelet-leukocyte aggregate formation and inflammation in patients with pulmonary arterial hypertension and CTEPH.

Pulmonary hypertension (PH) is defined by increased mean pulmonary artery pressure, and the clinical classification includes five etiologies, of which we investigated subgroup 1, pulmonary arterial hypertension (PAH) and subgroup 4, chronic thrombotic and/or embolic disease (CTEPH). Platelets participate in both innate and adaptive immune responses and could possibly contribute to the suggested systemic inflammation associated with PAH. In this study, we utilized flow cytometry to analyze platelet activation and platelet-monocyte (PMA) and granulocyte (PGA) aggregates in PAH and CTEPH patients and healthy control subjects. The plasma concentration of proinflammatory cytokines was measured by multiplex electrochemiluminescence. Our main finding is that circulating platelets are activated in the circulation and form aggregates with both monocytes and granulocytes in patients with idiopathic PAH (IPAH), associated PAH (APAH) and pulmonary hypertension due to CTEPH. There was a strong correlation between the platelet activation, assessed as P-selectin, and the number of aggregates formed. IL-6, IL-8, IL-10 and TNF-α were increased in all PH subgroups as compared to healthy controls, and PMAs were associated with circulating IL-6, IL-8 and IL-10, whereas PGAs were associated with IL-6. The increased concentrations of platelet-leukocyte aggregates found in PAH/CTEPH patients might thus contribute to the inflammatory state in PH.

MircoRNA in Extracellular Vesicles from Patients with Pulmonary Arterial Hypertension Alters Endothelial Angiogenic Response.

Pulmonary arterial hypertension (PAH) is characterized by a progressive elevation of pulmonary pressure leading to right ventricular dysfunction and is associated with a poor prognosis. Patients with PAH have increased numbers of circulating extracellular vesicles (EVs) and altered expression of circulating microRNAs (miRs). The study aimed to evaluate the miR profile contained within purified EVs derived from the plasma of PAH patients as compared to healthy controls (HC). Circulating EVs, purified from platelet-free plasma were analyzed using flow cytometry, western blot, and electron microscopy. Total RNA isolated from EVs was subjected to Microarray analysis using GeneChip miRNA 4.0 Array and bioinformatics tools. Overexpression and inhibition of miRs were conducted in human pulmonary artery endothelial cells (hPAECs) that had been incubated previously with either PAH- or HC-derived EVs. Cell proliferation (MTT assay) and angiogenesis (tube formation assay) were tested in hPAECs to determine miR functionality. MiR profiling revealed 370 heats while comparing PAH and HC groups, 22 of which were found to be down-regulated and 6 were up-regulated in the PAH EVs. Among the altered miRs, miR-486-5p was overexpressed, while miR-26a-5p was downregulated in PAH EVs compared to HC EVs. Inhibition of mir-486-5p or overexpression of miR-26a-5p in hPAECs post-exposure of PAH EVs abrogated proangiogenic and proliferative effects posed by PAH EVs contrary to HC EVs. The angiogenic and proliferative effects of the miRs from PAH EVs were observed to be mediated through nuclear factor (NF)-κB activation. PAH EVs carry and present an altered miR profile that can be targeted to restrict angiogenesis and reduce pulmonary endothelium activation. Further studies concerning miRs from circulating heterogeneous EVs in PAH patients are warranted to understand their potential as targets for treatment in PAH.

Role of Extracellular Vesicles in Pulmonary Arterial Hypertension: Modulation of Pulmonary Endothelial Function and Angiogenesis.

