Ramiro Sanchez

Effect of low-dose perindopril/indapamide on albuminuria in diabetes preterax in albuminuria regression: PREMIER

Abstract—Microalbuminuria in diabetes is a risk factor for early death and an indicator for aggressive blood pressure (BP) lowering. We compared a combination of 2 mg perindopril/0.625 mg indapamide with enalapril monotherapy on albumin excretion rate (AER) in patients with type 2 diabetes, albuminuria, and hypertension in a 12-month, randomized, double-blind, parallel-group international multicenter study. Four hundred eighty-one patients with type 2 diabetes and hypertension (systolic BP ≥140 mm Hg, <180 mm Hg, diastolic BP <110 mm Hg) were randomly assigned (age 59±9 years, 77% previously treated for hypertension). Results from 457 patients (intention-to-treat analysis) were available. After a 4-week placebo period, patients with albuminuria >20 and <500 &mgr;g/min were randomly assigned to a combination of 2 mg perindopril/0.625 mg indapamide or to 10 mg daily enalapril. After week 12, doses were adjusted on the basis of BP to a maximum of 8 mg perindopril/2.5 mg indapamide or 40 mg enalapril. The main outcome measures were overnight AER and supine BP. Both treatments reduced BP. Perindopril/indapamide treatment resulted in a statistically significant higher fall in both BP (−3.0 [95% CI −5.6, −0.4], P =0.012; systolic BP −1.5 [95% CI −3.0, −0.1] diastolic BP P =0.019) and AER −42% (95% CI −50%, −33%) versus −27% (95% CI −37%, −16%) with enalapril. The greater AER reduction remained significant after adjustment for mean BP. Adverse events were similar in the 2 groups. Thus, first-line treatment with low-dose combination perindopril/indapamide induces a greater decrease in albuminuria than enalapril, partially independent of BP reduction. A BP-independent effect of the combination may increase renal protection.

Latin American guidelines on hypertension. Latin American Expert Group.

Hypertension is a highly prevalent cardiovascular risk factor in the world and particularly overwhelming in low and middle-income countries. Recent reports from the WHO and the World Bank highlight the importance of chronic diseases such as hypertension as an obstacle to the achievement of good health status. It must be added that for most low and middle-income countries, deficient strategies of primary healthcare are the major obstacles for blood pressure control. Furthermore, the epidemiology of hypertension and related diseases, healthcare resources and priorities, the socioeconomic status of the population vary considerably in different countries and in different regions of individual countries. Considering the low rates of blood pressure control achieved in Latin America and the benefits that can be expected from an improved control, it was decided to invite specialists from different Latin American countries to analyze the regional situation and to provide a consensus document on detection, evaluation and treatment of hypertension that may prove to be cost-utility adequate. The recommendations here included are the result of preparatory documents by invited experts and a subsequent very active debate by different discussion panels, held during a 2-day sessions in Asuncion, Paraguay, in May 2008. Finally, in order to improve clinical practice, the publication of the guidelines should be followed by implementation of effective interventions capable of overcoming barriers (cognitive, behavioral and affective) preventing attitude changes in both physicians and patients.

Carotid Wall Viscosity Increase Is Related to Intima-Media Thickening in Hypertensive Patients

