N. Koletsos

Impaired Muscle Oxygenation and Elevated Exercise Blood Pressure in Hypertensive PatientsNovelty and Significance: Links With Vascular Stiffness

This study examined in vivo (1) skeletal muscle oxygenation and microvascular function, at rest and during handgrip exercise, and (2) their association with macrovascular function and exercise blood pressure (BP), in newly diagnosed, never-treated patients with hypertension and normotensive individuals. Ninety-one individuals (51 hypertensives and 40 normotensives) underwent office and 24-hour ambulatory BP, arterial stiffness, and central aortic BP assessment, followed by a 5-minute arterial occlusion and a 3-minute submaximal handgrip exercise. Changes in muscle oxygenated and deoxygenated hemoglobin and tissue oxygen saturation were continuously monitored by near-infrared spectroscopy and beat-by-beat BP by Finapres. Hypertensives had higher (P<0.001) central aortic BP and pulse wave velocity versus normotensives and exhibited (1) a blunted tissue oxygen saturation response during occlusion, with slower (P=0.006) deoxygenation rate, suggesting reduced muscle oxidative capacity, and (2) a slower reoxygenation rate and blunted hyperemic response (P<0.05), showing reduced microvascular reactivity. Muscle oxygenation responses were correlated with aortic systolic and pulse pressure and augmentation index (P<0.05; age and body mass index (BMI) adjusted). When exercising at the same submaximal intensity, hypertensives required a significantly greater (P<0.001) increase in BP for achieving similar muscle oxygenation levels as normotensives. This response was correlated with the magnitude of microvascular hyperemia and aortic BP. In conclusion, nontreated patients with hypertension exhibit prominent reductions in in vivo indices of skeletal muscle oxidative capacity, suggestive of mitochondrial dysfunction, and blunted muscle microvascular reactivity. These dysfunctions were associated with higher aortic systolic BP and arterial stiffness. Dysregulations in muscle oxygen delivery/utilization and microvascular stiffness, in hypertensive patients, partially contribute to their exaggerated BP during exercise.

Retinal vessel morphology in rheumatoid arthritis: association with systemic inflammation, subclinical atherosclerosis and cardiovascular risk

Quantification of retinal vessel morphology has emerged as a marker of cardiovascular health. We examined retinal microvascular diameters in RA, particularly in regard to systemic inflammation, subclinical atherosclerosis, and cardiovascular risk.

Predictors of impaired quality of life in patients with rheumatic diseases.

Quality of life (QoL) is a complex outcome and rheumatologic patients typically exhibit several comorbidities with a negative impact. In this study, we analyzed with respect to QoL for the first time a wide range of physical and psychological factors, including individual, clinical and disease-related parameters, mental health disorders, sexual dysfunction, and cardiovascular comorbidities among consecutive rheumatologic patients. QoL was evaluated using the EuroQol 5D (EQ-5D) utility index. The Health Assessment Questionnaire (HAQ) Disability Index, and the HAQ Pain Visual Analogue Scale were used as measures of physical disability and arthritis-related pain, respectively. The Hamilton Anxiety Scale and Zung Self-Rating Depression Scale, the International Index of Erectile Function and the Female Sexual Functioning Index were completed by all patients. In total, 360 patients were included, 301 females and 59 males. In the univariate analysis, pain, physical disability (p < 0.001 for both), disease duration (p = 0.014), anxiety and depression (p < 0.001 for both), as well as sexual dysfunction (p = 0.001 for females, p = 0.042 for males), correlated with QoL. Female sex (p < 0.001), advanced age (p = 0.029), lower educational level (p = 0.005), and cardiovascular factors (hypertension, dyslipidemia, diabetes, lack of systemic exercise) also appeared to negatively affect QoL. However, in the multiple regression model, only anxiety, pain, physical disability (p < 0.001 for all), and disease duration (p = 0.019) remained significant predictors of QoL. The emotional side and the disease-related physiological mode of rheumatic diseases appear as major independent correlates of QoL among rheumatologic patients, who may thus benefit the most from combined supportive psychological and pain-relieving interventions.