OBJECTIVE: Extracellular vesicles (EVs) have the potential to act as intercellular communicators. The aims were to characterize circulating EVs in patients with pulmonary arterial hypertension (PAH) and to explore whether these EVs contribute to endothelial activation and angiogenesis. Approach and Results: Patients with PAH (n=70) and healthy controls (HC; n=20) were included in this cross-sectional study. EVs were characterized and human pulmonary endothelial cells (hPAECs) were incubated with purified EVs. Endothelial cell activity and proangiogenic markers were analyzed. Tube formation analysis was performed for hPAECs, and the involvement of PSGL-1 (P-selectin glycoprotein ligand 1) was evaluated. The numbers of CD62P+, CD144+, and CD235a EVs were higher in blood from PAH compared with HC. Thirteen proteins were differently expressed in PAH and HC EVs, where complement fragment C1q was the most significantly elevated protein (P=0.0009) in PAH EVs. Upon EVs-internalization in hPAECs, more PAH compared with HC EVs evaded lysosomes (P<0.01). As oppose to HC, PAH EVs stimulated hPAEC activation and induced transcription and translation of VEGF-A (vascular endothelial growth factor A; P<0.05) and FGF (fibroblast growth factor; P<0.005) which were released in the cell supernatant. These proangiogenic proteins were higher in patient with PAH plasma compered with HC. PAH EVs induced a complex network of angiotubes in vitro, which was abolished by inhibitory PSGL-1antibody. Anti-PSGL-1 also inhibited EV-induced endothelial cell activation and PAH EV dependent increase of VEGF-A. CONCLUSIONS: Patients with PAH have higher levels of EVs harboring increased amounts of angiogenic proteins, which induce activation of hPAECs and in vitro angiogenesis. These effects were partly because of platelet-derived EVs evasion of lysosomes upon internalization within hPAEC and through possible involvement of P-selectin-PSGL-1 pathway.

Implantable cardiac devices in adult patients with repaired tetralogy of Fallot.

OBJECTIVES: Implantable cardiac devices are common in patients with tetralogy of Fallot (ToF) (18.3-21.3%) according to previous reports from large centres. We conducted this study to investigate the prevalence and incidence of cardiac devices in a less selected population of patients with ToF and assess factors other than arrhythmia associated with having a device. Design: 530 adult (≥18 years) patients with repaired ToF were identified in the national registry of congenital heart disease (SWEDCON) and matched with data from the Swedish pacemaker registry. Patients with implantable cardiac devices were compared with patients without devices. Results: Seventy-five patients (14.2%) had a device; 51 (9.6%) had a pacemaker and 24 (4.5%) had an implantable cardioverter defibrillator. The incidence in adult age (≥18 years) was 5.9/1000 patient years. Estimated device free survival was 97.5% at twenty, 87.2% at forty and 63.5% at sixty years of age. Compared with previous studies, the prevalence of devices was lower, especially for ICD. In multivariate logistic regression, cardiovascular medication (odds ratio [OR] 3.5, 95% confidence interval [CI] 1.8-6.8), impaired left ventricular function, (OR 2.6, 95%CI 1.3-5.0) and age (OR 1.02, 95%CI 1.002-1.05) were associated with having a device. Conclusion: The prevalence of devices in our population, representing a multicenter register cohort, was lower than previously reported, especially regarding ICD. This can be due to differences in treatment traditions with regard to ICD in this population, but it may also be that previous studies have reported selected patients with more severe disease.

Screening of biomarkers for prediction of multisite artery disease in patients with recent myocardial infarction.

A few studies have examined biomarkers in patients with myocardial infarction (MI) and peripheral artery disease (PAD), i.e. multisite artery disease (MSAD). The aim of the study was firstly, to associate biomarkers with the occurrence of PAD/MSAD and secondly, if those can, in addition to clinical characteristics, identify MI patients with MSAD.In two prospectively observational studies including unselected patients with recent MI, PAD was defined as an abnormal ankle-brachial index (ABI) score (<0.9 or >1.4). The proximity extension assay (PEA) technique was used, simultaneously analyzing 92 biomarkers with association to cardiovascular disease. Biomarkers were tested for univariate associations with PAD. Random forest was used to identify biomarkers with a higher association to PAD. The additional discriminatory accuracy of adding biomarkers to clinical characteristics was analyzed by the c-statistics. Nine biomarkers were identified as significantly associated with MSAD/PAD in the primary patient cohort, analyzed early after the MI. In the prediction analysis, six biomarkers were identified associated with PAD. Three of these; Tumor necrosis factor receptor (TNFR-1), Tumor necrosis factor receptor 2 (TNFR-2) and Growth Differentiation Factor 15 (GDF-15) improved c-statistics when added to clinical characteristics from 0.683 (95% CI 0.610-0.756) to 0.715 (95% CI 0.645-0.784) in the primary patient cohort with a similar result, 0.729 (95% CI 0.687-0.770) to 0.752 (95% CI 0.771-0.792) in the secondary patient cohort. Biomarkers associated with inflammatory pathways are associated with MSAD in MI patients. Three biomarkers of 92; TNFR-1, TNFR-2 and GDF-15, in this exploratory added information in the prediction of MSAD and emphasis the importance of further studies.

