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BACKGROUND: In congestive heart failure with water retention, subtraction of body fluid by ultrafiltration causes greater diuresis and clinical improvement in patients who are angiotensin-converting enzyme (ACE)-inhibited, suggesting an influence of ACE inhibitors on fluid metabolism. METHODS AND RESULTS: Patients with moderate congestive heart failure were subjected to ultrafiltration (around 2000 mL) and followed up for 3 months. Usual outpatient therapy, consisting of digoxin, furosemide, and ACE inhibitors (18 patients, group A) and of digoxin and furosemide only (18 patients, group B), was continued throughout the trial. Hemodynamics, renal function, body fluid and electrolytes, plasma norepinephrine, renin activity, aldosterone, and plasma volume were monitored. At 30 and 90 days after ultrafiltration, hormones, renal function, functional capacity (based on cardiopulmonary tests), and extravascular lung water (chest radiograph score) were determined. Soon after ultrafiltration, body weight, plasma volume, and diuresis were reduced (hypovolemia) and hormones were raised (reaction to hypovolemia). In the next 4 days, all these variables reverted to the pre-ultrafiltration values in group B; in group A diuresis and plasma volume recovered, body weight was still reduced, and hormones became lower than baseline. These changes persisted in the next 3 months. An early reduction of extravascular lung water continued long term in group A only, associated with increase of exercise tolerance time and oxygen uptake and decrease of the dead space/tidal volume ratio. CONCLUSIONS: In congestive heart failure, ACE inhibition persistently prevented fluid accumulation once the excess of body fluid had been withdrawn with a nonpharmacologic method, resulting in sustained improvement in functional capacity. Reduction in circulating norepinephrine, aldosterone, and renin did not seem to be the cause but the consequence of this action, whose mechanisms remain undefined. [ABSTRACT FROM AUTHOR]

Objectives: This study sought to test whether insulin improves exercise ventilatory efficiency (VE/VCO2 slope) and oxygen uptake at peak exercise (peak VO2) in patients with type 2 diabetes-heart failure (HF) comorbidity.Background: In type 2 diabetes-HF comorbidity, depression of alveolar-capillary diffusion (DL(CO)) correlates with deterioration of exercise VE/VCO2 slope and peak VO2. Insulin potentiates DL(CO) in these patients.Methods: Exercise ventilatory efficiency and peak VO2 (cycle ergometry ramp protocol), as well as DL(CO) at rest and its subdivisions (membrane conductance [D(M)] and pulmonary capillary blood volume [V(C)]) were assessed in 18 patients with type 2 diabetes-HF comorbidity at baseline and after 50 ml of saline + regular insulin (10 IU), or saline, was infused on consecutive days, according to a random crossover design. Glycemia was kept at pre-insulin level for the experiment duration.Results: Baseline DL(CO), D(M), peak VO2, and VE/VCO2 slope were compromised in these patients. At measurements performed in the 60 min after infusions, compared with at baseline, saline was ineffective, whereas insulin augmented peak VO2 (+13.5%) and lowered VE/VCO(2) slope (-18%), and also increased time to anaerobic threshold (+29.4%), maximal O2 pulse (+12.3%), aerobic efficiency (+21.2%), DL(CO) (+12.5%), and D(M) (+21.6%), despite a reduction in V(C) (-16.3%); insulin did not vary cardiac index and ejection fraction at rest. Changes in peak VO2 and VE/VCO2 slope (r = 0.67, p = 0.002; r = -0.73, p < 0.001, respectively) correlated with those in DL(CO). These responses were unrelated to glycohemoglobin and baseline fasting blood sugar. They were persistent at 6 h after insulin infusion, and were undetectable at 24 h.Conclusions: In diabetes-HF comorbidity, insulin causes a prolonged improvement in physical performance through activation of multiple factors, among which facilitation of gas conductance seems to be predominant. [ABSTRACT FROM AUTHOR]

