Prognostic association of circulating relaxin-2 in acute heart failure.

BACKGROUND: Despite the increasing interest in the study of the endogenous relaxin system in heart failure (HF), its role as a prognostic marker in acute HF remains unclear. We aimed to evaluate the association of relaxin-2 circulating levels with 6 months' mortality in acute HF. METHODS: We evaluated relaxin-2 serum levels at admission in a cohort of patients with acute HF (n = 202) using an enzyme immunoassay. The ability of relaxin-2 to predict all-cause death (primary outcome) and HF-specific death (secondary outcome) at 6 months was assessed using Cox-regression analysis. RESULTS: The median age was 79 (70-85) years old, 44% of the patients were male, and 43% had preserved ejection fraction (≥50%). Median serum relaxin-2 level was 25 pg/mL. Patients with higher relaxin-2 levels had more peripheral oedemas, higher sodium retention score, higher pulmonary artery pressures, higher prevalence of right ventricle dysfunction and lower inferior vena cava collapse at inspiration. Conversely, there was no association with left chambers parameters or with B-type natriuretic peptide (BNP). Higher relaxin-2 concentrations were associated with a higher risk of all-cause death [HR 1.15; 95%CI 1.01,1.30; P = 0.030] and HF-specific death [HR 1.21; 95% CI 1.03-1.42; P = 0.018], after adjustment for classical prognostic factors such as age, sex and BNP. CONCLUSIONS: In our acute HF population, relaxin-2 circulating levels were associated with clinical and echocardiographic markers of systemic congestion and with 6-months' mortality, independently of BNP. These results lay the groundwork for future investigations on the potential of relaxin-2 as an auxiliary biomarker in HF.

Exploring the use of ChatGPT in predicting anterior circulation stroke functional outcomes after mechanical thrombectomy: a pilot study.

BACKGROUND: Accurate prediction of functional outcomes is crucial in stroke management, but this remains challenging. OBJECTIVE: To evaluate the performance of the generative language model ChatGPT in predicting the functional outcome of patients with acute ischemic stroke (AIS) 3 months after mechanical thrombectomy (MT) in order to assess whether ChatGPT can used to be accurately predict the modified Rankin Scale (mRS) score at 3 months post-thrombectomy. METHODS: We conducted a retrospective analysis of clinical, neuroimaging, and procedure-related data from 163 patients with AIS undergoing MT. The agreement between ChatGPT's exact and dichotomized predictions and actual mRS scores was assessed using Cohen's κ. The added value of ChatGPT was measured by evaluating the agreement of predicted dichotomized outcomes using an existing validated score, the MT-DRAGON. RESULTS: ChatGPT demonstrated fair (κ=0.354, 95% CI 0.260 to 0.448) and good (κ=0.727, 95% CI 0.620 to 0.833) agreement with the true exact and dichotomized mRS scores at 3 months, respectively, outperforming MT-DRAGON in overall and subgroup predictions. ChatGPT agreement was higher for patients with shorter last-time-seen-well-to-door delay, distal occlusions, and better modified Thrombolysis in Cerebral Infarction scores. CONCLUSIONS: ChatGPT adequately predicted short-term functional outcomes in post-thrombectomy patients with AIS and was better than the existing risk score. Integrating AI models into clinical practice holds promise for patient care, yet refining these models is crucial for enhanced accuracy in stroke management.

Relaxin-2, pathophysiological insights and outcomes in heart failure with preserved ejection fraction: Findings from the NETDiamond cohort.

