Assessing Machine Learning for Diagnostic Classification of Hypertension Types Identified by Ambulatory Blood Pressure Monitoring.

Background: Inaccurate blood pressure (BP) classification results in inappropriate treatment. We tested whether machine learning (ML), using routine clinical data, can serve as a reliable alternative to ambulatory BP monitoring (ABPM) in classifying BP status. Methods: This study employed a multicentre approach involving 3 derivation cohorts from Glasgow, Gdansk, and Birmingham, and a fourth independent evaluation cohort. ML models were trained using office BP, ABPM, and clinical, laboratory, and demographic data, collected from patients referred for hypertension assessment. Seven ML algorithms were trained to classify patients into 5 groups, named as follows: Normal/Target; Hypertension-Masked; Normal/Target-White-Coat (WC); Hypertension-WC; and Hypertension. The 10-year cardiovascular outcomes and 27-year all-cause mortality risks were calculated for the ML-derived groups using the Cox proportional hazards model. Results: Overall, extreme gradient boosting (using XGBoost open source software) showed the highest area under the receiver operating characteristic curve of 0.85-0.88 across derivation cohorts, Glasgow (n = 923; 43% female; age 50.7 ± 16.3 years), Gdansk (n = 709; 46% female; age 54.4 ± 13 years), and Birmingham (n = 1222; 56% female; age 55.7 ± 14 years). But accuracy (0.57-0.72) and F1 (harmonic mean of precision and recall) scores (0.57-0.69) were low across the 3 patient cohorts. The evaluation cohort (n = 6213; 51% female; age 51.2 ± 10.8 years) indicated elevated 10-year risks of composite cardiovascular events in the Normal/Target-WC and the Hypertension-WC groups, with heightened 27-year all-cause mortality observed in all groups, except the Hypertension-Masked group, compared to the Normal/Target group. Conclusions: ML has limited potential in accurate BP classification when ABPM is unavailable. Larger studies including diverse patient groups and different resource settings are warranted.

Contexte: Les erreurs dans la classification des valeurs de la pression artérielle (PA) entraînent une inadéquation du traitement. Nous avons tâché de déterminer si l'apprentissage machine, à l'aide de données cliniques routinières, constituait une solution de rechange fiable à la surveillance ambulatoire de la PA pour définir le statut de la PA. Méthodologie: Cette étude a utilisé une approche multicentrique incluant trois cohortes de dérivation de Glasgow, Gdansk et Birmingham, et une quatrième cohorte d'évaluation indépendante. Les modèles d'apprentissage machine ont été développés en analysant les données démographiques, les valeurs de la PA mesurée au cabinet, les données relatives à la surveillance ambulatoire de la PA et aux épreuves de laboratoire recueillies auprès de patients adressés pour une évaluation de l'hypertension. Sept algorithmes d'apprentissage machine ont été appliqués pour classer les patients en cinq groupes : Normale/Cible; Hypertension-Masquée; Normal/Cible-Blouse blanche; Hypertension-Blouse blanche; Hypertension. Les événements cardiovasculaires sur 10 ans et le risque de mortalité toutes causes confondues sur 27 ans ont été calculés dans les groupes dérivés de l'apprentissage machine à l'aide d'un modèle de risques proportionnels de Cox. Résultats: D'une manière générale, l'amplification de gradient extrême (à l'aide du logiciel ouvert XGBoost) a mis en évidence l'aire sous la courbe de la fonction d'efficacité du récepteur (courbe ROC pour Receiver Operating Characteristic) la plus haute, soit 0,85 à 0,88, pour toutes les cohortes de dérivation : Glasgow (n = 923; 43 % de femmes; âge : 50,7 ± 16,3 ans); Gdansk (n = 709; 46 % de femmes; âge : 54,4 ± 13 ans); Birmingham (n = 1 222; 56 % de femmes; âge : 55,7 ± 14 ans). La précision (0,57 ­ 0,72) et le score F1 (moyenne harmonique de la précision et du rappel) (0,57 ­ 0,69) ont été faibles dans les trois cohortes de patients. La cohorte d'évaluation (n = 6 213; 51 % de femmes; âge : 51,2 ± 10,8 ans) a indiqué un risque d'événements cardiovasculaires composites sur 10 ans élevé dans les groupes Normale/Cible-Blouse blanche et Hypertension-Blouse blanche, tandis qu'une hausse de la mortalité toutes causes confondues sur 27 ans a été observée dans tous les groupes, sauf dans le groupe Hypertension-Masquée, comparativement au groupe Normale/Cible. Conclusions: Le potentiel d'exactitude de la classification de la PA à l'aide de l'apprentissage machine lorsque la surveillance ambulatoire de la PA n'est pas possible est limité. Des études de plus grande envergure portant sur des groupes de patients et des niveaux de ressources diversifiés s'imposent.

