Effect of rufinamide on gating properties of voltage-gated sodium channel Na(v)1.7

Background: Voltage-gated sodium channels (Nav1.x) are important players in chronic pain. A particular interest has grown in Nav1.7, expressed in nociceptors, since mutations in its gene are associated to two inherited pain syndromes or insensitivity to pain. Rufinamide, a drug used to treat refractory epilepsy such as the Lennox-Gastaut syndrome, has been shown to reduce the number of action potentials in cortical neurons without completely blocking Na channels. Aim: The goal of this study was to investigate the effect of rufinamide on Nav1.7 current. Methods and results: Whole-cell patch clamp experiments were performed using HEK293 cells stably expressing Nav1.7. Rufinamide significantly decreased peak sodium current by 28.3, 21.2 and 12.5% at concentrations of 500, 100 and 50μM respectively (precise EC50 could not be calculated since higher rufinamide concentrations could not be achieved in physiological buffer solution). No significant difference on the V1/2 of voltage-dependence of activation was seen; however a shift in the steady-state inactivation curve was observed (-82.6 mV to -88.8 mV and -81.8 to -87.6 mV for 50 and 100 μM rufinamide respectively, p <0.005). Frequency-dependent inhibition of Nav1.7 was also influenced by the drug. One hundred μM rufinamide reduced the peak sodium current (in % of the peak current taken at the first sweep of a train of 50) from 90.8 to 80.8% (5Hz), 88.7 to 71.8% (10 Hz), 69.1 to 49.2% (25 Hz) and 22.3 to 9.8% (50 Hz) (all p <0.05). Onset of fast inactivation was not influenced by the drug since no difference in the time constant of current decay was observed. Conclusion: In the concentration range of plasma level in human treated for epilepsy, 15 μM, rufinamide only minimally blocks Nav1.7. However, it stabilizes the inactivated state and exerts frequencydependent inhibition of Nav1.7. These pharmacological properties may be of use in reducing ectopic discharges as a causal and symptom related contributor of neuropathic pain syndrome.

Comparative effects of GLP-1-(7-36) amide, oxyntomodulin and glucagon on rabbit gastric parietal cell function.

We have investigated in vitro, the effects of glucagon-like peptide-1-(7-36) amide (GLP-1-(7-36) amide), oxyntomodulin and glucagon on two rabbit parietal cell-enriched fractions (F3, F3n), with parietal cell contents of 60% and 88%, respectively. Histamine (10(-5) M) stimulated [14C]aminopyrine accumulation to an amount of 850% in excess of the basal level, whereas GLP-1-(7-36) amide (10(-7) M) and oxyntomodulin (10(-6) M) induced increases of 50% and 30%, respectively. With a histamine concentration of 10(-6) M, [14C]aminopyrine accumulation was stimulated to 498% in excess of the basal level; GLP-1-(7-36) amide (10(-7) M) and oxyntomodulin (10(-7) M) induced increases of 18% and 15%, respectively. With these parameters, oxyntomodulin[19-37] and glucagon were without effect. Specific binding of [125I]GLP-1-(7-36) amide to parietal cell plasma membranes was inhibited dose-dependently by GLP-1-(7-36) amide, oxyntomodulin and glucagon with inhibitory concentrations of 0.25 nM, 65 nM and 800 nM, respectively. No specific binding of [125I]oxyntomodulin or [125I]glucagon was detectable. GLP-1-(7-36) amide receptor mRNA was only detected in parietal cell-enriched fractions. GLP-1-(7-36) amide, oxyntomodulin and glucagon stimulated parietal cell cAMP production to similar maximal levels with median values close to 0.28 nM, 10.5 nM and 331.7 nM, whereas oxyntomodulin[19-37] had no effect. The maximal cAMP production induced by GLP-1-(7-36) amide, oxyntomodulin or glucagon was additive to that induced by histamine.(ABSTRACT TRUNCATED AT 250 WORDS)

Glucagon-like peptide-1-(7-36) amide, oxyntomodulin, and glucagon interact with a common receptor in a somatostatin-secreting cell line.

