Giovanni Scandale

Basal nitric oxide production is not reduced in patients with noninsulin-dependent diabetes mellitus

Vascular disease is the leading cause of morbidity, disability and death in patients with noninsulin-dependent diabetes mellitus. Abnormalities in endothelium-derived nitric oxide (NO) have been demonstrated to be involved in the pathogenesis of vascular disease. By measuring hemodynamic responses to a NO synthase agonist or antagonist, previous studies have shown the presence of NO deficiency in patients with noninsulin-dependent diabetes mellitus, a method of assessing bioactive NO formation. However, direct biochemical evidence that this is the case, has not been produced. In vivo NO is metabolized into nitrate, an end breakdown product of NO, which can be used as an index of endogenous NO formation. To investigate further whether decreased basal synthesis of NO may be a major cause of endothelium-mediated vascular dysfunction in patients with noninsulin-dependent diabetes mellitus, the plasma nitrite/nitrate levels of 15 patients were examined and compared with 13 normal controls. The results showed that in basal conditions plasma nitrite/nitrate levels were not reduced in diabetic patients compared with normal controls (37.3 ± 14.7 versus 29.4 ± 8.6 μmol/l). It was concluded that in noninsulin-dependent diabetes mellitus patients, endothelium-derived basal NO formation is not impaired. This study, taken with previous observations, suggests that factors other than diminished basal NO production, such as reduced bioavailability of NO probably due to the augmented production of superoxide anion with subsequently increased inactivation of NO, contribute to the high incidence of vascular disease in patients with noninsulin-dependent diabetes mellitus.

Reply to Arterial Stiffness in Patients With Peripheral Arterial Disease

To the Editor: Many thanks to Balta and colleagues for the appreciation of our work “Increased Aortic Stiffness and Related Factors in Patients With Peripheral Arterial Disease” recently published in The Journal of Clinical Hypertension. However, we disagree on some remarks made by the same authors. We did not mention the effects of heart failure and inflammatory disease such as psoriasis on aortic stiffness. Neither of these conditions were included in our analysis because the patients did not present these symptoms at the time of enrollment in the study. In addition, it would be more interesting to conduct a study in patients without atherosclerosis disease, diabetes, or hypertension to clarify the relationship between alcohol intake and aortic stiffness. In the discussion, we mention the lack of relationship between the common risk factors (smoking and diabetes) and aortic pulse wave velocity (aPWV) illustrating the results (in Table 2) on the main determinants of aPWV (age, heart rate, blood pressure) leaving out, however, the lack of relationship between smoking (b=0.56, P=.31), dyslipidemia (b=0.82, P=.08), low-density lipoprotein (b=0.008, P=.19), cerebrovascular disease (b=2.87, P=.12), and aortic stiffness. These results are in agreement with the findings of a recent systematic review of the literature concerning aPWV and cardiovascular risk factors. In particular, Cecelja and Chowienczyk identified several studies with data relating aPWV to age, blood pressure, and a variable number of other cardiovascular risk factors, in which regression models were available. The results from this review demonstrate that only age and blood pressure are consistently related to aPWV. Other risk factors were no longer significant after adjusting for age and blood pressure, suggesting that the impact of traditional risk factors, other than BP, on aPWV is small or insignificant. Furthermore, atherosclerosis risk factors, per se, appear to play a minor role in aortic stiffening as highlighted by McEniery and colleagues. Finally, we report that the regression model could only predict a part of the variability of aPWV (R=11; 8%, P=.01) indicating that markers of inflammation and/or vascular calcification associated with PAD, not currently studied in our paper, may play an important role in aortic stiffness. Arteriosclerosis and atherosclerosis are two processes pathologically distinct and largely driven by different mechanisms.

Increased Aortic Stiffness and Related Factors in Patients With Peripheral Arterial Disease

A number of conditions have been associated with functional changes of large arteries. The aim of this study was to evaluate the factors associated with aortic stiffness in patients with peripheral arterial disease (PAD). The authors studied 86 patients with PAD (ankle‐brachial pressure index [ABPI] ≤0.9) and 86 controls. Aortic stiffness was determined by pulse wave velocity (aPWV) using applanation tonometry. In PAD patients, aPWV was higher compared with controls (11±3 vs 9.8±1.8; P=.002). In multiple regression analysis, aPWV was independently associated with pulse pressure (β=0.05, P=.01) in the PAD patients and with age in the control group (β=0.08, P=.0005). The results of this study confirm an aPWV increase in patients with PAD and emphasize the association between blood pressure and aPWV. Further studies are necessary to assess whether higher aortic stiffening adds prognostic value to ABPI, which is the most powerful prognostic indicator in PAD.