The importance of blood pressure measurements at the emergency department in detection of arterial hypertension.

BACKGROUND: Arterial hypertension (AH) is the most important modifiable risk factor for cardiovascular diseases in Poland and around the world. Unfortunately, despite its potentially catastrophic consequences, more than 30% of hypertensive patients in Poland remain undiagnosed. Therefore, emergency department (ED) triage may play a role in screening of a significant proportion of the population. The present study aimed to assess the prevalence of hypertension in patients reporting to the ED by verifying ad hoc measurements with ambulatory blood pressure monitoring (ABPM). METHODS: The study included 78,274 patients admitted to the ED of the University Clinical Center in Gdansk from 01.01.2019 to 31.12.2020, with elevated blood pressure values (systolic blood pressure [SBP] > 140 mmHg and/or diastolic blood pressure [DBP] > 90 mmHg) during triage according to the inclusion and exclusion criteria. RESULTS: Out of 34,597 patients with SBP > 140 mmHg and/or DBP > 90 mmHg, 27,896 patients (80.6% of patients) had previously been diagnosed with AH. Finally, a group of 6701 patients with elevated values of arterial blood pressure in triage, who had not yet been diagnosed with AH, was identified. This accounted for 8.6% of patients admitted to the ED. Ultimately, 58 patients (26 women and 36 men) agreed to undergo ABPM. Based on the analysis, AH 32 patients were diagnosed with AH (55.2%). CONCLUSIONS: The ED plays an essential role in diagnosing hypertension among people reporting to the ED for various reasons. There is a high probability of a diagnosis of AH in a group of patients who have elevated blood pressure values during triage and have not yet been diagnosed with hypertension.

Masked arterial hypertension in a 64-year-old man with primary aldosteronism.

PURPOSE: Primary aldosteronism is one of the most frequent causes of secondary arterial hypertension, and whether primary aldosteronism is associated with masked hypertension is unknown. MATERIALS AND METHODS: We describe a 64-year-old man with a history of hypothyroidism, recurring hypokalaemia, and normal home and office blood pressure values. Ambulatory blood pressure monitoring revealed masked hypertension with strikingly high systolic blood pressure variability and typical hypertension-mediated organ damage. RESULTS: The patient required gradual escalation of antihypertensive medication to four drugs. During the diagnostic process we identified primary aldosteronism, cobalamin deficiency, severe obstructive sleep apnoea, and low baroreflex sensitivity (1.63 ms/mmHg). Following unilateral adrenalectomy, cobalamin supplementation and continuous positive airway pressure, we observed a spectacular improvement in the patient's blood pressure control, baroreflex sensitivity (4.82 ms/mmHg) and quality of life. CONCLUSIONS: We report an unusual case of both masked arterial hypertension and primary aldosteronism. Elevated blood pressure values were masked in home and office measurements by coexisting hypotension which resulted most probably from deteriorated baroreflex sensitivity. Baroreflex sensitivity increased following treatment, including unilateral adrenalectomy. Hypertension can be masked by coexisting baroreceptor dysfunction which may derive from structural but also functional reversible changes.

Epilepsy and hypertension: The possible link for sudden unexpected death in epilepsy?

Epilepsy affects about 50 million people worldwide. Sudden unexpected death in epilepsy (SUDEP) is the main cause of death in epilepsy accounting for up to 17% of all deaths in epileptic patients, and therefore remains a major public health problem. SUDEP likely arises from a combination and interaction of multiple risk factors (such as being male, drug resistance, frequent generalized tonic-clonic seizures) making risk prediction and mitigation challenging. While there is a general understanding of the physiopathology of SUDEP, mechanistic hypotheses linking risk factors with a risk of SUDEP are still lacking. Identifying cross-talk between biological systems implicated in SUDEP may facilitate the development of improved models for SUDEP risk assessment, treatment and clinical management. In this review, the aim was to explore an overlap between the pathophysiology of hypertension, cardiovascular disease and epilepsy, and discuss its implication for SUDEP. Presented herein, evidence in literature in support of a cross-talk between the renin-angiotensin system (RAS) and sympathetic nervous system, both known to be involved in the development of hypertension and cardiovascular disease, and as one of the underlying mechanisms of SUDEP. This article also provides a brief description of local RAS in brain neuroinflammation and the role of centrally acting RAS inhibitors in epileptic seizure alleviation.