AIMS: The role of relaxin-2 as a circulating marker in heart failure (HF) with preserved ejection fraction (HFpEF) is poorly understood. We aimed to characterize relaxin-2 circulating levels in a population of chronic HFpEF patients and their association with long-term prognosis. METHODS: Relaxin-2 serum levels were measured in 85 chronic HFpEF patients from a prospective cohort study (NETDiamond). Clinical, imaging, and analytical data were compared across relaxin-2 tertiles. The primary outcome was a composite of cardiovascular death, HF hospitalisation, acute HF episode or diuretic intensification and the secondary outcome a composite of cardiovascular death and total HF hospitalisations. Cox regression and negative binomial models were used to assess the relation between relaxin-2 and the outcomes. RESULTS: Relaxin-2 levels were positively associated with left atrial volume, left ventricular mass and peripheral oedema, and negatively associated with ischemic heart disease and statin use. Higher relaxin-2 levels were associated with an increased risk of primary outcome, even after adjustment for age, B-type natriuretic peptide (BNP) and glomerular filtration rate (eGFR) (adjusted HR = 2.80, 95%CI 1.4-7.3, p = 0.034 for tertile 3). They were also associated with the occurrence of the secondary outcome (Incidence Rate Ratio = 5.28, 95%CI 1.2-23.2, p = 0.027), but this significance was lost when simultaneously adjusted for BNP and eGFR. CONCLUSION: In chronic HFpEF patients, higher relaxin-2 circulating levels were associated with left chambers remodelling, congestion, and adverse prognosis. These findings support a potential role for relaxin-2 as a pathophysiological agent and as a circulating biomarker in HFpEF.

Early anticoagulation in atrial fibrillation-related acute ischaemic stroke: efficacy and safety profile.

OBJECTIVES: To evaluate the effects of early anticoagulation on functional outcome, recurrent ischaemic events and haemorrhagic complications in Atrial Fibrillation (AF)-related acute ischaemic strokes (AIS). MATERIALS AND METHODS: We retrospectively evaluated patients hospitalised in a Stroke Unit due to AF-related AIS. Patients were divided according to anticoagulation initiation timing (0-4 days, 5-14 days, no anticoagulation by the 14th day). We assessed the following outcomes at 3 months: favourable functional outcome [modified Rankin Scale (mRS) score 0-2 or equal to pre-stroke], recurrent ischaemic events and haemorrhagic complications after anticoagulation initiation. RESULTS: We included 395 patients. Anticoagulation was initiated at days 0-4 in 33.9% of patients, days 5-14 in 25.3% and not initiated by the day 14 in 40.8%. Factors associated with earlier anticoagulation included lower previous mRS, valvular AF and lower stroke severity. Favourable functional outcome occurred in 40.2% of patients, with lower odds in those anticoagulated at 5-14 versus 0-4 days (OR: 0.47, 95% CI: 0.23-0.94), independently of age, previous mRS and stroke severity. Recurrent ischaemic events occurred in 8.3% of patients, with higher odds in non-anticoagulated patients by the 14th day, compared to the remainder groups (OR: 3.26, 95% CI: 1.29-8.22 vs. 0-4 days and OR: 8.16, 95% CI: 1.76-37.9 vs. 5-14 days). In patients who started anticoagulation (n = 288), haemorrhagic complications occurred in 10.8%, being more frequent in those who started at 0-4 days vs. > 14 days. However, it did not abolish the 0-4-day initiation's benefit on functional outcome. CONCLUSIONS: Early anticoagulation was associated with lower ischaemic recurrence and better functional outcome at 3 months. Additional studies are needed to better clarify its haemorrhagic risk.

Urocortin-2 in Acute Heart Failure: Role as a Marker of Volume Overload and Pulmonary Hypertension.