Glucagon-like peptide-1(7-36)amide (tGLP-1), oxyntomodulin (OXM), and glucagon are posttranslational end products of the glucagon gene expressed in intestinal L-cells. In vivo, these peptides are potent inhibitors of gastric acid secretion via several pathways, including stimulation of somatostatin release. We have examined the receptors through which these peptides stimulate somatostatin secretion using the somatostatin-secreting cell line RIN T3. tGLP-1, OXM, and glucagon stimulated somatostatin release and cAMP accumulation in RIN T3 cells to similar maximum levels, with ED50 values close to 0.2, 2, and 50 nM and 0.02, 0.3, and 8 nM, respectively. Binding of [125I]tGLP-1, [125I]OXM, and [125I]glucagon to RIN T3 plasma membranes was inhibited by the three peptides, with relative potencies as follows: tGLP-1 &gt; OXM &gt; glucagon. Whatever the tracer used, the IC50 for tGLP-1 was close to 0.15 nM and was shifted rightward for OXM and glucagon by about 1 and 2-3 orders of magnitude, respectively. Scatchard analyses for the three peptides were compatible with a single class of receptor sites displaying a similar maximal binding close to 2 pmol/mg protein. In the hamster lung fibroblast cell line CCL39 transfected with the receptor for tGLP-1, binding of [125I]tGLP-1 was inhibited by tGLP-1, OXM, and glucagon, with relative potencies close to those obtained with RIN T3 membranes. Chemical cross-linking of [125I]tGLP-1, [125I]OXM, and [125I]glucagon revealed a single band at 63,000 mol wt, the intensity of which was dose-dependently reduced by all three peptides. These data suggest that in the somatostatin-secreting cell line RIN T3, OXM and glucagon stimulate somatostatin release through a tGLP-1-preferring receptor. This suggests that some biological effects, previously described for these peptides, might be due to their interaction with this receptor.

Measurement of immunoreactive angiotensin-(1-7) heptapeptide in human blood.

BACKGROUND: The renal enzyme renin cleaves from the hepatic alpha(2)-globulin angiotensinogen angiotensin-(1-10) decapeptide [Ang-(1-10)], which is further metabolized to smaller peptides that help maintain cardiovascular homeostasis. The Ang-(1-7) heptapeptide has been reported to have several physiological effects, including natriuresis, diuresis, vasodilation, and release of vasopressin and prostaglandins. METHODS: To investigate Ang-(1-7) in clinical settings, we developed a method to measure immunoreactive (ir-) Ang-(1-7) in 2 mL of human blood and to estimate plasma concentrations by correcting for the hematocrit. A sensitive and specific antiserum against Ang-(1-7) was raised in a rabbit. Human blood was collected in the presence of an inhibitor mixture including a renin inhibitor to prevent peptide generation in vitro. Ang-(1-7) was extracted into ethanol and purified on phenylsilylsilica. The peptide was quantified by radioimmunoassay. Increasing doses of Ang-(1-7) were infused into volunteers, and plasma concentrations of the peptide were measured. RESULTS: The detection limit for plasma ir-Ang-(1-7) was 1 pmol/L. CVs for high and low blood concentrations were 4% and 20%, respectively, and between-assay CVs were 8% and 13%, respectively. Reference values for human plasma concentrations of ir-Ang-(1-7) were 1.0-9.5 pmol/L (median, 4.7 pmol/L) and increased linearly during infusion of increasing doses of Ang-(1-7). CONCLUSIONS: Reliable measurement of plasma ir-Ang-(1-7) is achieved with efficient inhibition of enzymes that generate or metabolize Ang-(1-7) after blood sampling, extraction in ethanol, and purification on phenylsilylsilica, and by use of a specific antiserum.

Daily physical activities and sports in adult survivors of childhood cancer and healthy controls: a population-based questionnaire survey.