Energetics of walking in patients with peripheral arterial disease: a proposed functional evaluation protocol.

The energy cost of walking (at 3.2 km x h(-1)) per unit distance (J x kg(-1) x m(-1)) at gradients of 0%, +7%, and +12% and during a progressive test (2% increase in gradient every 2 min), as well as the overall (aerobic plus anaerobic) net cumulative energy consumption and the corresponding maximal exercise duration were assessed in 19 patients with peripheral arterial disease (PAD) and in 13 moderately active control subjects. With a 0% gradient, the energy cost of walking was approximately 40% greater in patients with PAD than in controls (2.93+/-0.52 and 2.13+/-0.33 J x kg(-1) x m(-1) respectively; P <0.01). In contrast, at gradients of +7% and +12%, the energy cost of walking was similar in the two groups (+7%: PAD, 4.15+/-0.74 J x kg(-1) x m(-1); controls, 4.18+/-0.54 J x kg(-1) x m(-1); +12%: PAD, 5.59+/-1.03 J x kg(-1) x m(-1); controls, 5.64+/-0.75 J x kg(-1) x m(-1)). In patients with PAD, maximal exercise duration with gradients of 0%, +7% and +12% was 449+/-254, 322+/-200 and 229+/-150 s respectively, whereas the net cumulative energy consumption at fatigue was almost constant at approximately 1100 J x kg(-1) for all gradients. The greater energy cost of walking in PAD patients compared with controls in level, but not uphill, walking is interpreted as being mainly the consequence of an altered mechanical locomotory pattern, and not of lower metabolic efficiency. For a wide range of loads, net cumulative energy consumption appears to be independent of maximal exercise duration, a finding that provides a practical criterion for assessing the degree of functional impairment of patients with PAD on metabolic grounds.

Aortic augmentation index in patients with peripheral arterial disease.

Aortic augmentation index (AIx) is used to investigate arterial stiffness. The authors tested the hypothesis that patients with peripheral arterial disease (PAD) demonstrate a higher AIx and also evaluated several related factors. In 97 patients with PAD, identified by ankle‐brachial pressure index (ABPI ≤0.9), and 97 controls (ABPI ≥0.91<1.4), AIx (%) was determined using tonometry of the radial artery. There was no significant difference between patients and controls in characteristics of age, sex, height, diastolic blood pressure, mean blood pressure, and heart rate. AIx was higher in patients with PAD (32±9 vs 28±9; P=.001). In multivariate regression analysis, AIx was independently associated with heart rate (β=−0.40, P=.0005). This study showed that AIx increased in patients with PAD and that heart rate is a determinant of AIx. Further studies are necessary to assess the pathophysiological and clinical importance of AIx in patients with PAD.

Elastic properties and structure of the radial artery in patients with type 2 diabetes

Alterations of elastic properties may contribute to the accelerated atherosclerosis in patients with T2D. Little is known, however, about radial artery distensibility in this patient group. A total of 19 patients with T2D and 19 controls were investigated.An echotracking system coupled to a plethysmograph was used to assess the morphologic and elastic properties of radial artery. Distensibility and compliance were evaluated using Langewouters’ equations. Distensibility and compliance did not differ significantly in patients with diabetes compared with controls. In contrast, radial IMT and WCSA were significantly higher in patients with T2D than in controls. Multiple regression analyses revealed a significant association between SBP and IMT (r 2 = 0.40, p<0.001) as well as WCSA (r = 0.54; r 2 = 0.30; p<0.001 ) in individuals with diabetes. In conclusion, distensibility and compliance of the radial artery are not reduced in patients with T2D. In contrast, radial IMT and WCSA are significantly higher in patients with T2D than in controls.These modifications are chiefly and positively related to SBP.

Radial artery compliance in patients with peripheral vascular disease.