Urocortin (Ucn)-2 has shown promising therapeutic effects on heart failure (HF). However, there are still significant knowledge gaps regarding the role and modulation of the endogenous Ucn-2 axis in the cardiovascular system and, specifically, in acute HF. We evaluated Ucn-2 levels in admission serum samples of 80 acute HF patients and assessed their association with clinical, analytical and echocardiographic parameters. Median age was 76.5 years, and 37 patients (46%) were male. Median serum Ucn-2 was 2.3ng/mL. Ucn-2 levels were positively associated with peripheral edemas (P = 0.022), hepatomegaly (P = 0.007) and sodium retention score (ρ = 0.37, P = 0.001) and inversely correlated with inferior vena cava collapse at inspiration (ρ = -0.37, P = 0.001). Additionally, patients with higher Ucn-2 levels had a higher prevalence of right atrial dilation (P = 0.027), right ventricle dilation (P = 0.008), and higher systolic pulmonary artery pressure (ρ = 0.34, P = 0.002). Regarding analytical parameters, Ucn-2 correlated positively with log BNP (r = 0.22, P = 0.055) and inversely with uric acid (r = 0.24, P = 0.029) and total (r = -0.30, P = 0.007) and low-density lipoprotein cholesterol (r = -0.23, P = 0.038). No associations were found between Ucn-2 and age, sex or left heart structure or function. In conclusion, Circulating Ucn-2 was associated with clinical and echocardiographic markers of volume overload and pulmonary hypertension in acute HF patients.

Anticoagulation after intracerebral hemorrhage in patients with atrial fibrillation: between Scylla and Charybdis.

BACKGROUND: Oral anticoagulants (OAC) are indicated in patients with atrial fibrillation (AF) and high risk of ischemic stroke. However, the introduction of anticoagulation in patients with AF and previous intracerebral hemorrhage (ICH) is controversial. We aimed to better understand the efficacy and safety of OAC in this context and to assess the factors that may influence this decision. METHODS: In a single-center retrospective observational study, patients with AF and ICH who survived hospitalization at a level A Stroke Unit between 2009 and 2018 were included. Patients were followed for two years after discharge. Data were collected regarding the introduction or not of OAC and the occurrence of major thrombotic/hemorrhagic events and death. RESULTS: Ninety-five patients (75.2 ± 9.9 years) were included and 40 patients (42.1%) started OAC. Patients were more likely to initiate anticoagulation if they had: mechanical prosthetic valves, previous AF (p = 0.005) and previous OAC therapy (p < 0001); and less if they had previous hemorrhagic stroke (p < 0.005). During follow-up, 10.5% had at least one major hemorrhagic event (60% anticoagulated), 20% had at least one major thrombotic event (all non-anticoagulated) and 20% died. The only factor associated with the risk of bleeding was ICH score (OR:2.49 per 1-point increase; 95%CI:1.14-5.46). Patients who initiated anticoagulation had lower mortality than non-anticoagulated (OR:0.296; 95%CI:0.090-0-975). Previous ICH and higher CHA2DS2-VASc were associated with higher mortality. CONCLUSION: In this retrospective series, anticoagulation reduced thrombotic events and overall mortality in patients admitted for ICH and AF, without a significant increase in bleeding risk.

Outcomes of reperfusion therapy for acute ischaemic stroke in patients aged 90 years or older: a retrospective study.

The benefits and risks of acute reperfusion therapy (RT) in acute ischaemic stroke (AIS) remain uncertain in older patients, especially in nonagenarians. We aimed to assess the impact of RT in this population. Single-center retrospective cohort study comparing patients ≥ 90 years old admitted to a Stroke Unit (2008-2018) with AIS, submitted or not to RT [intravenous thrombolysis(IVT), mechanical thrombectomy(MT) or both]. Baseline characteristics, in-hospital complications and 3-month outcomes were compared. The primary outcome was 3-month "favorable outcome", defined as modified Rankin Scale score 0-2 or equal to pre-stroke. Secondary outcomes were haemorrhagic transformation (HT) and 3 months mortality. We included 167 patients (median age 92 years, 66.5% females); 46.1% underwent RT (59 IVT, 11 MT, 7 both). RT group had higher admission National Institutes of Health Stroke Scale (NIHSS) (16 versus 9.5, p < 0.001). Favorable outcome occurred in only 22% of patients, with no differences between groups; its odds decreased with higher NIHSS scores (OR 0.80, 95%CI 0.73-0.87, p < 0.001) and with the development of in-hospital respiratory infection (OR 0.22, 95%CI 0.07-0.67, p = 0.007). HT occurred in 16.2% of patients, being more prevalent (26.0% versus 7.8%, p = 0.001), symptomatic (14.3% versus 3.3%, p = 0.011) and severe (PH1/2 15.6% versus 2.2%, p = 0.012) in the RT group, although it did not influence the primary outcome. Mortality was 32% at 3 months, with no difference between groups. Although patients submitted to RT had worse admission NIHSS and increased HT, they had similar functional outcome at 3 months. Stroke severity and in-hospital respiratory infections were the most important predictors of 3 months' functional outcome.

