Sex Differences in the Prevalence, Outcomes and Management of Hypertension.

PURPOSE OF REVIEW: To review recent data on sex differences in the prevalence, outcomes and management of hypertension. RECENT FINDINGS: Although hypertension is overall more common in males, females experience a much sharper incline in blood pressure from the third decade of life and consequently the prevalence of hypertension accelerates comparatively with age. Mechanisms responsible for these blood pressure trajectories may include the sustained vascular influence of hypertensive disorders of pregnancy, interactions between the renin-angiotensin-aldosterone system and sex hormones or even psychosocial gendered factors such as socioeconomic deprivation. Moreover, the impact of hypertension is not uniform and females are at higher risk of developing a multitude of adverse cardiovascular outcomes at lower blood pressure thresholds. Blood pressure is a sexually dimorphic trait and although significant differences exist in the prevalence, pathophysiology and outcomes of hypertension in males and females, limited data exist to support sex-specific blood pressure targets.

Trans fatty acid elimination policy in member states of the Eurasian Economic Union: Implementation challenges and capacity for enforcement.

Removing trans fatty acids (TFAs) from the food supply in the Eurasian Economic Union (EAEU) are one of the most effective public health interventions for reducing the risk of noncommunicable diseases. EAEU Member States have taken important steps to reduce TFA in oil and fat products to <2% of the total fat content. The authors summarize existing policies in the region, identify challenges in implementation, and suggest measures to strengthen regulation to achieve compliance with WHO guidelines. Documents published between 2011 and 2019 in Russian and English were reviewed, including EAEU and Member State restrictions on TFA in food products, data on TFA content in foods, and food labeling policies. The EAEU has established TFA limits in oil and fat products; however, Member States are currently not achieving the WHO guideline of <2% of total fat content in food products. A lack of harmonized monitoring systems and sanctions create challenges in monitoring compliance. The authors recommend developing an EAEU-wide monitoring system to test TFA content and organize population intake surveys. Discrepancies exist within regulatory frameworks that allow higher levels of TFAs in dairy products and infant formula. The authors recommend extending the current regulation to mandate TFA limits for all food products. Research found that strengthening regulation to meet the WHO guidelines should be prioritized. Member States should implement actions to replace TFAs with healthier fats, develop standardized surveillance methods, and scale-up strategic communication to ensure the food industry and the public follow public health recommendations to protect the health of the EAEU population.

Nonvalidated Home Blood Pressure Devices Dominate the Online Marketplace in Australia: Major Implications for Cardiovascular Risk Management.

Self-home blood pressure (BP) monitoring is recommended to guide clinical decisions on hypertension and is used worldwide for cardiovascular risk management. People usually make their own decisions when purchasing BP devices, which can be made online. If patients purchase nonvalidated devices (those not proven accurate according to internationally accepted standards), hypertension management may be based on inaccurate readings resulting in under- or over-diagnosis or treatment. This study aimed to evaluate the number, type, percentage validated, and cost of home BP devices available online. A search of online businesses selling devices for home BP monitoring was conducted. Multinational companies make worldwide deliveries, so searches were restricted to BP devices available for one nation (Australia) as an example of device availability through the global online marketplace. Validation status of BP devices was determined according to established protocols. Fifty nine online businesses, selling 972 unique BP devices were identified. These included 278 upper-arm cuff devices (18.3% validated), 162 wrist-cuff devices (8.0% validated), and 532 wrist-band wearables (0% validated). Most BP devices (92.4%) were stocked by international e-commerce businesses (eg, eBay, Amazon), but only 5.5% were validated. Validated cuff BP devices were more expensive than nonvalidated devices: median (interquartile range) of 101.1 (75.0-151.5) versus 67.4 (30.4-112.8) Australian Dollars. Nonvalidated BP devices dominate the online marketplace and are sold at lower cost than validated ones, which is a major barrier to accurate home BP monitoring and cardiovascular risk management. Before purchasing a BP device, people should check it has been validated at https://www.stridebp.org.

Precision Medicine and Personalized Medicine in Cardiovascular Disease.