"Old School" Islet Purification Based on the Unit Gravity Sedimentation as a Rescue Technique for Intraportal Islet Transplantation-A Case Report.

Here, we present a case that required a supplemental "old school" islet purification for a safe intraportal infusion. Following pancreas procurement from a brain-dead 26-year-old male donor (body mass index: 21.9), 24.6 ml of islet tissue was isolated after continuous density gradient centrifugation. The islet yield was 504,000 islet equivalent (IEQ), distributed among the following three fractions: 64,161 IEQ in 0.6 ml of pellet, 182,058 IEQ in 10 ml, and 258,010 IEQ in 14 ml with 95%, 20%, and 10% purity, respectively. After a 23-h culture, we applied supplemental islet purification, based on the separation of tissue subfractions during unit gravity sedimentation, a technique developed over 60 years ago ("old school"). This method enabled the reduction of the total pellet volume to 11.6 ml, while retaining 374,940 IEQ with a viability of over 90%. The final islet product was prepared in three infusion bags, containing 130,926 IEQ in 2.6 ml of pellet, 108,079 IEQ in 4 ml of pellet, and 135,935 IEQ in 5 ml of pellet with 65%, 40%, and 30% purity, respectively, and with the addition of unfractionated heparin (70 units/kg body weight). Upon the islet infusion from all three bags, portal pressure increased from 7 to 16 mmHg. Antithrombotic prophylaxis with heparin was continued for 48 h after the infusion, with target activated partial thromboplastin time 50-60 s, followed by fractionated heparin subcutaneous injections for 2 weeks. ß-Cell graft function assessed on day 75 post-transplantation was good, according to Igls criteria, with complete elimination of severe hypoglycemic episodes and 50% reduction in insulin requirements. Time spent within the target glucose range (70-180 mg/dl) improved from 42% to 98% and HbA1c declined from 8.7% to 6.7%. Supplemental "old school" islet purification allowed for the safe and successful utilization of a robust and high-quality islet preparation, which otherwise would have been discarded.

Subclinical macroangiopathic target organ damage in type 1 diabetes mellitus patients.

PURPOSE: We have summarized key studies regarding the assessment of subclinical macroangiopathic target organ damage (TOD) in type 1 diabetes mellitus (T1DM). RESULTS: Although chronic complications resulting from hyperglycemia, in particular macroangiopathies, are still the first cause of death in T1DM, there has been growing recognition of the role of hypoglycemia in cardiovascular morbidity and mortality. Subclinical TOD diagnosis ensures early implementation of the complex management aiming at either partial reversal of these complications or at least its downturn. To better identify patients with early TODs, several non-invasive diagnostic techniques are employed, including the ultrasonographic assessment of the intima-media thickness (IMT), computed tomography (CT) for coronary artery calcium (CAC) scores, and pulse wave velocity (PWV) measurement for arterial stiffness evaluation. Various studies reported that T1DM patients present an increased IMT. An increasing IMT fairly correlates with the cardiovascular (CV) events risk even after the adjustment to age, diabetes duration, quality of glucose control as well as the presence of hypertension, and chronic complications. Another, well established marker of the organ damage - CAC score is recommended by ACC/AHA guidelines to assess the overall CV risk in T1DM. Also, the arterial stiffness evaluation with PWV may further improve CV risk prediction, which has been reported in multiple studies including the Framingham Heart Study. CONCLUSIONS: There is shortage of data from prospective studies which could confirm the benefits of early treatment initiation based on the presence of the subclinical organ damage in T1DM. Most evidence comes from T2DM trials, where effective preventive measures were identified i.e.: smoking cessation, reasonable blood glucose control, efficacious hypertension treatment, and dyslipidemia management, as well as renoprotection. There is still a field for further research to see if routine assessment of asymptomatic vascular damage and early implementation of aggressive treatment would reduce mortality excess from CVD in T1DM.