Increases in arterial wall viscosity and intima-media thickness (IMT) were found in hypertensive patients. Because smooth muscle cells are responsible for the viscous behavior of the arterial wall and they are involved in the process of thickening of the intima-media complex, this study evaluates the relationship between carotid thickness and wall viscosity. The simultaneous and noninvasive assessment of the intima-media complex and arterial diameter waveform was performed using high-resolution ultrasonography. This technique was contrasted against sonomicrometry in sheep, showing that the waveforms obtained by both methods were similar. The common carotid arteries of 11 normotensive subjects (NTA) and 11 patients with mild to moderate essential hypertension (HTA) were measured noninvasively by using tonometry and an automatic densitometric analysis of B-mode images to obtain IMT and instantaneous pressure and diameter loops. A viscoelastic model was used to derive the wall viscosity index (eta) using the hysteresis loop elimination criteria. In NTA, eta was 2.73+/-1.66 (mm Hg x s/mm) and IMT was 0.58+/-0.08 (mm), whereas in HTA, eta was 5.91+/-2.34 (P<.025) and IMT was 0.70+/-0.12 (P<.025), respectively. When all data of eta versus IMT of NTA and HTA were pooled in a linear regression analysis, a correlation coefficient of r=.71 (P<.05) was obtained. Partial correlation between eta and IMT holding constant pressure was r=.59 (P<.05). In conclusion, wall viscosity increase was associated with a higher IMT even maintaining blood pressure fixed, suggesting that the intima-media thickening might be related to smooth muscle alterations manifested as an increase in viscous behavior.

Smart Damping Modulation of Carotid Wall Energetics in Human Hypertension Effects of Angiotensin-Converting Enzyme Inhibition

Damping is the conversion of mechanical energy of a structure into thermal energy, and it is related to the material viscous behavior. To evaluate the role of damping in the common carotid artery (CCA) wall in human hypertension and the possible improvement of angiotensin-converting enzyme (ACE) inhibition, we used noninvasive CCA pressure (tonometry) and diameter (B-mode echography) waveforms in normotensive subjects (NT group; n=12) and in hypertensive patients (HT group; n=22) single-blind randomized into HT–placebo (n=10) or HT-treated (ramipril, 5 to 10 mg/d during 3 months; n=12). Vascular smooth muscle (VSM) null tonus condition was achieved from in vitro pressure and diameter waveforms (Konigsberg microtransducer and sonomicrometry) measured in explanted human CCA (n=14). Arterial wall dynamics was described by viscous (&eegr;), inertial (M), and compliance (C) parameters, mean circumferential wall stress, viscous energy dissipation (WD), peak strain energy (WSt), damping ratio (&xgr;=WD/WSt), and modeling isobaric indexes CIso and WSt(Iso). The lack of VSM tonus isobarically increased wall stress and reduced &eegr;, CIso, and damping (P<0.01). Wall stress, &eegr;, and WD were greater in HT than in NT (P<0.015) and arrived near normal in HT-treated (P<0.032 respect to HT), with no changes in HT–placebo. Whereas CIso increased in HT-treated (P<0.01) approaching the NT level, &xgr; did not vary among groups. During hypertension, because of the WSt increase, the arterial wall reacts increasing WD to maintain &xgr;. ACE inhibition modulates VSM activation and vessel wall remodeling, significantly improving wall energetics and wall stress. This protective vascular action reduces extra load to the heart and maintains enhanced arterial wall damping.

Ambulatory Blood Pressure Values in the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET)

In the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial, telmisartan (T; 80 mg daily) and ramipril (R; 10 mg daily) caused similar clinic blood pressure (BP) reductions, with a similar incidence of cardiovascular and renal events. The R+T combination lowered clinic BP somewhat more with no further cardiovascular or renal protection. The aim of this substudy was to see whether these clinic BP changes reflected the changes of 24-hour BP, a BP with a better prognostic value. In 422 patients in whom 24-hour BP monitoring was performed either before or after 6 to 24 months of treatment, demographic and clinical characteristics were similar in the 3 treated groups. Twenty-four-hour systolic BP was similarly reduced by R (−2.0 mm Hg) and T (−2.1 mm Hg), whereas the reduction was more than twice as large in the T+R group (−5.3 mm Hg), which showed a lower on-treatment 24-hour BP also in additional patients (n=408) in whom ambulatory BP was performed only on-treatment. Twenty-four-hour systolic BP was ≈14 mm Hg lower than clinic systolic BP at baseline, whereas during treatment the 2 values became progressively closer as clinic systolic BP was more tightly controlled and superimposable when clinic systolic BP was <120 mm Hg. Similar results were obtained for diastolic BP. These findings provide evidence on the relationship of clinic and ambulatory BP target drug treatment. They also show that in the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial, failure of the R+T combination to enhance cardiovascular and renal protection was not because of inability to more effectively control daily life BP.