Precision medicine aims to offer "the right treatment to the right patient at the right time." In cardiovascular medicine the potential of precision medicine applies to all stages of the disease development and includes risk prediction, preventative measures, and targeted therapeutic approaches. Precision medicine will benefit from new developments in the area of genomics and other omics but equally heavily depends on established biomarkers, functional tests, and imaging. Cardiovascular medicine often relies on noninvasive diagnostic procedures and symptom-based disease management. In contrast, other clinical disciplines including oncology and immunology have already moved to molecular diagnostics that lend themselves to precision medicine approaches. There are opportunities to implement precision medicine approaches by focusing on common diseases such as hypertension, conditions with diagnostic and prognostic uncertainty such as angina, and conditions that are associated with high mortality and involve costly and potentially harmful interventions such as dilated cardiomyopathy and cardiac resynchronization therapy. Sex and gender issues have not yet been fully explored in precision medicine although the opportunity to use molecular data to more accurately manage men and women with cardiovascular disease has been acknowledged. A mindshift is required in order to fully exploit the potential of precision medicine to tackle the global burden of cardiovascular diseases.

Future translational applications from the contemporary genomics era: a scientific statement from the American Heart Association.

The field of genetics and genomics has advanced considerably with the achievement of recent milestones encompassing the identification of many loci for cardiovascular disease and variable drug responses. Despite this achievement, a gap exists in the understanding and advancement to meaningful translation that directly affects disease prevention and clinical care. The purpose of this scientific statement is to address the gap between genetic discoveries and their practical application to cardiovascular clinical care. In brief, this scientific statement assesses the current timeline for effective translation of basic discoveries to clinical advances, highlighting past successes. Current discoveries in the area of genetics and genomics are covered next, followed by future expectations, tools, and competencies for achieving the goal of improving clinical care.

Diagnosis and Prediction of CKD Progression by Assessment of Urinary Peptides.

Progressive CKD is generally detected at a late stage by a sustained decline in eGFR and/or the presence of significant albuminuria. With the aim of early and improved risk stratification of patients with CKD, we studied urinary peptides in a large cross-sectional multicenter cohort of 1990 individuals, including 522 with follow-up data, using proteome analysis. We validated that a previously established multipeptide urinary biomarker classifier performed significantly better in detecting and predicting progression of CKD than the current clinical standard, urinary albumin. The classifier was also more sensitive for identifying patients with rapidly progressing CKD. Compared with the combination of baseline eGFR and albuminuria (area under the curve [AUC]=0.758), the addition of the multipeptide biomarker classifier significantly improved CKD risk prediction (AUC=0.831) as assessed by the net reclassification index (0.303±-0.065; P<0.001) and integrated discrimination improvement (0.058±0.014; P<0.001). Correlation of individual urinary peptides with CKD stage and progression showed that the peptides that associated with CKD, irrespective of CKD stage or CKD progression, were either fragments of the major circulating proteins, suggesting failure of the glomerular filtration barrier sieving properties, or different collagen fragments, suggesting accumulation of intrarenal extracellular matrix. Furthermore, protein fragments associated with progression of CKD originated mostly from proteins related to inflammation and tissue repair. Results of this study suggest that urinary proteome analysis might significantly improve the current state of the art of CKD detection and outcome prediction and that identification of the urinary peptides allows insight into various ongoing pathophysiologic processes in CKD.

Assessment of metabolomic and proteomic biomarkers in detection and prognosis of progression of renal function in chronic kidney disease.

Chronic kidney disease (CKD) is part of a number of systemic and renal diseases and may reach epidemic proportions over the next decade. Efforts have been made to improve diagnosis and management of CKD. We hypothesised that combining metabolomic and proteomic approaches could generate a more systemic and complete view of the disease mechanisms. To test this approach, we examined samples from a cohort of 49 patients representing different stages of CKD. Urine samples were analysed for proteomic changes using capillary electrophoresis-mass spectrometry and urine and plasma samples for metabolomic changes using different mass spectrometry-based techniques. The training set included 20 CKD patients selected according to their estimated glomerular filtration rate (eGFR) at mild (59.9±16.5 mL/min/1.73 m2; n = 10) or advanced (8.9±4.5 mL/min/1.73 m2; n = 10) CKD and the remaining 29 patients left for the test set. We identified a panel of 76 statistically significant metabolites and peptides that correlated with CKD in the training set. We combined these biomarkers in different classifiers and then performed correlation analyses with eGFR at baseline and follow-up after 2.8±0.8 years in the test set. A solely plasma metabolite biomarker-based classifier significantly correlated with the loss of kidney function in the test set at baseline and follow-up (ρ = -0.8031; p<0.0001 and ρ = -0.6009; p = 0.0019, respectively). Similarly, a urinary metabolite biomarker-based classifier did reveal significant association to kidney function (ρ = -0.6557; p = 0.0001 and ρ = -0.6574; p = 0.0005). A classifier utilising 46 identified urinary peptide biomarkers performed statistically equivalent to the urinary and plasma metabolite classifier (ρ = -0.7752; p<0.0001 and ρ = -0.8400; p<0.0001). The combination of both urinary proteomic and urinary and plasma metabolic biomarkers did not improve the correlation with eGFR. In conclusion, we found excellent association of plasma and urinary metabolites and urinary peptides with kidney function, and disease progression, but no added value in combining the different biomarkers data.