Background: In heart failure (HF), a defective nitric oxide signaling is involved in left ventricular (LV) diastolic abnormalities and remodeling. PDE5 inhibition, by blocking degradation of nitric oxide second-messenger cyclic guanosine monophosphate, might be beneficial. In a cohort of systolic HF patients, we tested the effects of PDE5 inhibition (sildenafil) on LV ejection fraction, diastolic function, cardiac geometry, and clinical status., Methods and Results: Forty-five HF patients (New York Heart Association class II-III) were randomly assigned to placebo or sildenafil (50 mg three times per day) for 1 year, with assessment (6 months and 1 year) of LV ejection fraction, diastolic function, geometry, cardiopulmonary exercise performance, and quality of life. In the sildenafil group only, at 6 months and 1 year, LV ejection fraction, early diastolic tissue Doppler velocities (E') at the mitral lateral (from 4.62 to 5.20 and 5.19 m/s) and septal (from 4.71 to 5.23 and 5.24 m/s) annuli significantly increased, whereas the ratio of early transmitral (E) to E' lateral decreased (from 13.1 to 9.8 to 9.4) (P<0.01). Changes were accompanied by a reverse remodeling of left atrial volume index (from 32.0 to 29.0 and 29.1 mL/m(2); P<0.01) and LV mass index (from 148.0 to 130.0 and 128.0 g/m(2); P<0.01). Furthermore, sildenafil improved exercise performance (peak Vo(2)), ventilation efficiency (ventilation to CO(2) production slope), and quality of life (P<0.01). Minor adverse effects were noted: flushing in 4 and headache in 2 treated patients., Conclusions: Findings confirm that in HF, sildenafil improves functional capacity and clinical status and provide the first human evidence that LV diastolic function and cardiac geometry are additional targets of benefits related to chronic PDE5 inhibition.

Aim: Nitric oxide (NO) is a mediator of the pulmonary vessel tone and permeability. We hypothesized that it may also regulate the alveolar-capillary membrane gas conductance and lung diffusion capacity., Methods: In 20 healthy subjects (age = 23 +/- 3 years) we measured lung diffusion capacity for carbon monoxide (DLco), its determinants (membrane conductance, D(m), and pulmonary capillary blood volume, V(c)), systolic pulmonary artery pressure (PAPs) and pulmonary vascular resistance (PVR). Measurements were performed before and after administration of N(g)-monomethyl-L-arginine (L-NMMA, 0.5 mg kg(-1) min(-1)), as a NO production inhibitor, and L-arginine (L-Arg, 0.5 mg kg(-1) min(1)) as a NO pathway activator. The effects of L-NMMA were also tested in combination with active L-Arg and inactive stereoisomer D-Arg vehicled by 150 mL of 5%d-glucose solution. For L-Arg and L-NMMA, saline (150 mL) was also tested as a vehicle., Results: L-NMMA reduced D(m) (-41%P < 0.01), DLco (-20%, P < 0.01) and cardiac output (CO), and increased PAPs and PVR. In 10 additional subjects, a dose of L-NMMA of 0.03 mg kg(-1) min(1) infused in the main stem of the pulmonary artery was able to lower D(m) (-32%, P < 0.01) despite no effect on PVR and CO. D(m) depression was significantly greater when L-NMMA was vehicled by saline than by glucose. L-Arg but not D-Arg abolished the effects of L-NMMA. L-Arg alone increased D(m) (+14%, P < 0.01)., Conclusion: The findings indicate that NO mediates the respiratory effects of L-NMMA and L-Arg, and is involved in the physiology of the alveolar-capillary membrane gas conductance in humans. NO deficiency may cause an excessive endothelial sodium exchange/water conduction and fluid leakage in alveolar interstitial space, lengthening the air-blood path and depressing diffusion capacity.

