Reuven Zimlichman

Clinical and hemodynamic effects of bosentan dose optimization in symptomatic heart failure patients with severe systolic dysfunction, associated with secondary pulmonary hypertension--a multi-center randomized study.

Objective: Toevaluate the effects of bosentan on echo-derived hemodynamic measurements, and clinical variables in symptomatic heart failure (HF) patients. Method: Multi- center, double-blind, randomized (2:1), placebo-controlled study comparing bosentan (8–125 mg b.i.d.) to placebo in patients with New York Heart Association class IIIb–IV HF, left ventricular ejection fraction <35% and systolic pulmonary artery pressure (SPAP) >40 mm Hg. Primary and secondary endpoints were change from baseline to 20 weeks in SPAP and cardiac index, respectively. Safety endpoints were treatment emergent adverse events (AEs), change in body weight, hemoglobin, hematocrit, systolic blood pressure and diuretic use. Results: Ninety-four patients enrolled: 60 to bosentan, 34 to placebo. There was no significant difference between the 2 arms in SPAP change (0.1 ± 11.5 mm Hg , 95% confidence limit (CL) –5.4 to 5.2, p = 0.97), cardiac index shift (0.12 ± 0.45, 95% CL –0.09 to 0.33 , p = 0.24 ) or any of the other 22 echocardigraphic measurements obtained. Therapy-duration was longer in the placebo arm, while more patients in the bosentan arm experienced adverse and serious AEs. Conclusion: In HF patients with left ventricular dysfunction and secondary pulmonary hypertension, bosentan did not provide any measurable hemodynamic benefit, and was associated with more frequent AEs, requiring drug discontinuation.

Effect of long-term treatment with antioxidants (vitamin C, vitamin E, coenzyme Q10 and selenium) on arterial compliance, humoral factors and inflammatory markers in patients with multiple cardiovascular risk factors.

BackgroundAntioxidant supplementations have the potential to alleviate the atherosclerotic damage caused by excessive production of reactive oxygen species (ROS). The present study evaluated the effects of prolonged antioxidant treatment on arterial elasticity, inflammatory and metabolic measures in patients with multiple cardiovascular risk factors.MethodsStudy participants were randomly assigned to two groups. Group 1 received oral supplementation with 2 capsules per day of Mid Life Guard, SupHerb, Israel. In each capsule vitamin C (500 mg) vitamin E (200 iu), co-enzyme Q10 (60 mg) and selenium (100 mcg), Group 2 received matching placebo(SupHerb) for 6 months. Patients were evaluated for lipid profile, HbA1C, insulin, C-peptide, hs-CRP, endothelin, aldosterone, plasma renin activity and Homeostasis model assessment-insulin resistance (HOMA-IR). Arterial elasticity was evaluated using pulse wave contour analysis (HDI CR 2000, Eagan, Minnesota).ResultsAntioxidant-treated patients exhibited significant increases in large arterial elasticity index (LAEI) as well as small arterial elasticity index (SAEI). A significant decline HbA1C and a significant increase in HDL-cholesterol were also observed. In the placebo group, significant changes in LAEI, SAEI or metabolic measures were not observed.ConclusionsAntioxidant supplementation significantly increased large and small artery elasticity in patients with multiple cardiovascular risk factors. This beneficial vascular effect was associated with an improvement in glucose and lipid metabolism as well as decrease in blood pressure.

Treatment with rosiglitazone reduces hyperinsulinemia and improves arterial elasticity in patients with type 2 diabetes mellitus

OBJECTIVEnThe aim of this study was to determine whether reduction of hyperinsulinemia with rosiglitazone will improve vascular elasticity in patients with non-insulin dependent diabetes mellitus.nnnMETHODSnIn an open label study 52 patients with non-insulin dependent diabetes mellitus and at least one additional cardiovascular risk factor, were treated for 6 months with 4 mg of rosiglitazone, and uptitrated to 8 mg after 3 months of treatment, if needed. At the beginning of the study and at its end, blood was drawn for insulin, C- peptide, and 24-h urine collected for microalbuminuria/proteinuria. Glucose, chemistry, lipid profile, and hemoglobin A1C were determined at 0, 3, and 6 months. Vascular compliance was measured in monthly intervals.nnnRESULTSnTreatment increased significantly small artery elasticity from 1.45 to 2.43 mL/mm Hg x 100. Large artery elasticity tended to increase toward the end of the study (P = not significant). Systolic blood pressure (BP)decreased from 144 to 124 mm Hg and diastolic BP decreased from 80 to 62.5 mm Hg, despite mild weight gain [corrected]. Heart rate tended to decrease from 76.3 to 74.7 beats/min (P = not significant). Systemic vascular resistance decreased from 1789.8 to 1329.4 dyne sec/cm(5). Plasma insulin, in patients not treated with insulin, decreased from 42.45 +/- 24.90 to 27.86 +/- 14.86 IU/mL (P =.0001).nnnCONCLUSIONSnTreatment with rosiglitazone reduced hyperinsulinemia and improved small artery elasticity with a tendency to improve large artery elasticity, in hypertensive and in normotensive patients. Because rosiglitazone improves insulin receptor sensitivity (IRS), it is logical to assume that the reduction in hyperinsulinemia reflects improvement in IRS. Our data support the hypothesis that hyperinsulinemia and IRS participate in the mechanisms of tissue injury and their improvement induces improvement in arterial elasticity.