Relaxin and the Cardiovascular System: from Basic Science to Clinical Practice.

The peptide hormone relaxin was originally linked to reproductive physiology, where it is believed to mediate systemic and renal hemodynamic adjustments to pregnancy. Recently, its broad range of effects in the cardiovascular system has been the focus of intensive research regarding its implications under pathological conditions and potential therapeutic potential. An understanding of the multitude of cardioprotective actions prompted the study of serelaxin, recombinant human relaxin-2, for the treatment of acute heart failure. Despite early promising results from phase II studies, recently revealed RELAX-AHF-2 outcomes were rather disappointing and the treatment for acute heart failure remains an unmet medical need. This article reviews the physiologic actions of relaxin on the cardiovascular system and its relevance in the pathophysiology of cardiovascular disease. We summarize the most updated clinical data and discuss future directions of serelaxin for the treatment of acute heart failure. This should encourage additional work to determine how can relaxin's beneficial effects be exploited for the treatment of cardiovascular disease.

Prognostic prediction in acute heart failure patients with extreme BNP values.

BACKGROUND: Some patients have good prognosis despite elevated B-type natriuretic peptide (BNP), while others have ominous outcome with low BNP. We aimed at characterising these groups of patients. METHODS: We analysed patients prospectively included in an acute HF registry. Vital status within 1-year post discharge was ascertained. A receiver-operating characteristic curve was used to define discharge BNP cut-offs for 1-year death prediction. Among survivors, we compared patients with low and not-low BNP (cut-off 400 pg/mL); and among non-survivors those with high vs not-high BNP (cut-off 2000 pg/mL). In the specific subgroups of patients with low and high BNP, mortality predictors were assessed with multivariate Cox-regression analysis. RESULTS: We studied 584 patients, median age 78 years, 62.5% had HF with reduced ejection fraction; and 199 (34.1%) died during the first year. Non-survivors were very homogeneous irrespective of BNP, survivors were substantially different. In patients discharged with BNP <400 pg/mL, increasing age independently predicted death; when BNP ≥2000 pg/mL death predictors were higher NYHA class, and non-use of evidence-based therapy. BNP was outcome associated in both groups. CONCLUSIONS: Different prognostic predictors may play a role in different BNP levels. We suggest that risk stratification in HF would probably be more accurate if made on top of BNP knowledge.

Relaxin serum levels in acute heart failure are associated with pulmonary hypertension and right heart overload.