In acute myocardial infarction (AMI), alveolar interstitium edema is generally attributed to a hydrostatic imbalance. However, inflammatory burden and/or neural/hormonal/hemodynamic stimulation might injure the microvascular endothelium, eliciting interstitial overflow and altering alveolar-capillary gas diffusion. In 118 patients with AMI (ejection fraction >or=50% and wedge pulmonary pressure <16 mmHg), admission alveolar-capillary gas diffusing membrane conductance (DM) averaged 35.1 ml.min(-1).mmHg(-1) and was 27% lower than in 25 controls (P < 0.01). Infusion of saline in the pulmonary circulation (to test sodium exchange across the pulmonary capillary wall) lowered DM by 7.1% (P < 0.01) and was neutral in controls. At 1 wk, 83 patients that showed DM improvement >5% were assigned to group 1, and 28 patients with DM worsening >5% were assigned to group 2. Saline retained efficacy in group 2 and had no DM effect in group 1 (supporting a link between changes in baseline DM and those in microvascular salt exchange). Ventricular function was unchanged in group 1, whereas group 2 had developed diastolic dysfunction. At 1 yr, 3% of cases in group 1 and 37% of cases in group 2 had alveolar edema. Thus, AMI is frequently associated with abnormal pulmonary microvascular sodium transport/water conductance that, in the case of ventricular dysfunction supervenience, may persist and worsen the outcome. In 37 AMI similar patients and 11 control subjects, nitric oxide overexpression with l-arginine improved baseline DM and in AMI patients prevented DM reduction by saline, suggesting a mechanistic role of an impaired nitric oxide pathway in the microvascular barrier dysfunction.

Reflex neural oversignaling sensitive to muscle by-products (ergoreflex) causes exercise hyperventilation in heart failure (HF). We probed whether an improved endothelial function with sildenafil intake may prevent this effect. In 16 chronic heart failure patients and 16 normal subjects, before and after sildenafil intake (50 mg) or placebo, we measured ergoreflex, flow-mediated brachial artery dilation (FMD, an index of endothelial function), and, during maximal exercise, the slope of ventilation to carbon dioxide production (VE/VCO2, an index of ventilatory efficiency), the ratio of changes in O2 uptake (VO2) versus work rate (WR) (deltaVO2/deltaWR, an index of aerobic efficiency). After sildenafil intake, patients, unlike controls, showed a significant decrease in ergoreflex and VE/VCO2 slope and an increase in FMD and deltaVO2/deltaWR. Ergoreflex changes with sildenafil intake correlated with those in FMD and VE/VCO2. Phosphodiesterase-5 inhibition, by improving endothelial activity and muscle perfusion, modulates signaling and improves ventilatory and aerobic efficiencies, potentially indicating a novel pathway in the HF therapeutic management.

Objectives: This study sought to test the functional exercise capacity and endothelial function in a cohort of chronic heart failure (CHF) patients treated with chronic type 5 phosphodiesterase (PDE5) inhibitor., Background: In CHF, endothelial dysfunction is involved in muscle underperfusion, ergoreflex oversignaling, and exercise ventilation inefficiency. Inhibition of PDE5 by improving endothelial dysfunction might be beneficial., Methods: Stable CHF patients were randomly assigned to placebo (23 patients) or sildenafil at the dose of 50 mg twice per day (23 patients) in addition to their current drug treatment for 6 months, with assessments (at 3 and 6 months) of endothelial function by brachial artery flow-mediated dilatation (FMD), cardiopulmonary exercise testing, and ergoreflex response., Results: In the sildenafil group only, at 3 and 6 months we observed reduction of systolic pulmonary artery pressure (from 33.7 to 25.2 mm Hg and 23.9 mm Hg), ergoreflex effect on ventilation (from 6.9 to 2.3 l x min(-1) and 1.9 l x min(-1)), ventilation to CO2 production slope (V(E)/VCO2, from 35.5 to 32.1 and 29.8), and breathlessness (score) (from 23.6 to 16.6 and 17.2), and an increase of FMD (from 8.5% to 13.4% and 14.2%), peak VO2 (from 14.8 to 18.5 ml x min(-1) x kg(-1) and 18.7 ml x min(-1) x kg(-1)), and ratio of VO2 to work rate changes (from 7.7 to 9.3 and 10.1). All changes were significant at p < 0.01. In the sildenafil group, a significant correlation was found at 3 and 6 months between changes in FMD and those in ergoreflex. Changes in ergoreflex correlated with those in peak VO2 and V(E)/VCO2 slope. No adverse effects were noted except for flushing in 3 patients., Conclusions: In CHF, improvement in exercise ventilation and aerobic efficiency with sildenafil is sustained and is significantly related with an endothelium-mediated attenuation of exercising muscle oversignaling. Chronic sildenafil seems to be a remedy based on CHF pathophysiology and devoid of remarkable adverse effects.