Association of non-invasive hemodynamics with arterial stiffness in rheumatoid arthritis

Abstract Objectives. Arterial stiffness has emerged as a surrogate marker of cardiovascular disease. We investigated the role of myocardial performance and hemodynamic parameters in arterial stiffness in patients with rheumatoid arthritis (RA), which is accompanied by excess cardiovascular risk. Design. Arterial stiffness was evaluated with pulse wave velocity (PWV) in RA patients and controls. Cardiac and hemodynamic characterization was based on impedance cardiography. Cardiovascular risk factors, inflammatory markers and disease-related parameters were assessed. Results. PWV (8.2 ± 2.1 vs 7.4 ± 1.4 m/s, p = .016) was higher among RA patients (n = 104) compared to controls (n = 52). In the RA group, PWV correlated with markers of cardiac contractibility (acceleration and velocity index), myocardial blood flow (cardiac output and stroke volume), preload (thoracic fluid content) and afterload (systemic vascular resistance) (p < .05 for all). PWV tended to increase with decreasing oxygen delivery to the myocardium (r = 0.055), as well as with shortening of the ejection duration of the left ventricle (p = .058). However, these associations no longer remained significant after adjustment for classical cardiovascular risk factors, inflammation and corticosteroid use, which were independently associated with PWV. Conclusions. Among patients with RA, arterial stiffness appears as the composite of cardiovascular risk factors and inflammation, while corticosteroid use emerges as an additional adverse factor.

Blunted cerebral oxygenation during exercise in women with gestational diabetes mellitus: associations with macrovascular function and cardiovascular risk factors

AIM/HYPOTHESIS This cross-sectional, observational, controlled study examined cerebral oxygenation during exercise, an index of cerebrovascular function and cortical activation, in pregnancies complicated by gestational diabetes mellitus (GDM) and unaffected pregnancies. The association of cerebral oxygenation with macrovascular and cardiovascular function indices was also evaluated. MATERIAL AND METHODS Vascular function and structure [aortic pulse-wave-velocity (PWV), augmentation index (AI), carotid intima-media thickness], as well as 24-hour ambulatory blood pressure (BP) were assessed in women with GDM (n = 21) and uncomplicated pregnancies (n = 16), at 26-32 gestational weeks. Changes in cerebral oxygenation [oxy- (O2Hb), deoxy- (HHb) and total- (tHb) hemoglobin] were continuously recorded by near-infrared spectroscopy (NIRS) during intermittent handgrip exercise. Beat-by-beat BP and systemic vascular resistance (SVR) were assessed (Finapres). RESULTS Women with GDM had higher AI than controls. During exercise, women with GDM maintained a smaller force (p < 0.05), despite similar ratings of perceived exertion. Despite similar increases in BP during exercise, the GDM group exhibited a lower average and total (AUC) increase in cerebral-O2Hb than controls (p < 0.05). In addition, GDM exhibited a slower rate of cerebral-O2Hb decay during recovery (p < 0.05). SVR was lower in GDM compared to controls throughout the protocol (p < 0.01). Cerebral oxygenation indices were correlated with PWV and AI (p < 0.05). CONCLUSIONS This study provided novel evidence for blunted cerebral oxygenation during exercise in women with GDM compared to uncomplicated pregnancies, suggesting a link between reduced cerebrovascular function with exercise intolerance in GDM. Cerebral oxygenation during physical stress was correlated with macrovascular function and cardiovascular risk factors. More studies are needed to examine whether this impaired cerebral oxygenation reflects early cerebrovascular disease.

ASSOCIATION OF SERUM URIC ACID LEVELS WITH ARTERIAL STIFFNESS AND ENDOTHELIAL DYSFUNCTION IN A POPULATION OF NORMOTENSIVE TO EARLY-STAGE HYPERTENSIVE INDIVIDUALS

Objective: Objective: Hyperuricemia appears to be associated with increased cardiovascular risk. Both accelerated vascular stiffness and endothelial injury caused by increased oxidative stress have been postulated as contributing potential mechanisms. We investigated whether serum uric acid levels correlate with robust markers of arterial stiffness and endothelial dysfunction in a population of untreated individuals free from cardiovascular diseases, whose blood pressure ranged from normal to early-stage essential hypertension. Design and method: Design and Method: Individuals free from cardiovascular comorbidities, who received no medication for any reason, were eligible to participate. Arterial stiffness was estimated by the carotid-femoral pulse wave velocity (PWV) measurement with applanation tonometry using the Sphygmocor device. Serum samples were drawn for the measurement of uric acid levels and other biochemical parameters. Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, was measured in serum samples using commercially available competitive enzyme-linked immunosorbent assay (ELISA) kit. Results: Results: A total of 241 individuals, 144 males and 97 females, with a mean age of 45.0 ± 11.2 years and mean systolic/diastolic blood pressure 138.8 ± 18.4/88.7 ± 12.0 mmHg, participated in the study. Mean PWV was 7.9 ± 1.8 m/s, while serum uric acid and ADMA levels were 5.1 ± 1.4 mg/dl and 1.00 ± 0.39 &mgr;mol/l, respectively. Uric acid positively correlated with both PWV (r = 0.152, p = 0.025) and ADMA levels (r = 0.141, p = 0.029). After adjustment for other variables (age, gender, body mass index, HDL cholesterol, triglycerides, glomerular filtration rate) in the multivariate analysis for uric acid, an independent association between with ADMA levels was observed (beta = 0.200, p < 0001), whereas the association between uric acid and PWV was no longer significant. Conclusions: Conclusion: In a population of untreated normotensive- to- early-stage hypertensive individuals, increased levels of uric acid are independently associated with endothelial dysfunction. On the other hand, the observed association between uric acid and arterial stiffness appears to be mediated by traditional cardiovascular risk factors. Uric acid might be implicated in the pathogenesis of cardiovascular diseases through endothelium-dependent mechanisms.