AIMS: Despite the promising results of serelaxin as a new potential acute heart failure (HF) therapy, its clinical use preceded the understanding of the endogenous relaxin system in HF. We aimed to evaluate relaxin circulating levels in a population of acute HF and their association with clinical and echocardiographic parameters. METHODS AND RESULTS: We included 117 patients from a registry of acute HF. Admission serum relaxin was measured using an enzyme-linked immunosorbent assay (ELISA) kit. Clinical, analytical, and echocardiographic parameters were compared between patients with relaxin levels above and below the median. Median age was 82 years [interquartile range (IQR) 72-87], 41% of the patients were male, and 63% had systolic dysfunction. Median serum relaxin was 31.4 pg/mL (IQR 0.6-89.8). Patients with relaxin levels above the median had more peripheral oedema (89.8% vs. 68.4%, P = 0.004) and a significantly higher sodium retention score (mean 4.8 ± 1.5 vs. 3.6 ± 2.0, P < 0.001). These patients also had significantly higher systolic pulmonary arterial pressure [median 47.0 (IQR 36.0-61.0) vs. 34.5 (IQR 25.0-51.0) mmHg, P = 0.002], higher prevalence of right ventricular (RV) systolic dysfunction (28.1% vs. 10.3%, P = 0.02), RV dilation (31.0% vs. 5.3%, P < 0.001), and right atrial dilation (66.1% vs. 36.5%, P = 0.002), and less inferior vena cava diameter variability (40% vs. 60%, P = 0.009). No differences were noted regarding admission blood pressure, left chamber dimensions, or LV function. CONCLUSION: In our population of acute HF patients, admission relaxin serum levels were associated with clinical and echocardiographic markers of pulmonary hypertension, RV dysfunction, and overload, suggesting a role for circulating relaxin as a biomarker in this setting.

Is there a heart rate paradox in acute heart failure?

BACKGROUND: Higher heart rate predicts higher mortality in chronic heart failure (HF). We studied the prognostic impact of admission heart rate in acute HF and analysed the importance of its change during hospitalization. METHODS: Acute HF patients were studied. Endpoint was all-cause death. Patients were followed-up for 12 months from hospital admission. Cox-regression analysis was used to study the association of heart rate (both as a continuous and as a categorical variable) with mortality. Analysis was stratified according to admission rhythm and to systolic dysfunction. Multivariate models were built. Patients surviving hospitalization were additionally cross-classified attending to admission and discharge heart rates ­ cut-offs: 100 and 80 beats per minute (bpm), respectively. RESULTS: We analysed 564 patients. Median age was 78 years and median admission heart rate 87 bpm. In a 12-month period 205 patients died, 23 in-hospital. Mortality increased steadily with heart rate decrease. Patients with heart rate ≥ 100 bpm had a multivariate-adjusted HR of 12-month death of 0.57 (95%CI: 0.39-0.81), and the HR was 0.92 (0.85-0.98) per 10 bpm increase in heart rate. Association of heart rate with mortality was stronger in patients in sinus rhythm (SR) and in those with systolic dysfunction. Eighty-seven patients had admission heart rate ≥ 100 and discharge heart rate < 80 bpm. In them, death rate was 14.9%; in the remaining patients it was 37.7%. CONCLUSIONS: Higher admission heart rate predicted survival advantage in acute HF. Patients presenting with tachycardia and discharged with a controlled heart rate had better outcome than those admitted non-tachycardic or discharged with a non-controlled heart rate.

Predictors of Six-Month Mortality in BNP-Matched Acute Heart Failure Patients.

Natriuretic peptides have established prognostic value in heart failure (HF). The role of many other clinical and laboratory variables is still to be proved. The aim of this study was to assess prognostic determinants of death in acute HF in B-type natriuretic peptide (BNP)-matched patients. We conducted a case-control study to assess prognostic predictors of 6-month mortality in acute HF. From a prospectively recruited population of hospital-admitted patients with acute HF, we retrospectively selected a convenience sample of age-, gender-, and admission BNP-matched patients who survived (controls) or died (cases) in the follow-up period. Prognostic predictors of death were analyzed using a Cox regression analysis. A multivariate model was built. Variables in the model included atrial fibrillation, hypertension, admission heart rate, systolic blood pressure, the New York Heart Association class, hemoglobin, urea, albumin, systolic dysfunction, ischemic etiology, prognostic-modifying therapy, and BNP decrease during hospitalization. We analyzed 224 patients: 112 surviving and 112 not surviving a 6-month period. Median age was 80 years, 42.9% of the patients were men, and 63.9% had systolic dysfunction. Patients surviving the first 6 months had higher admission systolic blood pressure and heart rate, higher hemoglobin, lower urea, and more often had >30% decrease in BNP during hospitalization; they were more often discharged on HF prognostic modifying therapy. However, in multivariate analysis, the only independent mortality predictor was BNP decrease: patients in whom BNP decreased >30% had an HR of death of 0.57 (0.37 to 0.89). In conclusion, in BNP-matched patients with acute HF, the only independent mortality predictor is BNP decrease. Other literature suggested death predictors do not seem independent of natriuretic peptides.