BACKGROUND: Healthy lifestyle including sufficient physical activity may mitigate or prevent adverse long-term effects of childhood cancer. We described daily physical activities and sports in childhood cancer survivors and controls, and assessed determinants of both activity patterns. METHODOLOGY/PRINCIPAL FINDINGS: The Swiss Childhood Cancer Survivor Study is a questionnaire survey including all children diagnosed with cancer 1976-2003 at age 0-15 years, registered in the Swiss Childhood Cancer Registry, who survived ≥5 years and reached adulthood (≥20 years). Controls came from the population-based Swiss Health Survey. We compared the two populations and determined risk factors for both outcomes in separate multivariable logistic regression models. The sample included 1058 survivors and 5593 controls (response rates 78% and 66%). Sufficient daily physical activities were reported by 52% (n = 521) of survivors and 37% (n = 2069) of controls (p<0.001). In contrast, 62% (n = 640) of survivors and 65% (n = 3635) of controls reported engaging in sports (p = 0.067). Risk factors for insufficient daily activities in both populations were: older age (OR for ≥35 years: 1.5, 95CI 1.2-2.0), female gender (OR 1.6, 95CI 1.3-1.9), French/Italian Speaking (OR 1.4, 95CI 1.1-1.7), and higher education (OR for university education: 2.0, 95CI 1.5-2.6). Risk factors for no sports were: being a survivor (OR 1.3, 95CI 1.1-1.6), older age (OR for ≥35 years: 1.4, 95CI 1.1-1.8), migration background (OR 1.5, 95CI 1.3-1.8), French/Italian speaking (OR 1.4, 95CI 1.2-1.7), lower education (OR for compulsory schooling only: 1.6, 95CI 1.2-2.2), being married (OR 1.7, 95CI 1.5-2.0), having children (OR 1.3, 95CI 1.4-1.9), obesity (OR 2.4, 95CI 1.7-3.3), and smoking (OR 1.7, 95CI 1.5-2.1). Type of diagnosis was only associated with sports. CONCLUSIONS/SIGNIFICANCE: Physical activity levels in survivors were lower than recommended, but comparable to controls and mainly determined by socio-demographic and cultural factors. Strategies to improve physical activity levels could be similar as for the general population.

Fatty acids decrease IDX-1 expression in rat pancreatic islets and reduce GLUT2, glucokinase, insulin, and somatostatin levels.

IDX-1 (islet/duodenum homeobox-1) is a transcription factor expressed in the duodenum and pancreatic beta and delta cells. It is required for embryonic development of the pancreas and transactivates the Glut2, glucokinase, insulin, and somatostatin genes. Here we show that exposure of isolated rat pancreatic islets to palmitic acid induced a approximately 70% decrease in IDX-1 mRNA and protein expression as well as 40 and 65% decreases in the binding activity of IDX-1 for its cognate cis-regulatory elements of the Glut2 and insulin promoters, respectively. The inhibitory effect of palmitic acid required its mitochondrial oxidation since it was prevented by the carnitine palmitoyltransferase I inhibitor bromopalmitic acid. The palmitic acid effect on IDX-1 was correlated with decreases in GLUT2 and glucokinase expression of 40 and 25%, respectively, at both the mRNA and protein levels. Insulin and somatostatin mRNA expression was also decreased by 40 and 60%, whereas glucagon mRNA expression was not modified. After 48 h of exposure to fatty acids, total islet insulin, somatostatin, and glucagon contents were decreased by 85, 55, and 65%, respectively. At the same time, total hormone release was strongly stimulated (13-fold) for glucagon, whereas its was only marginally increased for insulin and somatostatin (1.5- and 1.7-fold, respectively). These results indicate that elevated fatty acid levels 1) negatively regulate Idx-1 expression; 2) decrease the expression of genes transactivated by IDX-1 such as those for GLUT2, glucokinase, insulin, and somatostatin; and 3) lead to an important increase in glucagon synthesis and secretion. Fatty acids thus have pleiotropic effects on pancreatic islet gene expression, and the negative control of Idx-1 expression may be an initial event in the development of these multiple defects.

First-line temozolomide combined with bevacizumab in metastatic melanoma: a multicentre phase II trial (SAKK 50/07).

BACKGROUND: Oral temozolomide has shown similar efficacy to dacarbazine in phase III trials with median progression-free survival (PFS) of 2.1 months. Bevacizumab has an inhibitory effect on the proliferation of melanoma and sprouting endothelial cells. We evaluated the addition of bevacizumab to temozolomide to improve efficacy in stage IV melanoma. PATIENTS AND METHODS: Previously untreated metastatic melanoma patients with Eastern Cooperative Oncology Group performance status of two or more were treated with temozolomide 150 mg/m(2) days 1-7 orally and bevacizumab 10 mg/kg body weight i.v. day 1 every 2 weeks until disease progression or unacceptable toxicity. The primary end point was disease stabilisation rate [complete response (CR), partial response (PR) or stable disease (SD)] at week 12 (DSR12); secondary end points were best overall response, PFS, overall survival (OS) and adverse events. RESULTS: Sixty-two patients (median age 59 years) enrolled at nine Swiss centres. DSR12 was 52% (PR: 10 patients and SD: 22 patients). Confirmed overall response rate was 16.1% (CR: 1 patient and PR: 9 patients). Median PFS and OS were 4.2 and 9.6 months. OS (12.0 versus 9.2 months; P = 0.014) was higher in BRAF V600E wild-type patients. CONCLUSIONS: The primary end point was surpassed showing promising activity of this bevacizumab/temozolomide combination with a favourable toxicity profile. Response and OS were significantly higher in BRAF wild-type patients.