Assessment of a novel, capsid-modified adenovirus with an improved vascular gene transfer profile.

BACKGROUND: Cardiovascular disorders, including coronary artery bypass graft failure and in-stent restenosis remain significant opportunities for the advancement of novel therapeutics that target neointimal hyperplasia, a characteristic of both pathologies. Gene therapy may provide a successful approach to improve the clinical outcome of these conditions, but would benefit from the development of more efficient vectors for vascular gene delivery. The aim of this study was to assess whether a novel genetically engineered Adenovirus could be utilised to produce enhanced levels of vascular gene expression. METHODS: Vascular transduction capacity was assessed in primary human saphenous vein smooth muscle and endothelial cells using vectors expressing the LacZ reporter gene. The therapeutic capacity of the vectors was compared by measuring smooth muscle cell metabolic activity and migration following infection with vectors that over-express the candidate therapeutic gene tissue inhibitor of matrix metalloproteinase-3 (TIMP-3). RESULTS: Compared to Adenovirus serotype 5 (Ad5), the novel vector Ad5T*F35++ demonstrated improved binding and transduction of human vascular cells. Ad5T*F35++ mediated expression of TIMP-3 reduced smooth muscle cell metabolic activity and migration in vitro. We also demonstrated that in human serum samples pre-existing neutralising antibodies to Ad5T*F35++ were less prevalent than Ad5 neutralising antibodies. CONCLUSIONS: We have developed a novel vector with improved vascular transduction and improved resistance to human serum neutralisation. This may provide a novel vector platform for human vascular gene transfer.

Peripheral arterial tone: assessment of microcirculatory function in pregnancy.

OBJECTIVE: Endothelial dysfunction is known to play a key role in the pathogenesis of preeclampsia, but the majority of methods for its detection are too invasive to be used in pregnancy. In this study we report a novel method - peripheral arterial tonometry (PAT) - for examining microcirculatory function in pregnancy. METHODS: One hundred and eighty women with at least two risk factors for preeclampsia were examined at gestational weeks 16 and 28; 80 women were examined at 6-9 months postnatally. Twenty-four women developed preeclampsia or pregnancy-induced hypertension (cases), 156 remained normotensive (controls). PAT was measured using fingertip pneumatic probes; after baseline recordings the study arm was occluded with a blood pressure cuff then released after 5 min, causing reactive hyperaemia. PAT recordings pre and post occlusion were used to generate the reactive hyperaemia index (RHI). RESULTS: RHI was significantly lower at gestational week 28 compared to week 16, both in cases and controls. Baseline pulse amplitude was significantly higher at week 28 compared to week 16. There was no difference in RHI at either week 16 or 28 between cases and controls. Postnatally, there was no difference in RHI between cases and controls, but baseline pulse amplitude was lower in affected women. CONCLUSION: PAT and other methods which rely on flow-mediated dilatation for detection of endothelial dysfunction are less likely to be reliable in later pregnancy, when women are more vasodilated. PAT did not predict the development of hypertensive pregnancy complications, but demonstrated a relative peripheral vasoconstriction in affected women postnatally.

Urinary proteomics in the assessment of chronic kidney disease.

PURPOSE OF REVIEW: Urinary proteomics has emerged as an approach that could deliver relevant clinical information. In this review, we aim at highlighting the recent developments, especially with respect to clinical implementation. We review several of the recent publications reporting on larger cohorts, focusing on those that aim at qualification and/or validation of urinary proteomics biomarkers. RECENT FINDINGS: Several components of the urinary proteome, especially its low molecular weight fraction (sometimes referred to as the 'peptidome'), have been significantly associated with chronic kidney disease (CKD). Independent studies, encompassing sometimes close to 1000 independent samples, indicate that specific peptides from extracellular matrix (ECM) proteins encompass a major component of the urinary proteome. Highly significant changes in the abundance of some of these peptides are associated with CKD indicating that alterations in ECM, reflected via the urinary proteome, may represent an early stage in CKD pathology. These peptides may serve as specific early biomarkers, and interference with pathological ECM accumulation may be a valuable new therapeutic approach in CKD. SUMMARY: Urinary proteomic biomarkers have emerged as clinically relevant variables. First studies involving several hundred individuals indicate a potential added benefit of urinary proteomic biomarkers. First large clinical trials are being initiated to employ urinary proteomics in clinical decision making.