High prevalence of ascending aortic dilation in adults with repaired coarctation of the aorta.

BACKGROUND: Ascending aortic dilation is a feared complication in adults with repaired coarctation of the aorta, as the condition is associated with life-threatening complications such as aortic dissection and rupture. However, the data are currently limited regarding factors associated with ascending aortic dilation in these patients. METHODS AND RESULTS: From the national register of congenital heart disease, 165 adult patients (≥ 18 years old) with repaired coarctation of the aorta, and echocardiographic data on aortic dimensions, were identified (61.2% male, mean age 35.8 ± 14.5 years). Aortic dilation (aortic diameters > 2 SD above reference mean) was found in 55 (33.3%) of the 165 included patients, and was associated with manifest aortic valve disease in univariable logistic regression analysis (OR 2.44, 95% CI [1.23, 4.83]). CONCLUSIONS: Aortic dilation is common post-repair of coarctation of the aorta, and is associated with manifest aortic valve disease and thus indirectly with the presence of a bicuspid aortic valve. However, no association was found between aortic dilation and age or blood pressure.

Despite reductions in muscle mass and muscle strength in adults with CHD, the muscle strength per muscle mass relationship does not differ from controls.

BACKGROUND: Patients with CHD exhibit reduced isometric muscle strength and muscle mass; however, little is known how these parameters relate. Therefore, the aim was to investigate the relation between isometric limb muscle strength and muscle mass for patients in comparison to age- and sex-matched control subjects. METHODS: Seventy-four patients (35.6 ± 14.3 years, women n = 22) and 74 matched controls were included. Isometric muscle strength in elbow flexion, knee extension, and hand grip was assessed using dynamometers. Lean mass, reflecting skeletal muscle mass, in the arms and legs was assessed with dual-energy x-ray absorptiometry. RESULTS: Compared to controls, patients had lower muscle strength in elbow flexion, knee extension, and hand grip, and lower muscle mass in the arms (6.6 ± 1.8 kg versus 5.8 ± 1.7 kg, p < 0.001) and legs (18.4 ± 3.5 kg versus 15.9 ± 3.2 kg, p < 0.001). There was no difference in achieved muscle force per unit muscle mass in patients compared to controls (elbow flexion 0.03 ± 0.004 versus 0.03 ± 0.005 N/g, p = 0.5; grip strength 0.008 ± 0.001 versus 0.008 ± 0.001 N/g, p = 0.7; knee extension 0.027 ± 0.06 versus 0.028 ± 0.06 N/g, p = 0.5). For both groups, muscle mass in the arms correlated strongly with muscle strength in elbow flexion (patients r = 0.86, controls, r = 0.89), hand grip (patients, r = 0.84, controls, r = 0.81), and muscle mass in the leg to knee extension (patients r = 0.64, controls r = 0.68). CONCLUSION: The relationship between isometric muscle strength and limb muscle mass in adults with CHD indicates that the skeletal muscles have the same efficiency as in healthy controls.

Effect of medical treatment in patients with systemic right ventricle.

Objective: Congenitally corrected and surgical atrial redirected transposition of the great arteries (TGA) represents states where the morphological right ventricle serves as a systemic ventricle (S-RV). The S-RV is prone to failure, but data on medical treatment on this problem is limited. The purpose of this study was to evaluate the survival in adults with S-RV, with or without heart failure treatment. Design: The SWEDCON registry was used to collect data. All adults with S-RV and minimum follow-up of 1 year were included retrospectively. Medical treatment was defined as taking beta-blockers and/or ACE inhibitors and/or ARBs for more than 50% of the time. Results: We identified 343 patients with S-RV (median age: 21 years). Surgical atrial redirected TGA was present in 58% and congenitally corrected TGA in 42% of patients. The medically treated group (n = 126) had higher rates of impaired S-RV function, use of diuretics, pacemaker and higher NYHA functional class at baseline compared to controls. The proportion of patients with impaired functional class did not change over time in the medically treated group, but increased in controls (21% vs. 30%, p = .015). In Kaplan-Meier analysis, the mean follow-up was 10.3 years, no difference in survival was seen between the groups. Conclusions: Medical treatment may be beneficial in patients with S-RV and impaired functional class and appears to be safe in the long term. The treatment group had equal survival to controls, despite worse baseline characteristics, which might be a result of slower progression of disease in this group.