Is the GraftConnector a valid alternative to running suture in end-to-side coronary arteries anastomoses?

BACKGROUND: An animal study was carried out to compare long-term patency rates of coronary anastomoses performed with the GraftConnector versus running suture technique. METHODS: 10 sheep, 45 to 55 kg, underwent off-pump coronary artery bypass grafting (right internal mammary artery to left anterior descending artery). In 5 animals, the anastomosis was performed with a GraftConnector and in 5 animals with 7-0 running suture. Intraoperative fluoroscopy and a fluoroscopic control at 6 months were performed. After 6 months, the animals were sacrificed and the anastomoses were examined histologically. RESULTS: All animals survived at 6 months with 100% anastomosis patency rates in both groups. In the GraftConnector group, the anastomosis diameter at 6 months fluoroscopy was 118% of native left anterior descending artery versus 97% of the control group. Luminal anastomotic width at histology was 1.7 +/- 0.2 mm in the device group versus 1.6 +/- 0.1 mm in the control group. Mean intimal hyperplasia thickness was 0.21 +/- 0.1 mm in the device group versus 0.01 mm in the control group. CONCLUSIONS: The GraftConnector provides a consistent and reproducible coronary artery anastomosis and reduces technical demand and manual dexterity in coronary operations. Long-term results demonstrate that off-pump coronary artery bypass grafting performed with the GraftConnector had the same patency rate and luminal width as those performed with running suture.

Extent of hypoattenuation on CT angiography source images in basilar artery occlusion: prognostic value in the Basilar Artery International Cooperation Study.

BACKGROUND AND PURPOSE: The posterior circulation Acute Stroke Prognosis Early CT Score (pc-ASPECTS) quantifies the extent of early ischemic changes in the posterior circulation with a 10-point grading system. We hypothesized that pc-ASPECTS applied to CT angiography source images predicts functional outcome of patients in the Basilar Artery International Cooperation Study (BASICS). METHODS: BASICS was a prospective, observational registry of consecutive patients with acute symptomatic basilar artery occlusion. Functional outcome was assessed at 1 month. We applied pc-ASPECTS to CT angiography source images of patients with CT angiography for confirmation of basilar artery occlusion. We calculated unadjusted and adjusted risk ratios (RRs) of pc-ASPECTS dichotomized at ≥8 versus <8. Primary outcome measure was favorable outcome (modified Rankin Scale scores 0-3). Secondary outcome measures were mortality and functional independence (modified Rankin Scale scores 0-2). RESULTS: Of 158 patients included, 78 patients had a CT angiography source images pc-ASPECTS≥8. Patients with a pc-ASPECTS≥8 more often had a favorable outcome than patients with a pc-ASPECTS<8 (crude RR, 1.7; 95% CI, 0.98-3.0). After adjustment for age, baseline National Institutes of Health Stroke Scale score, and thrombolysis, pc-ASPECTS≥8 was not related to favorable outcome (RR, 1.3; 95% CI, 0.8-2.2), but it was related to reduced mortality (RR, 0.7; 95% CI, 0.5-0.98) and functional independence (RR, 2.0; 95% CI, 1.1-3.8). In post hoc analysis, pc-ASPECTS dichotomized at ≥6 versus <6 predicted a favorable outcome (adjusted RR, 3.1; 95% CI, 1.2-7.5). CONCLUSIONS: pc-ASPECTS on CT angiography source images independently predicted death and functional independence at 1 month in the CT angiography subgroup of patients in the BASICS registry.