Cardiac magnetic resonance findings predict increased resource utilization in elective coronary artery bypass grafting.

Morbidity following CABG (coronary artery bypass grafting) is difficult to predict and leads to increased healthcare costs. We hypothesized that pre-operative CMR (cardiac magnetic resonance) findings would predict resource utilization in elective CABG. Over a 12-month period, patients requiring elective CABG were invited to undergo CMR 1 day prior to CABG. Gadolinium-enhanced CMR was performed using a trueFISP inversion recovery sequence on a 1.5 tesla scanner (Sonata; Siemens). Clinical data were collected prospectively. Admission costs were quantified based on standardized actual cost/day. Admission cost greater than the median was defined as 'increased'. Of 458 elective CABG cases, 45 (10%) underwent pre-operative CMR. Pre-operative characteristics [mean (S.D.) age, 64 (9) years, mortality (1%) and median (interquartile range) admission duration, 7 (6-8) days] were similar in patients who did or did not undergo CMR. In the patients undergoing CMR, eight (18%) and 11 (24%) patients had reduced LV (left ventricular) systolic function by CMR [LVEF (LV ejection fraction) <55%] and echocardiography respectively. LE (late enhancement) with gadolinium was detected in 17 (38%) patients. The average cost/day was $2723. The median (interquartile range) admission cost was $19059 ($10891-157917). CMR LVEF {OR (odds ratio), 0.93 [95% CI (confidence interval), 0.87-0.99]; P=0.03} and SV (stroke volume) index [OR 1.07 (95% CI, 1.00-1.14); P=0.02] predicted increased admission cost. CMR LVEF (P=0.08) and EuroScore tended to predict actual admission cost (P=0.09), but SV by CMR (P=0.16) and LV function by echocardiography (P=0.95) did not. In conclusion, in this exploratory investigation, pre-operative CMR findings predicted admission duration and increased admission cost in elective CABG surgery. The cost-effectiveness of CMR in risk stratification in elective CABG surgery merits prospective assessment.

Assessment of endothelial function of the renal vasculature in human subjects.

BACKGROUND: L-Arginine, the substrate of nitric oxide (NO) synthase, and N(G)-monomethyl-L-arginine (L-NMMA), a competitive inhibitor of endothelial NO synthase, are used to analyze endothelial function of the renal vasculature. However, little is known about the appropriate dose of L-arginine to be used and the duration of action of L-arginine and L-NMMA. METHODS: Twenty-nine healthy male subjects (age, 27+/-1 years) were examined. In protocol 1 (N = 17), L-arginine at low (100 mg/kg) and high dose (250 mg/kg), and high-dose L-arginine combined either with L-NMMA (total dose, 4.25 mg/kg; N = 9) or placebo (N = 8) were given. In protocol 2 (N = 12), L-NMMA was given before L-arginine infusion (100 mg/kg). Glomerular filtration rate (GFR) and renal plasma flow (RPF) were measured at rest and at the end of each infusion step. RESULTS: In protocol 1, L-arginine dose dependently increased RPF and GFR (RPF: 599+/-19 v 630+/-18 v 690+/-24 mL/min, P <.05; GFR: 111+/-3 v 115+/-3 v 121+/-3 mL/min, P <.01; for baseline, L-arginine 100 mg/kg and 250 mg/kg, respectively). However, these changes could not be antagonized by coinfusion of L-NMMA to L-arginine 250 mg/kg: RPF and GFR remained unchanged in both the placebo and the L-NMMA group. In protocol 2, L-NMMA decreased RPF (492+/-18 v 567+/-27 mL/min, P <.01) and increased GFR (122+/-4 v 118+/-3 mL/min, P <.05). These changes could only be partially reversed by subsequent infusion of L-arginine (RPF: 533+/-15 mL/min; GFR: 121+/-4 mL/min; both parameters P = NS v L-NMMA and v baseline). CONCLUSIONS: L-arginine at a dose of 100 mg/kg is sufficient to analyze endothelial function of the renal vasculature. The prolonged effect of L-NMMA and L-arginine must be taken into account in study protocols using both substances. Thus, stimulation and blockade of NO synthase cannot be examined in the same protocol.