Haemorrhagic stroke and major bleeding after intervention with biological aortic valve prosthesis: risk factors and antithrombotic treatment.

The majority of patients with severe aortic stenosis are recommended intervention with a surgical biological prosthesis (bioSAVR) or a transcatheter aortic valve intervention (TAVI). The antithrombotic strategies after aortic valve intervention vary and include drugs targeting both platelets and the coagulation cascade. Long-term exposure and changes of antithrombotic treatment influence the risk of both bleeding and thromboembolic events.The aim was to describe an unselected sample of patients who have experienced haemorrhagic stroke and other major bleeding events after biological aortic prosthesis, their antithrombotic treatment and changes of treatments in relation to the bleeding event.All patients performing an bioSAVR or a TAVI 2008-2014 were identified in the SWEDEHEART registry and included in the study (n = 10 711). The outcome events were haemorrhagic stroke and other major bleeding event. Information of drug exposure was collected from the dispensed drug registry.The incidence rate of any bleeding event was 2.85/100 patient-years the first year after aortic valve intervention. Heart failure and atrial fibrillation were present more often in patients with a first haemorrhagic stroke or other major bleeding event compared to without. The proportion of exposure to warfarin was 28.7% vs. 21.3% in patients with and without a haemorrhagic stroke. Comparable figures were 31.2% vs. 19.0% in patients with and without other major bleeding event. During 1 month prior a haemorrhagic stroke or other major bleeding event 39.4% and 38.0%, respectively, of the patients not previously exposed to antithrombotic treatment started warfarin or single antiplatelet therapy.Major bleeding events are not uncommon after aortic valve intervention with a biological prosthesis. Evaluation of comorbidities and previous bleeding might improve risk stratification for bleeding in these elderly patients. The pattern of change of antithrombotic treatment was similar in the groups with and without a bleeding event and in most patients the antithrombotic regime was unchanged the month before an event.

A la mayoría de los pacientes con estenosis de la válvula aórtica grave se les recomienda someterse a una valvuloplastia con prótesis biológica (bioSAVR) o a una valvuloplastia aórtica transcateteral (TAVI). Las estrategias antitrombóticas tras una valvuloplastia aórtica son distintas y, entre ellas, se incluyen fármacos dirigidos tanto a las plaquetas como a la cascada de la coagulación. La exposición prolongada y los cambios en el tratamiento antitrombótico influyen en el riesgo de sufrir complicaciones hemorrágicas y tromboembólicas.El objetivo es describir una muestra de pacientes sin seleccionar que han padecido ictus hemorrágicos u otros episodios hemorrágicos importantes tras una valvuloplastia aórtica con prótesis biológica, así como el tratamiento antitrombótico y los cambios de tratamientos en relación con la hemorragia.Todos los pacientes sometidos a bioSAVR o TAVI en 2008-2014 se encontraban en el registro SWEDEHEART y se incluyeron en el estudio (n = 10 711). Los criterios de valoración fueron ictus hemorrágico y otras hemorragias importantes. La información de la exposición al fármaco se recogió del registro de dispensación de fármacos.En el primer año tras la valvuloplastia aórtica, la tasa de incidencia de cualquier episodio hemorrágico fue de 2,85 por 100 pacientes. La insuficiencia cardíaca y la fibrilación auricular fueron más frecuentes en pacientes con presencia de un primer ictus hemorrágico u otras hemorragias importantes en comparación con el grupo de control. La proporción de exposición a warfarina fue del 28,7% frente al 21,3% en pacientes con presencia y ausencia de un ictus hemorrágico, respectivamente. Cifras comparables fueron el 31,2% frente al 19,0% en pacientes con presencia y ausencia de otros episodios hemorrágicos importantes, respectivamente. Un mes antes de que se produjera el ictus hemorrágico u otras hemorragias importantes, el 39,4% y el 38,0%, respectivamente, de los pacientes que no estaban previamente expuestos a un tratamiento antitrombótico comenzaron un tratamiento con warfarina o antiagregante plaquetario simple.La presencia de episodios hemorrágicos importantes es frecuente tras una valvuloplastia aórtica con prótesis biológica. La evaluación de comorbilidades y hemorragias anteriores puede mejorar la estratificación de riesgos de sufrir hemorragias en pacientes de avanzada edad. El tipo de cambio del tratamiento antitrombótico fue similar en el grupo de control y en el grupo con presencia de un episodio hemorrágico y, en la mayoría de los pacientes, no se modificó la pauta de administración del antitrombótico en el mes previo al episodio hemorrágico.