Salt intake and type of intestinal metaplasia in Helicobacter pylori-infected Portuguese men.

The relation between salt intake and intestinal metaplasia (IM) types and the potential interaction with H. pylori virulence are poorly understood and may contribute to further understand gastric carcinogenesis. We quantified the association between dietary salt exposure and complete, incomplete, and mixed IM, taking into account the potential effect modification according to the virulence of H. pylori infecting strains. H. pylori-infected male volunteers (n = 233) underwent an upper digestive endoscopy and completed questionnaires comprising different measures of salt exposure (main food items/groups contributing to dietary salt intake, estimated dietary sodium intake, visual analogical scale for salt intake, preference for salty/salted foods). A histological diagnosis was assigned based on the most severe lesion observed. H. pylori virulence was assessed by characterizing vacA and cagA genes. Odds ratios were estimated through age- and education-adjusted logistic regression models. The risk of IM was not significantly increased in H. pylori infected subjects with higher levels of salt consumption. The lack of association was consistent across measures of salt exposure, categories of H. pylori virulence, and types of IM. In conclusion, in this H. pylori positive population, salt intake did not increase the risk of any IM type, regardless of the virulence of the infecting strains.

New pathways of the renin-angiotensin system: the role of ACE2 in cardiovascular pathophysiology and therapy.

IMPORTANCE OF THE FIELD: The renin-angiotensin system (RAS) is nowadays an important target in cardiovascular diseases and we are currently on the verge of a new interpretation of its role in cardiovascular homeostasis, mainly due to the identification of the new axis ACE2/angiotensin 1 - 7/Mas receptor. AREAS COVERED IN THIS REVIEW: The main aspects related to ACE2 role in cardiovascular physiology and possible pathological and therapeutic implications are reviewed. WHAT THE READER WILL GAIN: A description of the new view of the RAS, along with the key findings that support it. In the cardiovascular system, the ACE2/angiotensin 1 - 7/Mas axis, mainly through the inhibition of fibrosis, inflammation, thrombosis and cell proliferation, modulates RAS activity with significant pathophysiological implications in clinical conditions such as hypertension, myocardial ischemia and heart failure. A more complete understanding of this axis has significant therapeutic relevance and a major effort is being carried out in order to pursue this objective. TAKE HOME MESSAGE: There is increasing evidence that ACE2/angiotensin 1 - 7/Mas receptor axis has a key role in RAS activity regulation with significant pathophysiological implications in several disease states. A therapeutic intervention at this level may open new doors and change the current approach to RAS targeting.

Salt intake and risk of gastric intestinal metaplasia: systematic review and meta-analysis.

The understanding of the association between salt intake and precancerous lesions may contribute to clarify the causal relation with gastric cancer. We systematically reviewed 17 articles addressing the association between dietary salt exposure and gastric intestinal metaplasia and conducted meta-analyses for quantitative synthesis (random effects model). Salt exposure was estimated assessing salted/salty food consumption, preference for salted/salty foods, use of table salt, or sodium urinary excretion. Heterogeneity was also large regarding food items evaluated, consumption categories, and data analysis. The combined odds ratio (OR) was 1.68 (95% confidence interval (CI) = 0.98-2.90; I(2) = 55.4%) for the association between salted/salty meat and intestinal metaplasia (4 studies) and the OR was 1.53 (95% CI = 0.72-3.24; I(2) = 76.8%) for salt preference. There was a positive, nonstatistically significant association between intestinal metaplasia and urinary sodium excretion. The heterogeneity of methodological options and results preclude quantitative synthesis or its proper interpretation, even if the available evidence may suggest a positive association between salt and intestinal metaplasia.

