Barbara Nikolaidou

Exercise-induced pulse wave velocity changes in untreated patients with essential hypertension: the effect of an angiotensin receptor antagonist.

This study investigates arterial stiffness changes after acute exercise in young patients with untreated, recently diagnosed grade I essential hypertension (UH) compared with normotensive (NT) individuals and the effect of antihypertensive treatment on this phenomenon. Study 1 consisted of 25 UH and 15 NT patients. UH patients who received treatment were included in study 2 and were followed‐up after a 3‐month treatment period with an angiotensin II receptor blocker. Aortic pulse wave velocity (PWV) was assessed at baseline, at maximal exercise, and at 10, 30, and 60 minutes later. In UH patients, PWV increased significantly at maximal exercise and 10 and 30 minutes of recovery, despite blood pressure fall to baseline levels. No significant PWV changes were observed in NT patients. Post‐treatment PWV levels were significantly decreased and similar to those of NT patients. Arterial stiffness is impaired following high‐intensity acute exercise even in the early stages of hypertension. Antihypertensive treatment ameliorates these effects.

Combined angiotensin inhibition in diabetic nephropathy.

To the Editor: The Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) study reported by Fried et al. (Nov. 14 issue)1 showed that dual blockade of the renin–angiotensin–aldosterone system confers a high risk of adverse effects among patients with diabetic nephropathy. Inhibitors of the renin–angiotensin–aldosterone system have been used successfully for slowing progression of diabetic nephropathy, but increasing the dosage to achieve better outcomes with a low risk of adverse effects remains controversial.2,3 As in previous clinical trials, Fried et al. have shown that combining an angiotensin II–receptor blocker (ARB) and an angiotensin-converting–enzyme (ACE) inhibitor or a direct renin inhibitor did not result in a benefit but was associated with an increased risk of adverse events.1,3,4 In our recent study, the combination of equipotent half doses of an ACE inhibitor (lisinopril) and an ARB (irbesartan), as compared with each single agent at higher doses, did not show any benefit with respect to the risk of progression; however, the incidence of adverse effects was similar in the two groups.5 We do not support the use of dual blockade, even if it is used in equipotent doses, because of the lack of benefit and the risk of complications.To the Editor: The Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) study reported by Fried et al. (Nov. 14 issue)1 showed that dual blockade of the renin–angiotensin–aldosterone system confers a high risk of adverse effects among patients with diabetic nephropathy. Inhibitors of the renin–angiotensin–aldosterone system have been used successfully for slowing progression of diabetic nephropathy, but increasing the dosage to achieve better outcomes with a low risk of adverse effects remains controversial.2,3 As in previous clinical trials, Fried et al. have shown that combining an angiotensin II–receptor blocker (ARB) and an angiotensin-converting–enzyme (ACE) inhibitor or a direct renin inhibitor did not result in a benefit but was associated with an increased risk of adverse events.1,3,4 In our recent study, the combination of equipotent half doses of an ACE inhibitor (lisinopril) and an ARB (irbesartan), as compared with each single agent at higher doses, did not show any benefit with respect to the risk of progression; however, the incidence of adverse effects was similar in the two groups.5 We do not support the use of dual blockade, even if it is used in equipotent doses, because of the lack of benefit and the risk of complications.

Increased thrombotic and impaired fibrinolytic response to acute exercise in patients with essential hypertension: The effect of treatment with an angiotensin II receptor blocker

Essential hypertension (EH) is characterised by increased thrombotic tendency and impaired fibrinolytic activity. However, exercise-induced changes in coagulation and fibrinolysis have not yet been clarified. We aimed at determining thrombotic and fibrinolytic activity during exercise in patients with EH pre and post treatment with an Angiotensin II receptor blocker. Study 1 consisted of 30 untreated hypertensive (UH) and 15 normotensive (NT) individuals. The UH individuals who received treatment were included in study 2 and were followed up after a 3-month treatment period with valsartan. Thrombin–antithrombin (TAT) complexes and human plasminogen activator inhibitor-1 (PAI-1) were measured as markers of coagulation and fibrinolysis, respectively, at baseline, immediately after a treadmill exercise test and 30 min later. In UH, TAT and PAI-1 levels were significantly increased immediately after peak exercise and decreased 30 min later, as compared with baseline levels. At all time points, UH exhibited significantly higher TAT and PAI-1 levels compared with NT. No significant changes of TAT and PAI-1 levels were observed in NT and in patients post treatment. Acute high-intensity exercise results in impaired thrombotic and fibrinolytic response in untreated patients with EH. Angiotensin II receptor blockade with adequate blood pressure control greatly improves exercise-induced changes in coagulation and fibrinolysis in EH.