Arterial wall structure and dynamics in type 2 diabetes mellitus methodological aspects and pathophysiological findings.

Type 2 Diabetes Mellitus (DM), or adult-onset diabetes, is being considered as a new pandemic. Cardiovascular disease is the major cause of morbidity and mortality in type 2 DM, due to arterial structure and functional changes. Assessment of arterial structure and biomechanics, by non-invasive methods and parameters, can be used to detect early alterations related to DM. Three markers of vascular disease may help to a better evaluation of vascular dysfunction in type 2 DM patients: carotid intimamedia thickness (IMTc), arterial stiffness, assessed by pulse wave velocity (PWV), and endothelial function, evaluated through the brachial artery flow-mediated dilation (FMD). Among these parameters, IMTc is considered a marker of structural vessel wall properties, and arterial stiffness reflects functional wall properties. Endothelial function represents the arterial way to actively regulate its diameter (smooth muscle-dependent actions) and its visco-elastic properties (wall elasticity and viscosity). IMTc is increased in patients with type 2 DM and other independent risk factors, such as: age, hyperlipidemia and duration of DM. Subjects with DM have shown increased arterial stiffness. Type 2 DM is associated with reductions in FMD (endothelial dysfunction), which has already been reported to be inversely and strongly related to the extent of hyperglycemia. The underlying patho-physiological mechanisms are complex and remain to be fully elucidated. A complete understanding of the association between arterial alterations and early detection, and type 2 DM, may be critical for the primary prevention of DM-related macro-vascular disease.

Telmisartan improves insulin resistance in high renin nonmodulating salt-sensitive hypertensives.

Background Nonmodulating (NMHT) is a high-renin subtype of salt sensitive hypertension, which additionally develops insulin resistance and oxidative stress. Conversely, modulating hypertensives (MHT) normally regulates renal hemodynamics after high sodium intake without metabolic impairment. We postulate that telmisartan, an angiotensin receptor blocker with partial peroxisome proliferators-activated receptorγ partial agonist, may improve insulin resistance compared with ramipril, an angiotensin-converting enzyme inhibitor (ACEI) in NMHT. Methods We studied 18 NMTH (32 ± 5y nine men, BMI 29 ± 3 kg/m2) and 16 MHT (34 ± 4, 10 men, BMI 28 ± 5 kg/m2) before and after the crossover administration of ramipril 10 mg (3 months) or telmisartan 80 mg (3 months). In each patient studied we measured, before and after each treatment period, office blood pressure, glycemia and insulinemia before and 60 and 120 min after a glucose overload (75 g), total cholesterol, high-density lipoprotein and low-density lipoprotein fractions, triglycerides and highly sensitive C-protein-reactive protein. After that, HOMA-IR Index was calculated. Results Plasma renin activity was higher in NMHT 4.4 ± 0.5 than MHT 2.6 ± 0.9 ng.ml.h; P < 0.01. Blood pressure was similarly reduced either in MHT or NMHT by ramipril (MHT: from 159 ± 10/102 ± 4 to 142 ± 6/93 ± 3 mmHg, P < 0.05; NMHT: from 162 ± 12/97 ± 4 to 139 ± 7/89 ± 2 mmHg, P < 0.05) or telmisartan (MHT: from 154 ± 8/96 ± 5 to 137 ± 6/88 ± 4 mmHg, P < 0.05; NMHT: from 161 ± 9/96 ± 5 to 137 ± 5/86 ± 3 mmHg, P < 0.05). In NMHT, fasting glycemia (99 ± 10 mg%) and insulinemia (16 ± 4 μU%) and 120 min glycemia (110 ± 2 mg%) and insulinemia (57 ± 9 μU%) were higher than in MHT (fasting: 92 ± 8 mg% and 9.2 ± 2 mU%; 120 min: 95 ± 5 and 21 ± 5 μU%, P < 0.05). In MHT, after 3 months treatment with either ramipril or telmisartan no changes were found in fasting and 120 min glycemia and insulinemia. In NMHT, telmisartan, after 3 months treatment, significantly reduced fasting and 120 min insulinemia (fasting: 8.4 ± 2, 120 min: 25 ± 10 μU%; P < 0.01) compared either to basal values or ramipril treatment. Similarly, only in NMHT, compared with basal values and ramipril treatment, telmisartan improved the HOMA-IR index in both MHT (2.76 ± 0.16 to 2.24 ± 0.18, P < 0.05) and NMHT (from: 4.4 ± 1 to 2.3 ± 0.7) and triglyceride plasma levels (MHT: from 139 ± 1.85 to 122 ± 2.4 mg%, P < 0.05; NMHT: from: 223 ± 12 to 146 ± 10 mg%, P < 0.01). Finally, highly sensitive C-protein-reactive protein values were higher in NMHT (0.33 ± 0.07 mg.dl) than in MHT (0.14 ± 0.06 mg.dl; P < 0.01). Both treatments reduced highly sensitive C-protein-reactive protein in NMHT. (ramipril from 0.32 ± 0.05 mg.dl to 0.26 ± 0.06 m.dl (P < 0.05) and telmisartan from 0.34 ± 0.05± to 0.20 ± 0.05 mg.dl (P < 0.01). Conclusion Our data suggest that the improvement of the insulin sensitivity by telmisartan, instead of a similar effect on blood pressure shown by both drugs, could be ascribed to the PPAR agonistic action of telmisartan. This opens an interesting therapeutic approach for patients with hypertension and altered glycemic metabolism.