Background: Statins represent a modern mainstay of the drug treatment of coronary artery disease and acute coronary syndromes. Reduced aerobic work performance and slowed VO(2) kinetics are established features of the clinical picture of post-myocardial infarction (MI) patients. We tested the hypothesis that statin therapy improves VO(2) exercise performance in normocholesterolaemic post-MI patients., Materials and Methods: According to a double-blinded, randomized, crossover and placebo-controlled study design, in 18 patients with uncomplicated recent (3 days) MI we investigated the effects of atorvastatin (20 mg day(-1)) on gas exchange kinetics by calculating VO(2) effective time constant (tau) during a 50-watt constant workload exercise, brachial artery flow-mediated dilatation (FMD) as an index of endothelial function, left ventricular function (echocardiography) and C-reactive protein (CRP, as an index of inflammation). Atorvastatin or placebo was given for 3 months each., Results: Atorvastatin therapy significantly improved exercise VO(2) tau and FMD, and reduced CRP levels. We did not observe changes in cardiac contractile function and relaxation properties during all study periods in either group., Conclusions: In post-MI patients exercise performance is a potential additional target of benefits related to statin therapy. Endothelial function improvement is very likely implicated in this newly described therapeutic property.

Background: Increased slope of exercise ventilation to carbon dioxide production (VE/VCO2) is an established prognosticator in patients with heart failure. Recently, the occurrence of exercise oscillatory breathing (EOB) has emerged as an additional strong indicator of survival., Objective: The aim of this study is to define the respective prognostic significance of these variables and whether excess risk may be identified when either respiratory disorder is present., Methods: In 288 stable chronic HF patients (average left ventricular ejection fraction, 33 +/- 13%) who underwent cardiopulmonary exercise testing, the prognostic relevance of VE/VCO2 slope, EOB, and peak VO2 was evaluated by multivariate Cox regression., Results: During a mean interval of 28 +/- 13 months, 62 patients died of cardiac reasons. Thirty-five percent presented with EOB. Among patients exhibiting EOB, 54% had an elevated VE/VCO2 slope. The optimal threshold value for the VE/VCO2 slope identified by receiver operating characteristic analysis was < 36.2 or > or = 36.2 (sensitivity, 77%; specificity, 64%; P < .001). Univariate predictors of death included low left ventricular ejection fraction, low peak VO2, high VE/VCO2 slope, and EOB presence. Multivariate analysis selected EOB as the strongest predictor (chi2, 46.5; P < .001). The VE/VCO2 slope (threshold, < 36.2 or > or = 36.2) was the only other exercise test variable retained in the regression (residual chi2, 5.9; P = .02). The hazard ratio for subjects with EOB and a VE/VCO2 slope > or = 36.2 was 11.4 (95% confidence interval, 4.9-26.5; P < .001)., Conclusion: These findings identify EOB as a strong survival predictor even more powerful than VE/VCO2 slope. Exercise oscillatory breathing presence does not necessarily imply an elevated VE/VCO2 slope, but combination of either both yields to a burden of risk remarkably high.

Background: Cardioversion (CV) to sinus rhythm corrects endothelial dysfunction secondary to atrial fibrillation (AF). As AF often complicates hypertension and diabetes (disorders associated with impaired endothelial function) the study probed whether these comorbidities to AF produced an additive effect and to what extent CV might be advantageous., Materials and Methods: Brachial artery flow-mediated dilatation (FMD) was evaluated before and after CV in 17 lone AF patients (group 1), 16 patients with AF + hypertension (group 2) and 17 patients with AF + diabetes type II (group 3), while in supine and head-up tilting (HUT) positions, as this is when endothelial vasodilation is emphasized as a counterbalance to neurogenic vasoconstriction., Results: After 2 weeks, CV in group 1 increased (P < 0.01) supine FMD (from 7.22-->9.50%) and restored its HUT potentiation (from 9.31-->17.22%). In group 2, FMD also improved significantly with CV (supine from 4.92-->7.11% and HUT from 5.29-->11.83%; P < 0.01). In group 3, CV did not promote significant FMD changes (supine from 5.12-->4.92% and HUT from 4.98-->4.73%). After 3 months, FMD improvement persisted in groups 1 and 2 with enduring sinus rhythm, but not in those with AF relapse. In group 3, FMD remained unchanged regardless of cardiac rhythm., Conclusions: Cardioversion persistently increases supine shear stress endothelial responsiveness and restores the orthostatic modulation in AF alone or in association with hypertension, but not with diabetes. Differences in background endothelial impairment may explain the presence (hypertension) or the absence (diabetes) of an additive AF effect in comorbidities, as well as CV results.