Metabolomic Signature of Early Vascular Aging (EVA) in Hypertension.

Arterial stiffening is a hallmark of early vascular aging (EVA) syndrome and an independent predictor of cardiovascular morbidity and mortality. In this case-control study we sought to identify plasma metabolites associated with EVA syndrome in the setting of hypertension. An untargeted metabolomic approach was used to identify plasma metabolites in an age-, BMI-, and sex-matched groups of EVA (n = 79) and non-EVA (n = 73) individuals with hypertension. After raw data processing and filtration, 497 putative compounds were characterized, out of which 4 were identified as lysophosphaditylcholines (LPCs) [LPC (18:2), LPC (16:0), LPC (18:0), and LPC (18:1)]. A main finding of this study shows that identified LPCs were independently associated with EVA status. Although LPCs have been shown previously to be positively associated with inflammation and atherosclerosis, we observed that hypertensive individuals characterized by 4 down-regulated LPCs had 3.8 times higher risk of EVA compared to those with higher LPC levels (OR = 3.8, 95% CI 1.7-8.5, P < 0.001). Our results provide new insights into a metabolomic phenotype of vascular aging and warrants further investigation of negative association of LPCs with EVA status. This study suggests that LPCs are potential candidates to be considered for further evaluation and validation as predictors of EVA in patients with hypertension.

Untargeted Metabolomics Provides Insight into the Mechanisms Underlying Resistant Hypertension.

BACKGROUND: Resistant hypertension (RH) affects about 15-20% of treated hypertensive patients worldwide. RH increases the risk of cardiovascular events such as myocardial infarction and stroke by 50%. The pathological mechanisms underlying resistance to treatment are still poorly understood. OBJECTIVE: The main goal of this pilot study was to determine and compare plasma metabolomic profiles in resistant and non-resistant hypertensive patients. METHODS: We applied untargeted metabolomic profiling in plasma samples collected from 69 subjects with RH and 81 subjects with controlled hypertension. To confirm patients' compliance to antihypertensive treatment, levels of selected drugs and their metabolites were determined in plasma samples with the LC-ESI-TOF/MS technique. RESULTS: The results showed no statistically significant differences in the administration of antihypertensive drug in the compared groups. We identified 19 up-regulated and 13 downregulated metabolites in the RH. CONCLUSION: The metabolites altered in RH are linked to oxidative stress and inflammation, endothelium dysfunction, vasoconstriction and cell proliferation. Our results may generate new hypothesis about RH development and progression.

Prevalence and distribution of left ventricular diastolic dysfunction in treated patients with long-lasting hypertension.

BACKGROUND: Although the presence of sub-clinical left ventricular diastolic dysfunction (LVDD) increases cardiovascular risk, the current ESH/ESC guidelines do not include the presence of this condition in the list of target organ damage or cardiovascular risk charts dedicated to the hypertensive population. Several conditions may predict the LVDD occurrence, however, clustering of these factors with hypertension makes the relationship less clear. Therefore, the aim of this study was to evaluate both the occurrence and the severity of diastolic dysfunction in a large cohort of treated hypertensives. METHODS: We retrospectively analyzed records of 610 hypertensive participants of the CARE NORTH Study who consented to echocardiography and were free of overt cardiovascular disease. Mean age was 54.0 ± 13.9 years (mean ± SD), BMI 29.7 ± 4.8 kg/m2. The exclusion criteria were: established heart failure, LVEF <45%, coronary revascularization, valvular defect, atrial fibrillation, or stroke. The staging of LVDD was based on comprehensive transthoracic echocardiographic measurements. RESULTS: 49.7% percent of the patients had normal diastolic function (38.8% vs. 59.0%, females (F) vs. males (M), respectively; p < .001). Grade 1 LVDD was documented in 24.4% (27.8% and 21.6%; F and M; p = .08) and grade 2 LVDD in 19.3% (24.9% and 14.6%; F and M; p = .001) of the patients. None were diagnosed with grade 3 LVDD. In the logistic regression model, female sex, advancing age, obesity status, established diabetes mellitus, higher 24-hour SBP, and increasing LVMI were identified as the independent variables increasing the odds for the presence of LVDD, whereas blood-lowering therapy attenuated the risk. CONCLUSIONS: There is an unexpectedly high prevalence of different forms of diastolic dysfunction in treated hypertensive patients who are free of overt cardiovascular disease.