Association Between Cardiotrophin 1 Levels and Central Blood Pressure in Untreated Patients With Essential Hypertension

BACKGROUND Cardiotrophin 1 (CT-1) is an interleukin 6-related cytokine recently implicated in cardiac hypertrophy and vascular damage in essential hypertension (EH). We aimed first to determine CT-1 levels in naive, untreated patients with grade I EH (UH) as compared with normotensive (NT) individuals and, second, to investigate a possible association of CT-1 levels with indices of arterial stiffness. METHODS We enrolled 45 consecutive untreated patients recently diagnosed with grade I EH by means of office and ambulatory blood pressure (BP) measurements and 25 age- and sex-matched NT subjects. CT-1 levels were measured with a commercially available enzyme-linked immunosorbent assay kit, and indices of arterial stiffness were determined by applanation tonometry. RESULTS CT-1 levels were significantly elevated in UH patients compared with NT subjects (P < 0.001). Furthermore, CT-1 levels correlated positively with office, ambulatory and central BP. A significant bivariable correlation was also found between CT-1 levels and pulse wave velocity (P = 0.02). In the multivariable analysis, central systolic and diastolic BP proved the only significant predictors of CT-1 levels after controlling for other related factors. CONCLUSIONS To our knowledge, this is the first study that correlates CT-1 levels with ambulatory and central BP, as well as with pulse wave velocity in patients with essential hypertension. Thus, studying the effects of CT-1 in the cardiovascular system in patients with EH represents a promising area of investigation in the future.

More fuel in the obesity paradox debate

We enjoyed reading the paper by Kolade et al. on the association of body size indices with central blood pressure and arterial stiffness in healthy individuals and populations with cardiovascular and kidney disease. We congratulate the authors for the meticulous selection of study population subgroups and their excellent work, which demonstrated that although body mass index (BMI) was clearly correlated with central systolic blood pressure (SBP) in apparently healthy individuals, this association was not observed in the subgroups with established vascular disease. What is more, none of the examined body size measures was able to predict arterial stiffness in the healthy control subgroup with relevant data after correcting for brachial BP. In our opinion, these results may actually add another stone in the pathophysiological foundation of the so-named obesity paradox. Although increased BMI represents a well-acknowledged cardiovascular risk factor aggravating mortality risk in the general population, consistent findings among specific population subgroups with various manifestations of established vascular disease, including those examined in the present study (coronary heart disease, type 2 diabetes mellitus, chronic kidney disease, heart failure, hypertension, peripheral artery disease), support a protective role of overweight towards mortality. Interestingly, a similar role has also been reported in divergent healthier populations. Of note, a recent study on a nationally representative sample demonstrated that being overweight and underweight was associated with a decreased and increased risk for allcause mortality, respectively. With the association between BMI and cardiovascular mortality being eliminated after adjustment for several traditional cardiovascular risk factors, it has been suggested that a substantial part of the BMI-associated risk of cardiovascular mortality is mediated through conventional risk factors. Although the findings of the present study imply a neutral rather than protective effect of obesity on arterial stiffness in healthy and on central hemodynamics in diseased participants, it would be of major interest to determine the impact of increased BMI on the above parameters along with other factors not addressed in the study. When fitness was taken into account, the risk for premature death associated with obesity was paradoxically reversed in middle-aged men with known or suspected coronary artery disease; highly fit overweight men had the lowest mortality risk of any subgroup, including highly fit normal-weight men. Likewise, increased longevity was observed in overweight and obese but fit individuals compared with normal weight but unfit hypertensive men. In the light of this evidence, a separate analysis in the present paper investigating fitness and fatness interactions would be of great use, in case relevant data are available. Furthermore, it would be useful to examine whether divergent findings are observed according to gender differentiation. Women are more affected by obesity, but cardiovascular disease risk conferred by increased BMI is in general lower compared with men. Whether concomitant medications or coexiting diseases in the disease groups may partially account for the reported outcomes was not clarified. In addition, the relationship between body size measures and brachial and central diastolic BP was not addressed, although relevant data were gathered.