Exercising muscle hypoperfusion stimulates afferents (metaboreceptors) involved in the regulation of ventilation. Atrial fibrillation (AF), particularly when combined with diseases causing endothelial (ED) impairment, such as hypertension (HP) and diabetes mellitus (DM), depresses the ED activity and enhances exercise hyperventilation. The relationship between these two functions and the underlying mechanisms have not been explored previously. In lone AF or AF associated with HP or DM (12 subjects in each cohort), we investigated the brachial artery flow-mediated dilatation (ED function) and ventilation during the recovery phase of handgrip (metaboreflex) exercise for subjects receiving placebo or oral vitamin C (double-blind crossover), both before and after cardioversion (CV) to sinus rhythm. Baseline ED impairment was increasingly more severe and the ergoreflex activity more pronounced in AF + HP and AF + DM compared with lone AF. Vitamin C and CV significantly improved both flow-mediated dilatation and metaboreflex activity in lone AF and AF + HP, and vitamin C did not produce any additive effect when administered after CV. In AF + DM, neither vitamin C nor CV was effective. This study provides the following information: AF generates oxidative injury, which is less when the arrhythmia is lone AF and greater when the arrhythmia is associated with HP. In DM, the oxidative injury generated by AF is refractory to a rather weak antioxidant, like vitamin C, or the baseline damage is such as to prevent any additive influence of AF. In AF, a cause-effect link exists between ED dysfunction and metaboreflex activity. Ventilatory advantages of CV seem to be inversely related with the extension of the underlying ED oxidative impairment.

Endothelial dysfunction and underperfusion of exercising muscle contribute to exercise intolerance, hyperventilation, and breathlessness in atrial fibrillation (AF). Cardioversion (CV) improves endothelial function and exercise performance. We examined whether CV is equally beneficial in diabetes and hypertension, diseases that cause endothelial dysfunction and are often associated with AF. Cardiopulmonary exercise and pulmonary and endothelial (brachial artery flow-mediated dilation) function were tested before and after CV in patients with AF alone (n = 18, group 1) or AF with hypertension (n = 19, group 2) or diabetes (n = 19, group 3). Compared with group 1, peak exercise workload, O2 consumption (Vo2), O2 pulse, aerobic efficiency (Delta Vo2/Delta WR), and ratio of brachial diameter changes to flow changes (Delta D/Delta F) were reduced in group 2 and, to a greater extent, in group 3; exercise ventilation efficiency (Ve/Vco2 slope) and dead space-to-tidal volume ratio (Vd/Vt) were similar among groups. CV had less effect on peak workload (+7% vs. +18%), peak Vo2 (+12% vs. +17%), O2 pulse (+33% vs. +50%), Delta Vo2/Delta WR (+7% vs. +12%), Ve/Vco2 slope (-6% vs. -12%), Delta D/Delta F (+7% vs. +10%), and breathlessness (Borg scale) in group 2 than in group 1 and was ineffective in group 3. The antioxidant vitamin C, tested in eight additional patients in each cohort, improved flow-mediated dilation in groups 1 and 2 before, but not after, CV and was ineffective in group 3, suggesting that the oxidative injury is least in lone AF, greater in hypertension with AF, and greater still in diabetes with AF. Comorbidities that impair endothelial activity worsen endothelial dysfunction and exercise intolerance in AF. The advantages of CV appear to be inversely related to the extent of the underlying oxidative injury.