Acute modulation of myocardial function by angiotensin 1-7.

Angiotensin 1-7 is a bioactive heptapeptide of the renin-angiotensin system. Its cardiovascular actions have recently acquired growing relevance, mainly due to its counter-regulatory actions in the angiotensin cascade. The aim of the present study was to evaluate the actions of angiotensin 1-7 on myocardial function. Increasing concentrations of angiotensin 1-7 (10(-9) to 10(-5)M) were added to rabbit right papillary muscles: (1) in baseline conditions with intact endocardial endothelium (EE); (2) after selective removal of the EE with Triton X-100 (1s, 0.01%); (3) with intact EE in the presence of the Mas receptor antagonist A-779, the AT(1) receptor antagonist ZD-7155, the AT(2) receptor antagonist PD-123,319 or the nitric oxide synthesis inhibitor NG-nitro-l-arginine (l-NA). Concerning the effects on contractility, we observed a significant decrease on active tension, dT/dt(max), peak shortening and dL/dt(max) of -10.5+/-3.6%, -8.0+/-3.0%, -5.3+/-2.6% and -5.7+/-2.3%, respectively. There was no change on relaxation parameters, namely dT/dt(min) or dL/dt(min). Time to half relaxation was significantly decreased. The presence of ZD-7155 or PD-123,319 did not change these effects. However, angiotensin 1-7 effects on myocardial properties were abolished after selective EE removal and in the presence of A-779 or l-NA. In conclusion, in this animal species, angiotensin 1-7 through its binding to Mas receptor induces a negative inotropic effect modulated by the EE and nitric oxide and independent of AT(1) or AT(2) receptors activation. As the effects described in the present work were influenced by the endocardial endothelium, they may be disrupted in situations associated to endothelial dysfunction, as in heart failure or myocardial ischemia.

Angiotensin II-induced increase in myocardial distensibility and its modulation by the endocardial endothelium in the rabbit heart.

As recently demonstrated, angiotensin II (Ang II) induces an increase in myocardial distensibility. Although endothelin-1 and the endocardial endothelium (EE) also modulate myocardial diastolic properties, their interaction with Ang II at this level has not yet been investigated. Increasing concentrations of Ang II (from 10(-8) to 10(-5) M) were studied in rabbit right papillary muscles in the following conditions: (1) baseline; (2) after selective removal of EE with Triton X-100; and (3) with intact EE in presence of a non-selective endothelin receptor antagonist (PD-145065), a selective endothelin type A receptor antagonist (BQ-123), an inhibitor of nitric oxide synthesis (N(G)-nitro-L-arginine (L-NA) or an inhibitor of the NAD(P)H oxidase (apocynin). At baseline, Ang II induced a concentration-dependent positive inotropic effect and an increase in passive muscle length (L) up to 1.020 +/- 0.004 L/L(max). After restoring muscle length to maximal physiological length (L(max)), passive tension decreased by 46.1 +/- 4.0%. When the EE was removed, the effect on myocardial distensibility was abolished. With intact EE in presence of PD-145065, BQ-123 or L-NA, the effects of Ang II on myocardial distensibility were attenuated, with a maximal increase in passive muscle length of 1.0087 +/- 0.0012, 1.0068 +/- 0.0022 and 1.0066 +/- 0.0020 L/L(max) and a decrease in resting tension of 22.6 +/- 3.6, 16.1 +/- 6.0 and 20.4 +/- 5.6%, respectively. In the presence of apocynin, the effect on myocardial distensibility was abolished. In conclusion, the Ang II-dependent acute increase in myocardial distensibility is abolished by the selective removal of the EE and attenuated in the presence of endothelin-1 receptor antagonists, an inhibitor of nitric oxide synthesis or an inhibitor of NAD(P)H oxidase.