A multilocus genetic risk score is associated with arterial stiffness in hypertensive patients: the CARE NORTH study.

INTRODUCTION: Arterial stiffness is recognized as an intermediate phenotype and predictor of cardiovascular disease. Arterial stiffness is complex in origin with contributions from lifestyle and genetic factors. However, the association between single nucleotide polymorphisms (SNPs) and arterial stiffness remains unclear. OBJECTIVE: The aim is to assess whether a multilocus genetic risk score (GRS), composed of selected SNPs linked to cardiovascular traits and outcomes, is associated with arterial stiffness in patients with hypertension. DESIGN AND METHODS: This study included 730 participants derived from the CARE NORTH study. The arterial stiffness was evaluated by carotid-femoral pulse wave velocity (cfPWV). An adjusted linear regression was used to evaluate the association between cfPWV and each individual SNP using multiple genetic models. The association between a constructed GRS and cfPWV was tested in an unadjusted and adjusted model. RESULTS: We selected 13 SNPs found to be associated with cfPWV (P < .05): 6 SNPs in additive, 4 SNPs in recessive and 3 SNPs in dominant mode of inheritance. The GRS based on these SNPs was positively associated with cfPWV both in unadjusted and adjusted models (ß = 0.2 m/s, 95% CI 0.11 - 0.29, P = 7.6 × 10 and ß = 0.22 m/s, 95% CI 0.15 - 0.28, P = 1.4 × 10, respectively). The GRS explained an additional 3.6% cfPWV variance above clinical covariates. CONCLUSION: We demonstrate that the GRS composed of 13 SNPs related to cardiovascular phenotypes is associated with an increased arterial stiffness in hypertensive patients. Our findings may help to clarify genetic basis of arterial stiffening and provide insight into mechanisms underlying this phenotype.

Insufficiency of the zona glomerulosa of the adrenal cortex and progressive kidney insufficiency following unilateral adrenalectomy - case report and discussion.

BACKGROUND: Primary aldosteronism (PA) is the most common cause of secondary hypertension and bilateral adrenal hyperplasia (BAH) and aldosterone-producing adenoma (APA) seem to be the most common causes of PA. Unilateral adrenalectomy (UA) is the preferred treatment for APA, although the benefits are still difficult to assess. CASE REPORT: We present a case report of a 69-year old man with a 30 year history of hypertension and probably long-standing PA due to APA, with typical organ complications. Since repeated abdominal CT scans were equivocal, not showing radiological changes characteristic for PA, the diagnosis of APA was delayed and was only finally confirmed by adrenal venous sampling which demonstrated unilateral aldosteronism. The patient underwent UA, complicated by mineralocorticoid deficiency syndrome and increased creatinine and potassium levels. At 12 months follow-up the patient still had hyperkalemia and was fludrocortisone dependent. CONCLUSIONS: Older patients and patients with long-lasting PA who are treated with UA may demonstrate deterioration of renal function and develop transient or persistent insufficiency of the zona glomerulosa of the remaining adrenal gland necessitating fludrocortisone supplementation. Transient hyperkalemia may be observed following UA as a result of the prolonged effects of aldosterone antagonists and/or transient mineralocorticoid/glucocorticoid insufficiency. Additionally, the level of progression of chronic kidney disease after UA is difficult to predict. There likely exists a group of patients who might paradoxically have higher cardiovascular risk due to significant deterioration in kidney function not only resulting from the removal of the aldosterone induced glomerular hyperfiltration phenomenon. Identification of such a group requires further detailed investigation.

Genetic risk factors influence nighttime blood pressure and related cardiovascular complications in patients with coronary heart disease.