Background: In heart failure (HF), changes in lung mechanics and gas diffusion are limiting factors to exercise. Their contribution to an increased exercise ventilation to CO2 production (VE/VCO2) slope is undefined., Methods: A total of 67 stable HF patients underwent cardiopulmonary exercise and pulmonary function tests, including forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1), maximal voluntary ventilation (MVV), total lung capacity (TLC) and alveolar diffusing capacity with its subcomponents (alveolar-capillary membrane conductance (D(m)) and capillary blood volume (V(c)))., Results: Patients showed a mild restrictive pattern (FEV1=85+/-15% and FVC=75+/-13% of normal predicted) and a moderate D(m) reduction (32+/-12 ml min(-1) mm Hg(-1)). Average peak VO(2) was 15.6+/-4.0 ml min(-1) kg(-1) and the VE/VCO2 slope was 39.6+/-11.0. At simple Spearman correlation analysis, all variables, but V(c), correlated with peak VO2; only D(m) correlated with VE/VCO2 slope. At partial Spearman correlation, all variables lost the peak VO2 correlation, and D(m) still inversely correlated with VE/VCO2 slope (r=-0.35; p=0.005). In patients with a high VE/VCO2 slope (cutoff value 34), despite comparable lung volumes, D(m) was significantly more depressed (30+/-13 vs. 35+/-10 ml min(-1) mm Hg(-1); p<0.01)., Conclusions: Pulmonary function tests and alveolar gas diffusing capacity poorly correlate with peak VO2. D(m) impairment rather than lung volumes correlates with exercise ventilation efficiency. This finding further adds to the pathophysiological relevance of an abnormal gas exchange in HF patients.

Background: Sympathetically mediated vasoconstriction, to compensate for reduced venous return and cardiac output, characterizes the circulatory adaptation to head-up tilting (HUT). It has not been clarified whether this is coupled with a modulating endothelial vasorelaxation and whether diseases causing endothelial dysfunction, such as diabetes and hypertension, may impair this counterregulatory mechanism., Methods: In patients with hypertension (group 1), diabetes (group 2), or both diseases (group 3) and in healthy control subjects (12 subjects per group) we investigated the brachial artery vasodilating response to the release of distal circulatory arrest (DCA) while they were supine and during 60 degrees HUT., Results: The supine increase in lumen was smaller (P<.01) in groups 1 (+4.5%+/-1.5%), 2 (+4.8%+/-1.4%), and 3 (+3.9%+/-1.3%) than in the control group (+8.6%+/-1.6%). Vasorelaxation by nitroglycerin was similar in each population. During HUT, the lumen response to DCA was enhanced (P<.01 v supine) in control subjects (+15.4%+/-2.5%) and group 1 (+10.0+/-2.4%) and was reduced (P<.01 v supine) in groups 2 (+2.9%+/-0.5%) and 3 (+2.1%+/-0.4%), even though the hyperemic reaction to DCA was similar. The ratio of lumen changes to changes in flow (mm/mL/min x 1000) during reactive hyperemia to DCA increased (P<.01) with HUT, compared with that in the supine position, in control subjects (1.75v1.19) and group 1 (1.61v0.95), and decreased (P<.01) in groups 2 (0.62v0.87) and 3 (0.48v0.77)., Conclusions: The HUT posture is characterized by an increased endothelium-dependent, flow-mediated vasodilation as a possible modulator of the neural vasoconstriction. This effect is persistent but blunted in hypertension and is abolished in diabetes, either alone or in association with high BP. Thus, vasoconstrictor factors could remain unmodulated during an event such as orthostasis, making the risk posed by these disorders more critical.

Aims: In chronic heart failure (CHF) patients, the ventilation (Ve) needed to eliminate metabolically produced CO(2) during exercise (i.e. the Ve/Vco(2) slope) is a strong prognosticator. Ve/Vco(2) slope determinants are the dead space-tidal volume (Vd/Vt) ratio and the arterial CO(2) partial pressure (Paco(2)). We aimed at defining the respective prognostic role of these two variables., Methods and Results: One hundred and twenty-eight stable CHF patients (average left ventricular ejection fraction 34+/-10%) underwent cardiopulmonary exercise testing and blood gas analysis. The prognostic relevance of the Ve/Vco(2) slope, Vd/Vt, and Paco(2) at peak exercise was evaluated by the Kaplan-Meier approach with log-rank testing and by multivariate Cox regression analysis. During a mean period of 31.3+/-20 months, 24 patients died from cardiac causes. In univariate analysis, predictors of death included the use of anti-aldosterone drugs, low peak Vo(2), peak Ve/Vo(2), peak Paco(2) and high Ve/Vco(2) slope, and peak Vd/Vt. Multivariate analysis identified a low peak Paco(2) (<35 mmHg) as the strongest independent prognostic indicator [hazard ratio 4.65, 95% confidence interval (CI) (1.695-12.751), P=0.003] that primarily accounts for the Ve/Vco(2) slope prognostic power., Conclusion: These findings imply that regulatory mechanisms involved in the tight control of ventilatory command and blood gas tension, rather than lung function abnormalities, play a critical pathophysiological role in the exercise ventilation inefficiency of CHF patients.