Do self-reported pregnancy complications add to risk evaluation in older women with established cardiovascular disease?

BACKGROUND: In postmenopausal women with established cardiovascular disease (CVD), it is unknown whether a history of pregnancy complications are related to multisite artery disease (MSAD), defined as atherosclerotic lesions in at least two major vascular beds. Pregnancy complications are an established risk factor for CVD. This study aimed to investigate the frequency of pregnancy complications and their association to specific atherosclerotic manifestations and prediction of MSAD in older women with and without CVD. METHODS: In total, 556 women were invited to participate in the study. Of these women 307 reported former pregnancy from a cohort of women with (n = 233) and without CVD (n = 74). The self-reported frequency of pregnancy complications were surveyed retrospectively by a questionnaire that included miscarriage, subfertility, gestational hypertension (GHT) and/or preeclampsia (PE), low birth weight, preterm birth, bleeding in late pregnancy, gestational diabetes mellitus and high birth weight. Three vascular beds were examined, the peripheral, carotid and coronary arteries. RESULTS: The mean age was 67.5 (SD 9.5) years. GHT and/or PE tended to be more common, but not significant, in women with CVD than in women without (20.3% vs 10.8%, p = 0.066). Among women with GHT and/or PE, hypertension later in life were more frequent than in women without (66.7% vs 47.4%, p = 0.010). GHT and/or PE were not associated with specific atherosclerotic manifestations or prediction of MSAD. CONCLUSIONS: In older women with established CVD, pregnancy complications was not associated to specific atherosclerotic manifestations and may not provide additional value to the risk evaluation for MSAD.

Poor blood pressure control in adults with repaired coarctation of the aorta and hypertension: a register-based study of associated factors.

BACKGROUND: Arterial hypertension is common in adults with repaired coarctation of the aorta, and is associated with several severe complications. Aims This study aimed to investigate the prevalence of poorly controlled (⩾140/90 mmHg) blood pressure among patients with diagnosed hypertension and to identify associated factors. METHODS: In the national register for CHD, adults with repaired coarctation of the aorta and diagnosed hypertension - defined as a registry diagnosis and/or use of anti-hypertensive prescription medication - were identified. Logistic regression analysis was used to identify variables associated with poorly controlled blood pressure. RESULTS: Of the 243 included patients, 27.2% were female, the mean age was 45.4±15.3 years, and 52.3% had poorly controlled blood pressure at the last registration. In a multivariable model, age (years) (OR 1.03, CI 1.01-1.06, p=0.008) was independently associated with poorly controlled blood pressure and so was systolic arm-leg blood pressure gradient in the ranges [10, 20] mmHg (OR 4.92, CI 1.76-13.79, p=0.002) to >20 mmHg (OR 9.93, CI 2.99-33.02, p<0.001), in comparison with the reference interval [0, 10] mmHg. Patients with poorly controlled blood pressure had, on average, more types of anti-hypertensive medication classes prescribed (1.9 versus 1.5, p=0.003). CONCLUSIONS: Poorly controlled blood pressure is common among patients with repaired coarctation of the aorta and diagnosed hypertension, despite what seems to be more intensive treatment. A systolic arm-leg blood pressure gradient is associated with poorly controlled blood pressure, even at low levels usually not considered for intervention, and may be an indicator of hypertension that is difficult to treat.

A randomized trial of genotype-guided dosing of warfarin.