Latin American consensus on diabetes mellitus and hypertension.

Diabetes mellitus and hypertension, responsible of a major burden of cardiovascular complications, are increasing their incidence in Latin America in similar proportions to the rest of the world. The metabolic syndrome, a strong predictor of both diabetes and hypertension deserves more attention from the primary care physicians. Evidence based and updated guidelines on detection, prevention and treatment of diabetes and hypertension, issued by local experts, are willing to inform and translate these recommendations to the clinical practice of physicians assisting these patients throughout Latin America.

Guías Latinoamericanas de Hipertensión Arterial

Ramiro A. Sanchez, Miryam Ayala, Hugo Baglivo, Carlos Velazquez, Guillermo Burlando, Oswaldo Kohlmann, Jorge Jimenez, Patricio Lopez Jaramillo, Ayrton Brandao, Gloria Valdes, Luis Alcocer, Mario Bendersky, Agustin Jose Ramirez, Alberto Zanchetti, de parte del Grupo Latinoamericano de Expertos.

Carotid wall inertial index increase is related to intima-media thickening in hypertensive patients

OBJECTIVE The aim of this study is to evaluate the relationship between carotid intima-media thickness (IMT) and arterial wall inertial behaviour. METHODS The simultaneous and noninvasive assessment of the intima-media complex and arterial diameter waveform was performed using high-resolution ultrasonography. The common carotid artery of eleven normotensive subjects (NTA) and eleven mild-to-moderate essential hypertensive patients (HTA) were measured noninvasively using tonometry and an automatic densitometric analysis of B-mode images to obtain IMT and instantaneous pressure (P) and diameter (D) loops. A linear discrete time model was used to estimate the inertial index (K(M)) using a system modelling-identification approach. RESULTS In NTA K(M) was 0.333+/-0.256 (mmHg x s2/mm) and IMT 0.643+/-0.061 (mm), whereas in HTA K(M) was 0.798+/-0.590 (P < 0.05) and IMT 0.760+/-0.034 (P < 0.025). When all data of K(M) versus IMT of NTA and HTA were pooled in a linear regression analysis, a correlation coefficient of r = 0.61 (P < 0.05) was obtained. CONCLUSION Wall inertia increase was associated with a higher IMT, suggesting that the intima-media thickening might be partially related to vascular hypertrophy manifested as increase of inertial behaviour.