Diabetes Mellitus and Erectile Dysfunction

Diabetes mellitus, a contemporary growing pandemic, causes severe complications and provokes diminishing effects on the patient’s quality of life. Erectile dysfunction is one of the most common and earliest presented morbidity affecting diabetic men. Erectile dysfunction in diabetics is more severe and resistant to treatment, and its prevalence is two to three times higher than in nondiabetics. The etiology of this disorder induced by diabetes is multifactorial and complex. Ongoing research is focused on elucidating the physiology of the erectile mechanism and unraveling the mystery of the pathogenesis implicated in the development of erectile dysfunction. Endothelial dysfunction, autonomic and peripheral neuropathy, and endocrinological and psychological disorders are involved in the pathogenesis of diabetes-induced erectile dysfunction. The progress achieved in the comprehension of these mechanisms has led to the introduction of novel and promising molecule-based treatment options. Evidence suggests that combination therapy tailored to the individual is of high efficacy and results in the improvement of the sex-related daily life of men with diabetes.

Antihypertensive Therapy After Acute Ischemic Stroke

The China Antihypertensive Trial in Acute Ischemic Stroke (CATIS) study reported that antihypertensive therapy immediately after an acute ischemic stroke did not reduce the likelihood of death or major disability compared with placebo.1 In the trial, the effects of antihypertensive therapy seemed to be time dependent. Although the study revealed no effect of antihypertensive therapy when treatment was administered within the first day of stroke, blood pressure lowering was associated with a 27% reduction in the primary outcome among patients treated after 24 hours of stroke onset. This finding is in accordance with the results from the Acute Candesartan Cilexetil Therapy in Stroke Survivors (ACCESS) study,2 in which candesartan was administered an average of 30 hours after recognition of stroke symptoms. Did Dr He and colleagues1 perform a formal interaction test3 to verify this finding? This finding comes from a subgroup analysis and can only be considered hypothesis generating, requiring further testing in future trials.

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.

INTRACARDIAC AND PERIPHERAL CIRCULATING ENDOTHELIAL MICROPARTICLES ARE ASSOCIATED WITH CENTRAL SYSTOLIC BLOOD PRESSURE IN PATIENTS WITH CORONARY ARTERY DISEASE

Objective: Circulating endothelial microparticles (EMPs) are expected to reflect underlying endothelial damage observed in coronary artery disease (CAD). However, it is not clear if and in what extent, EMPs increase in acute coronary syndromes (ACS) compared to stable CAD and whether they reflect local or systemic cardiovascular damage. Design and method: We enrolled consecutive adult patients with a clinical indication for coronary angiography in our Cardiology Department during a 1-year period. Central blood pressure (cBP) measured during angiography and patients’ history were recorded. Coronary sinus and peripheral blood samples were collected. Flow cytometry protocol was standardized based on previous studies. Double-positive events for Annexin and CD144 in the microparticles region were measured and quantified using Flow Count Fluorospheres. Results: We have studied 38 patients with ACS (22 STEMI and 16 NSTEMI), 17 patients with stable CAD and 6 control patients (Table 1). We found significantly increased EMPs in patients with CAD compared to controls, both in peripheral (p = 0.001) and coronary circulation (p = 0.003). This confirmed the validity of our method and the absence of artificial or ex vivo activation. Then, we analyzed EMPs in ACS versus stable CAD. ACS patients had significantly increased EMPs both in peripheral (p = 0.008) and coronary circulation (p = 0.045), compared to stable CAD (Figure 1). No difference was found in patients with STEMI versus NSTEMI. Furthermore, coronary EMPs were significantly increased compared to peripheral (p = 0.021). Although no association was found with traditional cardiovascular risk factors, both peripheral (r = 0.489, p = 0.003) and coronary (r = 0.312, p = 0.048) EMPs were associated with cSBP. Figure. No caption available. Conclusions: EMPs are increased in patients with ACS versus stable CAD and exhibit a profound increase in the coronary circulation compared to periphery, indicative of ongoing endothelial damage during acute myocardial ischemia. The extent of this damage may have implications regarding treatment and prognosis in these patients. The association between EMPs and cSBP possibly reflects an effect of endothelial dysfunction on central hemodynamics and aortic stiffness. Further prospective studies are needed to better clarify the role of microparticles as prognostic and possibly therapeutic targets.

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.