Treatment with amlodipine andatorvastatin have additive effect in improvement of arterial compliance in hypertensive hyperlipidemic patients

BACKGROUNDnThis study investigates the effect of amlodipine on arterial compliance (AC), and the effect of atorvastatin on AC when given in combination with amlodipine.nnnMETHODSnTwenty-one consecutive hypertensive hyperlipidemic patients were included in this study. Patients were followed every month for 6 months (3 months of amlodipine therapy and 3 months of amlodipine and atorvastatin combination).nnnRESULTSnDuring the 3 months of amlodipine monotherapy, large and small AC were improved by 26% and 38%, respectively, and the systemic vascular resistance was reduced by 10%. The addition of atorvastatin during the next 3 months improved small AC by an additional 42% and decreased the systemic vascular resistance by another 5%, but large AC and blood pressure did not change.nnnCONCLUSIONSnAmlodipine improves large and small AC, and the beneficial effect of atorvastatin on small AC is additive to the effect achieved by amlodipine.

Prolonged treatment with the at1 receptor blocker, valsartan, increases small and large artery compliance in uncomplicated essential hypertension

BACKGROUNDnDecreased arterial compliance (AC) is considered an early marker of vascular wall damage. Hypertension gradually decreases arterial compliance. We studied whether treatment with the angiotensin type 1 (AT(1)) antagonist valsartan will affect AC in patients with essential hypertension (EH).nnnMETHODSnTwenty-two patients with EH, 6 men and 16 women, mean age 58.7 +/- 4.1 years, without overt target organ damage were included. Antihypertensive medications were withdrawn for 3 weeks, Valsartan was given at 80- and 160-mg doses. The AC, blood pressure (BP), blood, and urine were measured monthly. Large (C1) and small (C2) AC were derived from radial artery waveforms, obtained using a calibrated tonometer (model CR-2000, HDI Inc., Eagan, MN).nnnRESULTSnAfter 3 months, systolic BP decreased from 172 +/- 17 to 142 +/- 13 mm Hg (P <.0001) and diastolic BP from 95 +/- 9 to 82 +/- 8 mm Hg (P <.0001). The decrease in BP was significant within 1 month and improved further on. The C1 increased by 22%, from 8.0 +/- 3.1 to 9.7 +/- 2.3 mL/mm Hg x 10 (P <.01). The C2 increased by 35%, from 2.9 +/- 1.3 to 3.9 +/- 1.9 mL/mm Hg x 100 (P <.01). Both C1 and C2 reached statistical significance only after 3 months. Systemic vascular resistance (SVR) decreased by 15% from 2,140 +/- 376 to 1,817 +/- 262 dynes/sec/cm(-5) (P <.0001).nnnCONCLUSIONSnTreatment with valsartan in patients with EH improves small and large AC. The improvement in AC was significant only after 3 months of treatment, whereas systolic BP, diastolic BP, and SVR decreased earlier. The AT(1) receptor blockade with valsartan seems to be an effective means of not only lowering BP but of reversal of vascular wall damage, which predisposes to cardiovascular events.