Genetic predisposition of elevated nighttime blood pressure (BP) in patients with coronary heart disease is unknown. We evaluated genetic predisposition and the relationship between elevated nighttime BP and cardiovascular complications over a median of 8.6 years of observation of hypertensive subjects with coronary atherosclerosis confirmed by coronary angiography. Genetic Risk Score (GRS19) was constructed to evaluate the additive effect of single-nucleotide polymorphisms for daytime and nighttime BP. The Receiver Operating Characteristic was used for determination of cutoff points for daytime BP (systolic BP (SBP) 133 mm Hg and diastolic BP (DBP) 77 mm Hg) and nighttime BP (SBP 122 mm Hg and DBP 73 mm Hg). The curves of cumulative incidence revealed an increased risk of major advanced cardiovascular events in subjects with elevated nighttime BP compared with those without elevated nighttime BP during the follow-up period. Subjects with normal daytime and elevated nighttime BP exhibited increased GRS19 compared with those with normal daytime and nighttime BPs (8.6±3.0 vs. 7.9±3.0, P<0.01). After adjustment for cardiovascular risk factors, GRS19 determined nighttime SBP (ß 0.4, 95% confidence interval (CI) 0.3-0.5, P<0.01). Our study confirmed that elevated nighttime SBP was genetically determined and related to an increased risk of major adverse coronary events in patients with confirmed coronary atherosclerosis.

Serum of obstructive sleep apnea patients impairs human coronary endothelial cell migration.

INTRODUCTION: Endothelial cell migration and proliferation play an important role in the growth and development of new blood vessels and endothelium healing. This process occurs in response to injury, inflammation and immune reactions. Dysfunction of the endothelium may play a significant role in development and progression of cardiovascular disease related to sleep-disordered breathing. The aim of our study was to evaluate the chemo-attractant activity of serum from obstructive sleep apnea (OSA) and normal subjects on coronary artery endothelial cell migration. MATERIAL AND METHODS: We studied 12 severe OSA patients, free of other co-morbidities and on no treatment, along with 12 age-, body mass index, and gender matched healthy controls. Blood was collected at three time points: at 21:00 before sleep, at 6:00 after waking from sleep, and at 11:00 (after 5 h of normal daytime activity). Serum chemo-attractant activity for human coronary endothelial cells was assessed using a colorimetric cell migration assay kit. RESULTS: In healthy subjects, serum chemo-attractant activity peaked in the morning after waking from sleep (p = 0.02). This early morning increase was blunted in severe OSA subjects, in whom chemo-attractant activity was weaker than in normal controls (p = 0.02), and did not change significantly at the different time-points (p < 0.001 vs. controls). CONCLUSIONS: Chemo-attractant activity of the serum from OSA patients is lower compared to serum from healthy subjects, especially in the morning. Altered chemo-attractant serum activity may conceivably contribute to the impairment of endothelial function in obstructive sleep apnea patients.

Elevated ambulatory systolic-diastolic pressure regression index is genetically determined in hypertensive patients with coronary heart disease.

OBJECTIVES: Ambulatory systolic-diastolic pressure regression index (ASDPRI) as a composite marker of cardiovascular (CV) properties is related to CV complications. However, genetic determinants of ASDPRI are not known. The aim of this study is to report the relationship between certain single nucleotide polymorphisms (SNP) and ASDPRI in hypertensive patients with CAD confirmed by coronary angiography. METHODS: A total of 1345 hypertensive subjects with CAD were included. SNPs were selected from genome-wide association studies. SNPs were reported to be associated with coronary artery disease risk. There were significant differences in 24 h and daytime and nighttime ASDPRIs for PHCTR1, LPA and ADAMTS7 polymorphisms. Genetic risk score (GRS18) was constructed to evaluate additive effect of 18 SNPs for ASDPRI. RESULTS: Analysis of covariance revealed a significant relationship between the PPAB2B (ß - 0.85; 95 CI -1.85--0.16, p < 0.02), WDR12 (ß - 1.31; 95 CI -2.19--0.43, p < 0.01) polymorphisms and nighttime ASDPRI dipping. Analysis of covariance revealed a significant relationship between GRS 18 and 24-h ASDPRI (ß 0.34; 95 CI 0.16-0.31, p < 0.01). CONCLUSIONS: In conclusion, ADAMTS7 and LPA polymorphisms are related to 24-h ASDPRI but PPAB2B and WDR12 gene polymorphisms are associated with nighttime ASDPRI dipping. A total of 24-h ASDPRI is determined by GRS18.

Relationship between selected DNA polymorphisms and coronary artery disease complications.