SYSTOLIC BLOOD PRESSURE PHENOTYPING BASED ON BOTH AORTIC AND BRACHIAL MEASUREMENTS AND ITS RELATIONSHIP WITH INTERMEDIATE HYPERTENSION PHENOTYPES AND ARTERIAL STIFFNESS

Objective: High aortic systolic blood pressure (aSBP) is stronger associated with target organ damage as compared to brachial systolic BP (bSBP). Office SBP phenotypes based on both brachial and aortic measurements have been recently proposed as a new classification system that could improve cardiovascular risk stratification and reveal subgroups of higher or lower risk of vascular damage. We sought to investigate: A) whether the above phenotyping could help to identify all hypertension phenotypes [True (TH), white-coat (WCH) and masked hypertensives (MH)] without applying ambulatory BP monitoring (ABPM), a gold standard method in the diagnosis of hypertension, however not always available in everyday clinical practice, and B) if the above combination of aSBP and bSBP is more sensitive to detect subgroups with increased arterial stiffness and thereby increased cardiovascular risk. Design and method: Based on their office bSBP and aSBP values, participants were classified into four office SBP phenotypes, using both the sex-adjusted 90th percentile and the rounded threshold of 130mmHg: type I was defined as both normal bSBP and aSBP, type II high bSBP with normal aSBP, type III normal bSBP but high aSBP and type IV both high bSBP and aSBP. Moreover, all participants underwent ABPM and were further classified into normotensives (NT), WCH, MH and TH. Arterial stiffness was assessed via pulse wave velocity (PWV). Results: The study included 391 untreated individuals (58.1% male) with a mean age of 44.0 ± 12.6 years (138 NT, 21 WCH, 52 MH and 180TH).No differences were observed in age, body mass index and smoking status. Most TH (68.9–87.8%) were type IV, while > 90% of normotensives were classified as type I. The majority of WCH (47.6–71.4%) were type IV, while < 45% of the MH had high aSBP and were type III. PWV was significantly lower between type I and all other types, as well as between III and IV type (p < 0.001). Conclusions: Our results showed that high aSBP deteriorates arterial stiffness regardless of the levels of bSBP. Therefore although SBP phenotyping doesn’t help to identify WCH or MH, its use in the everyday clinical practice can improve cardiovascular risk stratification.

ASSOCIATION OF ENDOTHELIAL DYSFUNCTION IN MICROCIRCULATION USING LASER SPECKLE CONTRAST ANALYSIS WITH MARKERS OF ARTERIAL STIFFNESS

Objective: Endothelial dysfunction has a key role in microcirculation promoting very early structural and vascular alterations that precede any clinically detectable vascular damage and contribute to the pathogenesis of hypertension. Small artery alterations though are interdependent with large artery lesions and interact in a vicius cycle that sustains and exaggerates vascular damage. It has been speculated that a common denominator in that cross-talk between micro- and macrocirculation is endothelial dysfunction. In this study we evaluated the association of endothelial dysfunction of skin microcirculation using Laser Speckle Contrast Analysis (LASCA) with central blood pressures (cBP) as recorded with the Mobil-O-Graph device, in treatment-naïve hypertensive patients. Design and method: We studied a group of 31 untreated, hypertensive patients with new-onset essential hypertension, without cardiovascular comorbidities, mean age 50.3 ± 18.5 years. Central BPs were recorded in all subjects using the Mobil-O-Graph NG (IEM, Stolberg, Germany) device. In addition, microvascular blood flow of the skin forearm was evaluated using LASCA (PeriCam PSI NR System, Perimed Järfälla, Sweden). Results of microvascular flow are expressed as baseline Cutaneous Vascular Conductance (CVC), peak CVC and peak CVC minus baseline CVC. Pearsons and Spearmans correlations were used, based on the variables normality of distribution. Results: We observed a significant negative correlation between peak CVC and 24-hour cBP (r = −564 for central systolic BP [cSBP], r = −458 for central diastolic BP [cDBP]), day cSBP (r = −560), day cDBP (r = −466) and night cSBP (r = −457) (p < 0.05). In addition, peak CVC minus baseline CVC showed a significant negative correlation will all cBP parameters (p < 0.05). Baseline CVC showed a significant negative correlation with 24-h cSBP (r = −482) and day cSBP (r = −488) (p < 0.05). Conclusions: A significant inverse relationship was revealed between most central BP parameters and markers of endothelial dysfunction of skin microcirculation in treatment-naïve patients with new onset essential hypertension. In this group of patients, the endothelial dysfunction of skin microcirculation may be already associated with a higher central hemodynamic load although the exact cause and effect relationship of this bidirectional communication between small and large arteries has not been fully elucidated yet.