Insulin induces medial hypertrophy of myocardial arterioles in rats

To investigate the effect of hyperinsulinemia on arteriolar hypertrophy, myocardial hypertrophy, and blood pressure, we administered insulin intraperitoneally to SHR and WKY rats for 3 consecutive weeks. To prevent hypoglycemia, the drinking water contained 10% sugar, and to accentuate the blood pressure, their chow contained 8% table salt. Blood pressure was measured by the tail-cuff method. Heart weights were factored with body weights. Arterioles of approximately 100 microns in diameter were examined at the end of the experiment and the vascular wall thickness was factored with the lumen diameter. At the end of 3 weeks, blood pressure rose in the SHR but not in the WKY rats. The heart weights in the WKY normotensive rats did not increase, whereas in the SHR they did. Furthermore, there was a significant rise in vessel wall thickness in the rats that received insulin, whether there was a rise in blood pressure or not and whether they had an increase in heart weight or not. There was a similar rise in blood glucose in all the groups, with slightly more accentuated rise in the SHR that received insulin. Nevertheless the increase in vascular wall thickness occurred only in the groups which received insulin. This seems to preclude the importance of hyperglycemia per se as the causative agent for the increase in vascular wall thickness in this study. The increase was in the form of medial hypertrophy without any sign of atherosclerosis. It seems, therefore, that hyperinsulinemia is associated with hypertrophy of the media of arterioles regardless of the increase in heart weight or the rise in blood pressure.

Ľanesthésie rachidienne et péridurale combinée, et péridurale seule, ont une incidence similaire ďhypotension lors de ľarthroplastie du genou

Objectif nNous avons emis ľhypothese que ľincidence ďhypotension pendant ľarthroplastie totale du genou (ATG) serait plus faible avec ľanesthesie rachidienne et peridurale combinee (RPC) qu’avec ľanesthesie peridurale seule.BackgroundWe hypothesized that the incidence of hypotension during total knee replacement (TKR) surgery is lower in patients given combined spinal-epidural (CSE) anesthesia vs those receiving epidural anesthesia alone.MethodsIn a prospective study, 80 American Society of Anesthesiologists I–II patients (aged 40–80 yr), undergoing elective TKR surgery were randomly assigned to either CSE anesthesia (CSE,n = 40) or epidural anesthesia alone (Epidural,n = 40). Hemodynamic measurements included oscillometric mean arterial blood pressure (MAP), heart rate (HR), and cardiac index (CI) as determined by thoracic bioimpedance; systemic vascular resistance (SVR) was calculated. Our primary endpoint (outcome) was the number of hypotension episodes (defined as MAP < 70 mmHg).ResultsUsing univariate analysis, we found no differences between the groups in regards to MAP, HR, CI, or SVR during the perioperative period. The incidence of hypotension was similar in both groups (two patients in each group), as was the incidence of bradycardia (12 patients in CSE, 7 in Epidural;P = 0.2). There were no differences between groups in other hemodynamic measurements including CI and calculated SVR. Analgesia supplementation with fentanyl was more frequently required in the Epidural group (20 vs 6 patients —P = 0.03).ConclusionCombined spinal-epidural anesthesia and epidural anesthesia alone during TKR surgery are associated with the same incidence of hypotension with statistically and clinically similar hemodynamic responses.RésuméObjectifNous avons émis ľhypothèse que ľincidence ďhypotension pendant ľarthroplastie totale du genou (ATG) serait plus faible avec ľanesthésie rachidienne et péridurale combinée (RPC) qu’avec ľanesthésie péridurale seule.MéthodeLors ďune étude prospective, 80 patients ďétat physique ASA I–II, de 40 à 80 ans, subissant une ATG réglée, ont été répartis aléatoirement pour recevoir une anesthésie RPC (groupe RPC, n = 40) ou péridurale seule (groupe péridural,n = 40). Les mesures hémodynamiques comprenaient la tension artérielle moyenne (TAM) oscillométrique, la fréquence cardiaque (FC) et ľindex cardiaque (IC) déterminé par la bio-impédance thoracique; la résistance vasculaire générale (RVG) a été calculée. Notre principal paramètre était le nombre ďépisodes ďhypotension définie par une TAM < 70 mmHg).RésultatsSelon une analyse univariée, il n’y avait aucune différence intergroupe quant à la TAM, la FC, ľIC ou la RVG périopératoires. Ľincidence ďhypotension était similaire dans les deux groupes (deux dans chaque groupe), aussi ľincidence de bradycardie (12 avec ľanesthésie RPC et 7 avec la péridurale; P = 0,2). Les autres mesures hémodynamiques ne présentaient pas de différence intergroupe, y compris ĽIC et la RVG calculée. Un supplément ďanalgésie avec du fentanyl a été plus souvent requis dans le groupe péridural (20 vs 6 patients — P = 0,03).ConclusionĽanesthésie rachidienne et péridurale combinée et ľanesthésie péridurale seule, utilisées pendant ľATG, sont associées à la même incidence ďhypotension et à des réactions hémodynamiques similaires au plan statistique et clinique.