The significance of pre-existing minority Y181C mutations on virological failure of NNRTI-based, first-line antiretroviral therapy

Background: Reduced re'nal function has been reported with tenofovir disoproxil fumarate (TDF). It is not clear whether TDF co-administered with a boosted protease inhibitor (PI) leads to a greater decline in renal function than TDF co-administered with a non-nucleoside reverse transcriptase inhibitor (NNRTI).Methods: We selected ail antiretroviral therapy-naive patients in the Swiss HIV Cohort Study (SHCS) with calibrated or corrected serum creatinine measurements starting antiretroviral therapy with TDF and either efavirenz (EFV) or the ritonavir-boosted PIs, lopinavir (LPV/r) or atazanavir (ATV/r). As a measure of renal function, we used the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation to estimate the glomerular filtration rate (eGFR). We calculated the difference in eGFR over time between two therapies using a marginal model for repeated measures. In weighted analyses, observations were weighted by the product of their point of treatment and censoring weights to adjust for differences both in the sort of patients starting each therapy and in the sort of patients remaining on each therapy over time.Results: By March 2011, 940 patients with at least one creatinine measurement on a first therapy with either TDF and EFV (n=484), TDF and LPVlr (n=269) or TDF and ATV/r (n=187) had been followed for a median of 1. 7, 1.2 and 1.3 years, respectively. Table 1 shows the difference in average estimated GFR (eGFR) over time since starting cART for two marginal models. The first model was not adjusted for potential confounders; the second mode! used weights to adjust for confounders. The results suggest a greater decline in renal function during the first 6 months if TDF is used with a PI rather than with an NNRTI, but no further difference between these therapies after the first 6 months. TDF and ATV/r may lead to a greater decline in the first 6 months than TDF and LPVlr.Conclusions: TDF co-administered with a boosted PI leads to a greater de cline in renal function over the first 6 months of therapy than TDF co-administered with an NNRTI; this decline may be worse with ATV/r than with LPV/r.

Prévention des adhérences péricardiques avec une membrane biorésorbable [Prevention of pericardial adhesions with a bioresorbable membrane]

A bioresorbable membrane made of sodium hyaluronate and carboxymethycellulose, has been reported to prevent peritoneal adhesion. This study was designed to test its efficiency in the prevention of pericardial adhesions. Two groups of six pigs (mean weight 72 +/- 8 kg) were chosen for the experiment. The heart was exposed through a left thoracotomy and a wide patch of pericardium was excised. In the test group (n = 6), the left ventricular area without pericardium was divided into two areas: area A where six stitches of Prolene were performed, and area B which was left intact. The membrane was applied on the both areas as well as on the adjacent area covered with pericardium (area C). In the control group (n = 6), the same protocol was performed except for the membrane application. The animals were sacrificed one month later. The adhesion status as well as the visibility of the coronary anatomy was assessed according to severity scores ranging from 0 to 3 for the adhesions and from 0 to 2 for the visibility. The difference between groups was considered significant when p < 0.05. The adhesion score of the area A was 1.7 +/- 0.5 in the test group versus 2.5 +/- 0.5 in the control group (p = 0.02) and the visibility score was 1.3 +/- 0.8 and 2 +/- 0 respectively (p = 0.07). In the area B, the adhesion score was 1 +/- 0 in the test group versus 2 +/- 0.6 in the control group (p = 0.03) and the visibility score was 0.7 +/- 0.5 and 2 +/- 0 respectively (p = 0.001). Lastly, in the area C, the adhesion score was 1 +/- 0 in both groups (n.s.) and the visibility score was 0.7 +/- 0.4 in the test group versus 0.5 +/- 0.5 in the control group (n.s.). In this animal model, the role of the bioresorbable membrane in the prevention of pericardial adhesions is limited to the areas without pericardial cover and without foreign material. The presence of foreign material neutralizes its effect.

Incidence and risk factors for Contegra graft infection following right ventricular outflow tract reconstruction: long-term results.