BACKGROUND: Coronary heart disease (CHD) development is complex in origin, with contributions from well-defined lifestyle and not well-determined genetic risk factors. The aim of this study is to report the relationship between certain SNPs and the risk of cardiovascular (CV) complications in patients with CAD confirmed by coronary angiography. METHODS: In the present study, 1345 subjects with CHD were included. The median follow-up period was 8.6years. 19 SNPs were investigated for any association with Major Advanced CV Events (MACE), Acute Coronary Syndromes (ACS) and Revascularizations. We modeled the 19 SNPs as a multilocus genetic risk score (GRS19). RESULTS: During follow-up period, 245 participants died; 114 due to CV causes. A fatal or non-fatal CV event occurred in 882 participants including 214 ACS, 578 revascularizations and 90 strokes. The alleles of the following SNPs: rs1746048 (CXCL12), rs9818870 (MRAS) and rs17114036 (PPAP2B) were associated with a higher risk of MACE and the alleles of SNPs rs1746048 (CXCL12) and rs1122608 (LDLR) were associated with a higher risk of revascularization. The alleles of rs12190287 (MRAS), rs121902287 (TCF21) and rs2259816 (HNF1a) were associated with a higher risk of ACS. Despite the lack of relationship between significant CAD and GRS19, in the top quartile of GRS19 there was significant relationship between GRS19 and combined endpoint, MACE, ACS, and revascularization. CONCLUSIONS: Conclusions. The SNPs of CXCL12 and LDLR were associated with risk of revascularization and CXCL12, LPA, MRAS, and PPAP2B were associated with the risk of MACE. GRS19 determines CV complications in CAD patients with the highest genetic risk score values.

A single-centre experience of the implementation of adrenal vein sampling procedure: the impact on the diagnostic work-up in primary aldosteronism.

BACKGROUND: Primary aldosteronism is one of the most common causes of secondary hypertension. Adrenal vein sampling (AVS) remains a "gold standard" procedure in differentiation between unilateral (adenoma) and bilateral (hyperplasia) disease. AIM: The aim of this study was to present our single-centre experience in establishing and implementating the AVS procedure. METHODS: All patients had primary aldosteronism confirmed in a salt-infusion test. AVS was performed sequentially during a continuous intravenous infusion of cosyntropin and was preceded by multislice contrast-enhanced computed tomography (CT) examination of adrenal glands performed a few weeks before AVS in the majority of patients. AVS was regarded as successful if the ratio of each adrenal vein cortisol to inferior vena cava cortisol levels (selectivity index [SI]) was higher than 3.0. In the case of failure, a second attempt was considered in a few weeks. Patients were divided into four groups according to the order of the procedure by quartiles. RESULTS: Between 31 May, 2012 and 5 May, 2016, AVS was performed in 124 patients (69% males, aged 55.3 ± 10.3 years) and was successful in 120 (96.8%) patients. All failed cases were due to the failure of cannulation of the right adrenal vein. The first-attempt success rate was 94.3% (117 of 124 patients) and increased from 83.9% in the first 31 patients to 100% in the last 31 patients. Similarly, the overall success rate increased from 93.5% to 100%. The right SI was significantly higher than the left one (26.4 vs. 11.0, p < 0.0001). Both indices did not differ across quartiles of patients. No complications occurred during the procedure. CONCLUSIONS: The AVS procedure, preceded by adrenal CT, may be implemented into daily diagnostic practice safely with an excellent success rate.

The Relationship Between Gene Polymorphisms and Dipping Profile in Patients With Coronary Heart Disease.

BACKGROUND: The aim of this study is to report the relationship between certain single-nucleotide polymorphisms (SNPs) and blunted nighttime blood pressure (BP) fall in patients with coronary artery disease confirmed by coronary angiography. METHODS: According to the percentage decrease in mean systolic BP (SBP) and diastolic BP (DBP) during the nighttime period, subjects were classified as dippers or nondippers (nighttime relative SBP or DBP decline ≥10% and <10%, respectively). Genetic risk score (GRS18) was constructed to evaluate additive effect of 18 SNPs for nondipping status. RESULTS: In the present study, 1,345 subjects with coronary heart disease (CHD) were included. During follow-up period (median 8.3 years, interquartile range 5.3-9.0 years), there were 245 all-cause deaths (18.2%) including 114 cardiovascular deaths (8.5%). There were significant differences in the number of revascularizations between nondippers SBP and DBP and dippers SBP and DBP (48.0% vs. 36.4%, P < 0.01). SNPs of the genes, MIA3, MRAS, PCSK9, SMG6, and ZC3HC1, were related to a higher risk of nondipping SBP and DBP status. CONCLUSIONS: In the present study, polymorphisms of genes related to CHD (MIA3, MRAS, PCSK9, SMG6, and ZC3HC1) were associated with nondipping SBP and DBP profile, and GRS18 was associated with nondipping status. In addition, this profile was related to a higher risk of revascularization.