Response to the Letter from Landman et al

The comments of Landman et al position three underpowered studies [1–3] and a review [4] as the main reliable evidence that should be considered in evaluating the paced breathing device RESPeRATE. According to the comments, almost all other studies performed with the device were inappropriately designed [4] or biased by being sponsored by the manufacturer of the device (originally stated by Mahtani el al. [5]). I am not aware of a clinical study dealing with a pharmaceutical product that was not sponsored by a Pharma company that manufactured the product. These studies are widely accepted and considered reliable. I do not see a reason to exclude studies sponsored by a company which produced the device. The relevant methodological question is how to evaluate the potential benefit of a self-treatment device added to the patient’s usual care in the real world. It is likely that the optimal way is to compare response to treatment added to that the benefits of usual care (approach 1). A widely accepted methodology is to use a control device that is not expected to have any therapeutic effect, i.e., a placebo or sham device, and to estimate the difference between the response to treatment by these devices as the “net effect” of the first intervention (approach 2). Another approach is to take as a control an “active comparator device” lacking one or more aspects of the treatment component assumed to contribute independently to the therapeutic effect (approach 3). In case such a control does have a therapeutic effect, the net effect clearly underestimates the efficacy of the treatment device as a whole. Unfortunately, most of the controlled studies with the device adopted approach 3, using different active comparator devices. In the meta-analysis done by Mahtani et al. [5], it is taken for granted these active comparator devices as “placebo devices” without justification, and defined the net effect as the device efficacy [5]. A number of studies on the RESPeRATE device did include controls that we consider appropriate for achieving the main goal (considered by Landman et al as inappropriate design). These included “waiting list” [6], and home BP measurement (after pre-baseline washout period) [7] that resulted in small and non-significant SBP reductions of 2.9 and 0.2 mmHg, respectively, that were also significantly smaller than the response to the treatment. This was the reason behind our decision to review in the present and previous analysis [8] both controlled and uncontrolled studies, as we believe that the response to treatment only was a fair estimation of the device’s antihypertensive effect for real patients, who add a self-treatment option to their usual care. In fact, the office SBP response to the treatment, as reported by Mahtani [5] was between 5.5 to 15.5 mmHg (including studies [1–3]), which are clinically important. The device interaction with its user involves at least 3 nonindependent components with assumed therapeutic potential: slow breathing, music adaptive to breathing movements, and voluntary synchronization between breathing and tones. Music is known to affect the cardiovascular and cerebral system in a complex way that largely depends on the nature and rhythm of the music; [9] the said synchronization has been shown to have a great antihypertensive effect [10].Therefore, the effect of the device depends also on the way it is used, e.g., high or low synchronization. Landman and Logtenberg et al consider their last study [3] as “the highest level of evidence” for using This reply refers to the comment available at doi: 10.1007/s11906-0170760-z.

Contents Vol. 109, 2008

E. Abadie, Saint Denis C.W. Akins, Boston, Mass. J.S. Alpert, Tucson, Ariz. E.A. Amsterdam, Sacramento, Calif. J.J. Badimon, New York, N.Y. A. Battler, Petah Tikva R. Becker, Durham, N.C. G.A. Beller, Charlottesville, Va. P.C. Block, Atlanta, Ga. R.O. Bonow, Chicago, Ill. J. Camm, London B. Carabello, Houston, Tex. K. Chatterjee, San Francisco, Calif. P.F. Cohn, Stony Brook, N.Y. M.H. Crawford, San Francisco, Calif. H. Cuénoud, Worcester, Mass. J.E. Dalen, Tucson, Ariz. S. Dalla Volta, Padova P.C. Deedwania, Fresno, Calif. A.N. De Maria, San Diego, Calif. P.S. Douglas, Durham, N.C. J.A. Eleft eriades, New Haven, Conn. U. Elkayam, Los Angeles, Calif. G. Ewy, Tucson, Ariz. M. Ezekowitz, Wynnewood, Pa. R. Ferrari, Milan G. Filippatos, Athens G.I. Fishman, New York, N.Y. K. Fox, London G.S. Francis, Cleveland, Ohio V. Fuster, New York, N.Y. B.J. Gersh, Rochester, Minn. W. Gersony, New York, N.Y. J. Gold, Toledo, Ohio R. Goldberg, Worcester, Mass. S. Goldberg, Philadelphia, Pa. M. Goldman, New York, N.Y. P.J. Goldschmidt, Miami, Fla. J. Gore, Worcester, Mass. T.H. Haghfelt, Odense J.L. Halperin, New York, N.Y. C.L. Hanis, Houston, Tex. S. Haunsø, Copenhagen Z.-X. He, Beijing