BACKGROUND: The level of anticoagulation in response to a fixed-dose regimen of warfarin is difficult to predict during the initiation of therapy. We prospectively compared the effect of genotype-guided dosing with that of standard dosing on anticoagulation control in patients starting warfarin therapy. METHODS: We conducted a multicenter, randomized, controlled trial involving patients with atrial fibrillation or venous thromboembolism. Genotyping for CYP2C9*2, CYP2C9*3, and VKORC1 (-1639G→A) was performed with the use of a point-of-care test. For patients assigned to the genotype-guided group, warfarin doses were prescribed according to pharmacogenetic-based algorithms for the first 5 days. Patients in the control (standard dosing) group received a 3-day loading-dose regimen. After the initiation period, the treatment of all patients was managed according to routine clinical practice. The primary outcome measure was the percentage of time in the therapeutic range of 2.0 to 3.0 for the international normalized ratio (INR) during the first 12 weeks after warfarin initiation. RESULTS: A total of 455 patients were recruited, with 227 randomly assigned to the genotype-guided group and 228 assigned to the control group. The mean percentage of time in the therapeutic range was 67.4% in the genotype-guided group as compared with 60.3% in the control group (adjusted difference, 7.0 percentage points; 95% confidence interval, 3.3 to 10.6; P<0.001). There were significantly fewer incidences of excessive anticoagulation (INR ≥4.0) in the genotype-guided group. The median time to reach a therapeutic INR was 21 days in the genotype-guided group as compared with 29 days in the control group (P<0.001). CONCLUSIONS: Pharmacogenetic-based dosing was associated with a higher percentage of time in the therapeutic INR range than was standard dosing during the initiation of warfarin therapy. (Funded by the European Commission Seventh Framework Programme and others; ClinicalTrials.gov number, NCT01119300.).

Hypertension in adults with repaired coarctation of the aorta.

AIMS: In adults with coarctation of the aorta (CoA), hypertension (HTN) is a common long-term complication. We investigated the prevalence of HTN and analyzed factors associated with HTN. METHODS AND RESULTS: In the national register for congenital heart disease, 653 adults with repaired CoA were identified (mean age 36.9±14.4years); 344 (52.7%) of them had HTN, defined as either an existing diagnosis or blood pressure (BP) ≥140/90mmHg at the clinical visit. In a multivariable model, age (years) (odds ratio [OR] 1.07, CI 1.05-1.10), sex (male) (OR 3.35, CI 1.98-5.68), and body mass index (kilograms per square meter) (OR 1.09, CI 1.03-1.16) were independently associated with having HTN, and so was systolic arm-leg BP gradient where an association with HTN was found at the ranges of (10, 20] and >20mmHg, in comparison to the interval ≤10mmHg (OR 3.58, CI 1.70-7.55, and OR 11.38, CI 4.03-32.11). This model remained valid when all patients who had increased BP (≥140/90mmHg) without having been diagnosed with HTN were excluded from the analyses. CONCLUSIONS: Hypertension is common in patients with previously repaired CoA and is associated with increasing age, male sex, and elevated body mass index. There is also an association with arm-leg BP gradient, starting at relatively low levels that are usually not considered for intervention.

The composition and daily variation of microparticles in whole blood in stable coronary artery disease.

INTRODUCTION: The knowledge of circadian variation of microparticles (MPs) in stable coronary artery disease (SCAD) is limited. The aim of this study was to evaluate the daily variation of platelet-, endothelial- and monocyte-derived MPs in whole blood and their tissue factor expression (TF) in SCAD and whether these MPs were related to other endothelial and coagulation markers. MATERIALS AND METHODS: Serial blood samples from patients with SCAD were collected during one day. Flow cytometry was used to evaluate the amount of large MPs 0.5-1.0 µm, positive for annexin, and their expression of CD41, CD62P, CD144, CD14 and TF. The lag time and endogenous thrombin potential (ETP) was calculated by Calibrated Automated Thrombogram and soluble (s)P-selectin, sTF and vWF by ELISA. RESULTS: The majority of MPs in whole blood consisted of CD41 + MPs with no significant daily variation. In contrast, the concentration of CD62P + MPs described a daily variation with the lowest concentrations found in the evening (p = 0.031). CD62P + and CD144 + MPs had the highest expression of TF, 52.6% and 42.9%, respectively, and correlated to the endothelial activity evaluated by vWF. There was a circadian rhythm of lag time (p < 0.001) and ETP (p = 0.001). The CD62P+, CD14 + and CD144 + MPs correlated to the lag time. CONCLUSION: The different subsets of platelet-, endothelial- and monocyte-derived MPs do not present the same circadian variation and they differ in TF expression in SCAD. The MPs from activated platelets, endothelial cells and monocytes exist in low concentrations in whole blood but are related to the endothelial and coagulation activity found in SCAD.