OBJECTIVES: The aim of this study was to evaluate the risk factors associated with Contegra graft (Medtronic Minneapolis, MN, USA) infection after reconstruction of the right ventricular outflow tract. METHODS: One hundred and six Contegra grafts were implanted between April 1999 and April 2010 for the Ross procedure (n = 46), isolated pulmonary valve replacement (n = 32), tetralogy of Fallot (n = 24), double-outlet right ventricle (n = 7), troncus arteriosus (n = 4), switch operation (n = 1) and redo of pulmonary valve replacement (n = 2). The median age of the patients was 13 years (range 0-54 years). A follow-up was completed in all cases with a median duration of 7.6 years (range 1.7-12.7 years). RESULTS: There were 3 cases of in-hospital mortality. The survival rate during 7 years was 95.7%. Despite the lifelong endocarditis prophylaxis, Contegra graft infection was diagnosed in 12 (11.3%) patients at a median time of 4.4 years (ranging from 0.4 to 8.7 years). Univariate analysis of preoperative, perioperative and postoperative variables was performed and the following risk factors for time to infection were identified: female gender with a hazard ratio (HR) of 0.19 (P = 0.042), systemic-to-pulmonary shunt (HR 6.46, P < 0.01), hypothermia (HR 0.79, P = 0.014), postoperative renal insufficiency (HR 11.97, P = 0.015) and implantation of permanent pacemaker during hospitalization (HR 5.29, P = 0.075). In 2 cases, conservative therapy was successful and, in 10 patients, replacement of the infected valve was performed. The Contegra graft was replaced by a homograft in 2 cases and by a new Contegra graft in 8 cases. Cox's proportional hazard model indicated that time to graft infection was significantly associated with tetralogy of Fallot (HR 0.06, P = 0.01), systemic-to-pulmonary shunt (HR 64.71, P < 0.01) and hypothermia (HR 0.77, P < 0.01). CONCLUSION: Contegra graft infection affected 11.3% of cases in our cohort, and thus may be considered as a frequent entity that can be predicted by both intraoperative and early postoperative factors. After the diagnosis of infection associated with the Contegra graft was confirmed, surgical treatment was the therapy of choice.

Are there vascular density gradients along myocardial laser channels?

BACKGROUND: Clinical studies suggest that transmyocardial laser revascularization may improve regional blood flow of the subendocardial layer. The vascular growth pattern of laser channels was analyzed. METHODS: Twenty pigs were randomized to undergo ligation of left marginal arteries (n = 5), to undergo transmyocardial laser revascularization of the left lateral wall (n = 5), to undergo both procedures (n = 5) or to a control group (n = 5). All the animals were sacrificed after 1 month. Computed morphometric analysis of vascular density of the involved area was expressed as number of vascular structures per square millimeter (+/-1 standard deviation). RESULTS: The vascular density of the scar tissue of the laser channel was significantly increased in comparison with myocardial infarction alone: 49.6+/-12.8/mm2 versus 25.5+/-8.6/mm2 (p < 0.0001). The vascular densities of subendocardial and subepicardial channel areas were similar: 52.9+/-16.8/mm2 versus 46.3+/-13.6/mm2 (p = 0.41). The area immediately adjacent to the channels showed a vascular density similar to that of normal tissue: 6.02+/-1.7/mm2 versus 5.2+/-1.9/mm2 (p = 0.08). In the infarction + transmyocardial laser revascularization group, the channels were indistinguishable from infarction scar. CONCLUSIONS: Scars of transmyocardial laser revascularization channels exhibit an increased vascular density in comparison with scar tissue of myocardial infarction, which does not extend into their immediate vicinity. There was no vascular density gradient along the longitudinal axis of the channels.

Reshaping the remodelled left ventricle: a new concept.

OBJECTIVE: Based on the law of Laplace, transventricular tension members were designed to diminish wall stress by changing the left ventricle (LV) globular shape to a bilobular one, thus reducing the ventricular wall radius of curvature. This concept was tested in a model of congestive heart failure. METHODS: Seven calves were used for the study (74.3+/-4.2 kg). Treatment efficacy was assessed with sonomicrometric wall motion analysis coupled with intraventricular pressure measurement. Preload increase was applied stepwise with tension members in released and tightened position. RESULTS: Tightening of the tension members improved systolic function for CVP>10 mmHg (dP/dt: 828+/-122 vs. 895+/-112 mmHg/s, P=0.019, for baseline and 20% stress level reduction respectively; wall thickening: 11.6+/-1.5 vs. 13.3+/-1.7%, P<0.001) and diastolic function (LV end-diastolic pressure: 15.9+/-4.8 vs. 13.6+/-2.7 mmHg, P<0.001, for CVP>10 mmHg; peak rate of wall thinning: -12.2+/-2.2 vs. -14+/-2.3 cm(2)/s, P<0.001 and logistic time constant of isovolumic relaxation: 48.4 +/-10.9 vs. 39.8+/-9.6ms, P<0.001, for CVP>5 mmHg). CONCLUSIONS: This less aggressive LV reduction method significantly improves contractility and relaxation parameters in this model of congestive heart failure.