DIPPING PROFILE, NIGHTTIME SYSTOLIC BLOOD PRESSURE AND VASCULAR DAMAGE IN PATIENTS WITH RHEUMATOID ARTHRITIS

Objective: Both increased nighttime systolic blood pressure (SBP) and a non-dipping pattern are predictors of adverse cardiovascular outcomes. We investigated dipping profile and nighttime SBP in relationship with subclinical vascular damage in patients with rheumatoid arthritis (RA), a disease characterized by excess cardiovascular risk. Design and method: Patients with RA and non-RA individuals underwent 24-hour ambulatory blood pressure monitoring. Carotid-femoral pulse wave velocity (PWV) was assessed with applanation tonometry as a measure of central arterial stiffness. Carotid atherosclerosis was evaluated from carotid ultrasound by measurement of carotid intima-media thickness (cIMT). Peripheral vascular resistance was estimated from impedance cardiography. Disease-related characteristics were addressed, including erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), disease duration and activity, and pain. Results: RA patients (n = 91) exhibited a higher prevalence of non-dipping pattern (64.8 vs 28.0 %, p < 0.001), elevated nighttime SBP (112.6 ± 12.8 vs 105.8 ± 9.7 mmHg, p = 0.001) and a lower degree of dipping (6.5 ± 7.4 vs 13.0 ± 5.6 %, p < 0.001), compared to non-RA individuals (n = 50), whereas both office and daytime SBP did not differ. In the RA group, dipping (%) was inversely associated with PWV (r = –0.218, p = 0.045). Nighttime SBP strongly correlated with all vascular indices, including PWV (r = 0.493, p < 0.001), cIMT (r = 0.407, p < 0.001) and systemic vascular resistance index (r = 0.383, p < 0.001). In addition, nighttime SBP increased with increasing ESR (r = 0.213, p = 0.046), CRP (r = 0.245, p = 0.022), intensity of pain over the past 24-hour hours (r = 0.255, p = 0.042) and disease duration (r = 0.246, p = 0.027). The combination of a non-dipping profile with high nighttime SBP was accompanied by the highest (p = 0.019) PWV (10.0 ± 2.5 m/s), compared to both non-dippers with normal nighttime SBP (7.8 ± 2.1 m/s, p = 0.003) and dippers (8.1 ± 1.9 m/s). In the multivariate analysis for dipping, ESR was identified as an independent predictor (beta = –0.234, p = 0.037), and the same was observed in the multivariate analysis for nighttime SBP (beta = 0.201, p = 0.019). Conclusions: Patients with RA exhibit high prevalence of blunted dipping due to elevated nighttime SBP. Inflammation appears to mediate the observed associations of nighttime SBP and dipping with markers of central and peripheral vascular damage. The combination of a non-dipping profile with abnormal nighttime SBP is accompanied by pronounced subclinical vascular impairment.

Asymmetric dimethylarginine levels are associated with augmentation index across naïve untreated patients with different hypertension phenotypes

Asymmetric dimethylarginine (ADMA) is a robust marker of endothelial dysfunction in patients with essential hypertension. We investigated ADMA levels and their association with vascular damage in untreated hypertension. We enrolled consecutive patients with untreated, recently diagnosed hypertension and age‐matched normotensive individuals. 24‐hour blood pressure, central hemodynamics, and arterial stiffness were recorded. A total of 311 individuals were studied: 165 with essential hypertension, 50 with masked hypertension, 25 with white‐coat hypertension, and 71 normotensive individuals. ADMA levels significantly correlated with aortic augmentation index (AIx75) (r = .156, P = .006), aortic pulse pressure (r = .153, P = .007) and marginally with carotid‐femoral pulse wave velocity (r = .110, P = .051), as well as with diastolic office BP. In the multivariate model, aortic AIx75 and age were the only statistically significant predictors of ADMA. This is the largest study to document an independent association between ADMA and aortic AIx75 but not with other indices of arterial stiffness.