Compliance in largely central arteries of patients with peripheral vascular disease (PVD) has been reported to be reduced. However, the arterial tree is an inhomogeneous system, and there remains uncertainty about whether the peripheral arteries (e.g. the medium-sized muscular radial artery) undergo a similar change to the central arteries. The aim of this study was to investigate the radial artery elasticity in 19 patients with PVD compared with 18 normal subjects of comparable age and sex. Using a noninvasive high-resolution echo-tracking device coupled to a photoplethysmograph (Finapres system) allowing simultaneous arterial diameter and finger blood pressure monitoring, we measured the radial artery compliance by determining the diameter–pressure, compliance–pressure and distensibility–pressure curves. The results showed that the diameter of the radial artery was similar in the two groups, but that the compliance and distensibility were not further reduced in patients with PVD than in the normal controls at 100 mmHg and for a common blood pressure range. The present studies demonstrate that in patients with PVD the radial arterial compliance is not reduced, which indicates that the change in arterial elasticity is not identical. The potential mechanisms involved in this change in radial artery compliance are discussed.

Microcirculation and hemorheology in NIDDM patients.

The authors studied 10 patients with non-insulin-dependent diabetes mellitus and 5 controls matched for age, sex, blood lipids, and smoking habit. The two groups were also comparable for hemorheologic characteristics as evaluated by viscosimetry on whole blood, plasma and serum, erythrocyte filtration and aggregation. The microcirculation was studied in the subjects of both groups by microalbuminuria determination, retinal fluorangiography, and capillaroscopic examination of the bulbar conjunctive and nail folds. None of the patients presented microalbuminuria values higher than the upper limit of normal (20mg/24h). Fluorangiographic alterations were observed in 4 patients, and all 10 pre sented capillaroscopic alterations at the bulbar conjunctiva (microaneurysms, erythrocyte aggregates) and nail folds (more frequently of the fingers than toes). Similar alterations were detected in controls. Thus these abnormalities seem independent of hemorheologic values.

Arterial stiffness and subendocardial viability ratio in patients with peripheral arterial disease

Arterial stiffening is a hallmark of the aging process and atherosclerosis, including peripheral arterial disease (PAD). We investigated the associations between carotid‐femoral pulse wave velocity (c‐fPWV), augmentation index corrected for heart rate (Aix@HR75), ankle brachial index (ABI), and subendocardial viability ratio (SEVR), an indicator of cardiac perfusion. The c‐fPWV, Aix@HR75, and SEVR was estimated using applanation tonometry. The ankle systolic pressure measurements for the calculation of the ABI were obtained using an 8‐mHz Doppler probe. The study group included 555 subjects, mean age 63 ± 11 years (248 PAD (ABI < 1.0), and 307 non‐PAD (ABI ≥ 1.0 ≤ 1.3). After the stepwise selection process in both PAD and non‐PAD patients SEVR was not related to c‐fPWV and ABI (P = .154; P = .156) and (P = .101; P = .402), respectively. In PAD patients, SEVR was negatively related to Aix@HR75 (P < .0001) and aortic PP (P = .0005). In conclusion, arterial stiffness is associated with non‐invasive indices of myocardial perfusion in PAD patients, suggesting a potential pathophysiological link for increased cardiovascular events.

Arterial Stiffness: A Review in Type 2 Diabetes

Diabetes is a growing health problem worldwide in [1]. In a prospective study the risk of cardiovascular death in patients with diabetes, without previous coronary heart disease (CHD) is equal to that of patients with CHD without diabetes, with a higher risk factor in women in [2]. This excessive risk is not explained by classic risk factors for cardiovascular disease such as smoking, LDL-cholesterol, hypertension in [3]. This has led to a search for early markers of vascular dysfunction (arterial stiffness) in diabetic patients that may pre-date the development of overt clinical disease, offer a target for early intervention and delay the progress of cardio‐ vascular disease complications. Arterial walls stiffen with age. Once, the aging-associated changes in arterial structural and functional changes were thought to be part of natural aging, but this concept changed when data emerged showing that these changes are accelerated with coexistent cardiovascular disease. For example, patients with diabetes exhibit increased stiffness even after adjusting for age in [4] and this ‘accelerated’ arterial aging is well confirmed to be a risk. Several non-invasive methods are currently used to assess vascular stiffness. An extensive theoretical review of models underlying the definitions and assessment methods of arterial stiffness estimates have been recently published in [5].