Obstructive sleep apnea and intermittent hypoxia increase expression of dual specificity phosphatase 1.

OBJECTIVE: Dual specificity phosphatase 1 (DUSP1) inhibits mitogen activated protein kinase activity, and is activated by several stimuli such as sustained hypoxia, oxidative stress, and hormones. However, the effect of intermittent hypoxia is not known. The aim of this study was to evaluate the role of intermittent hypoxia on DUSP1 expression, and to validate its role in a human model of intermittent hypoxia, as seen in obstructive sleep apnea (OSA). OSA is characterized by recurrent episodes of hypoxemia/reoxygenation and is a known risk factor for cardiovascular morbidity. METHODS: In-vitro studies using human coronary artery endothelial cells (HCAEC) and ex-vivo studies using white blood cells isolated from healthy and OSA subjects. RESULTS: Intermittent hypoxia induced DUSP1 expression in human coronary artery endothelial cells (HCAEC), and in granulocytes isolated from healthy human subjects. Functionally, DUSP1 increased the expression and activity of manganese superoxide dismutase (MnSOD) in HCAEC. Further, significant increases in DUSP1 mRNA from total blood, and in DUSP1 protein in mononuclear cells and granulocytes isolated from OSA subjects, were observed in the early morning hours after one night of intermittent hypoxemia due to untreated OSA. This early-morning OSA-induced augmentation of DUSP1 gene expression was attenuated by continuous positive airway pressure (CPAP) treatment of OSA. CONCLUSION: Intermittent hypoxia increases MnSOD activity via increased DUSP1 expression in HCAEC. Similarly, overnight intermittent hypoxemia in patients with OSA induces expression of DUSP1, which may mediate increases of MnSOD expression and activity. This may contribute significantly to neutralizing the effects of reactive oxygen species, a consequence of the intermittent hypoxemia/reperfusion elicited by OSA.

Plasma lipid composition and risk of developing cardiovascular disease.

AIMS: We tested whether characteristic changes of the plasma lipidome in individuals with comparable total lipids level associate with future cardiovascular disease (CVD) outcome and whether 23 validated gene variants associated with coronary artery disease (CAD) affect CVD associated lipid species. METHODS AND RESULTS: Screening of the fasted plasma lipidome was performed by top-down shotgun analysis and lipidome compositions compared between incident CVD cases (n = 211) and controls (n = 216) from the prospective population-based MDC study using logistic regression adjusting for Framingham risk factors. Associations with incident CVD were seen for eight lipid species (0.21≤q≤0.23). Each standard deviation unit higher baseline levels of two lysophosphatidylcholine species (LPC), LPC16∶0 and LPC20∶4, was associated with a decreased risk for CVD (P = 0.024-0.028). Sphingomyelin (SM) 38∶2 was associated with increased odds of CVD (P = 0.057). Five triglyceride (TAG) species were associated with protection (P = 0.031-0.049). LPC16∶0 was negatively correlated with the carotid intima-media thickness (P = 0.010) and with HbA1c (P = 0.012) whereas SM38∶2 was positively correlated with LDL-cholesterol (P = 0.0*10(-6)) and the q-values were good (q≤0.03). The risk allele of 8 CAD-associated gene variants showed significant association with the plasma level of several lipid species. However, the q-values were high for many of the associations (0.015≤q≤0.75). Risk allele carriers of 3 CAD-loci had reduced level of LPC16∶0 and/or LPC 20∶4 (P≤0.056). CONCLUSION: Our study suggests that CVD development is preceded by reduced levels of LPC16∶0, LPC20∶4 and some specific TAG species and by increased levels of SM38∶2. It also indicates that certain lipid species are intermediate phenotypes between genetic susceptibility and overt CVD. But it is a preliminary study that awaits replication in a larger population because statistical significance was lost for the associations between lipid species and future cardiovascular events when correcting for multiple testing.