Objectives: We sought to investigate the effects of sildenafil, a phosphodiesterase-5 (PDE(5)) inhibitor, on lung function and exercise performance in chronic heart failure (CHF)., Background: In CHF, nitric oxide-mediated regulation of lung vascular tone and alveolar-capillary membrane conductance is impaired and contributes to exercise intolerance. The potential for benefits due to increased nitric-oxide availability is unexplored., Methods: In 16 patients with CHF and 8 normal subjects, we measured-before and 60 min after sildenafil (50 mg) or placebo-ejection fraction, pulmonary hemodynamics, carbon monoxide diffusion capacity (DLco), with its membrane (D(M)) and capillary blood volume (V(c)) subcomponents, endothelial function (brachial reactive hyperemia) at rest, peak oxygen uptake (VO(2)), increments in VO(2) versus work rate (DeltaVO(2)/DeltaWR), changes in ventilation versus CO(2) production (VE/VCO(2)) slope, and recovery VO(2) time constant (tau) on exertion., Results: In CHF, sildenafil did not affect cardiac index, wedge pulmonary pressure, or ejection fraction; it significantly (p < 0.01) decreased pulmonary mean artery pressure (-20.4%) and arteriolar resistance (-45.1%), VE/VCO(2) slope (-9.0%) and recovery tau (-25.8%), and increased (p < 0.01) DLco (+11.1%), D(M) (+9.9%) peak VO(2) (+19.7%), DeltaVO(2)/DeltaWR (+11.0%), and brachial reactive hyperemia (+33.3%). No variations occurred in normal subjects and after placebo. Changes in DLco were related to those in VE/VCO(2) slope (r = -0.71; p = 0.002), and changes in brachial hyperemia correlated with those in DeltaVO(2)/DeltaWR (r = 0.80; p = 0.0002)., Conclusions: This study shows that in CHF PDE(5) inhibition modulates pulmonary pressure and vascular tone, and improves DLco, exercise peak VO(2), aerobic (DeltaVO(2)/DeltaWR) and ventilatory (VE/VCO(2) slope) efficiencies, and oxygen debt (recovery tau). Endothelial mechanisms may underlie these effects.

Lone atrial fibrillation may be associated with daily life disability and exercise limitation. The extracardiac pathophysiology of these effects is poorly explored. In 35 subjects with lone atrial fibrillation (mean age 67 +/- 7 yr), we investigated pulmonary function, symptom-limited cardiopulmonary exercise performance, muscle ergoreflex (handgrip exercise) contribution to ventilation, and brachial artery flow-mediated dilation (as a measure of endothelial function) before and after (average interval 20 +/- 5 days) restoring sinus rhythm with external cardioversion. Respiratory volumes and lung diffusing capacity at rest were within normal limits during both atrial fibrillation and after restoring sinus rhythm. Cardioversion was associated with the following changes: a decrease of the slope of exercise ventilation vs. CO2 production (from 35 +/- 5 to 29 +/- 3; P <0.01) and of dyspnea sensation (Borg score from 4 to 2) and an increase of peak oxygen uptake (Vo2; from 16 +/- 4 to 20 +/- 5 ml.min(-1).kg(-1); P <0.01), Vo2 at anaerobic threshold (from 11 +/- 2 to 13 +/- 2 ml.min(-1).kg(-1); P <0.05), and O2 pulse (from 8 +/- 3 to 11 +/- 3 ml/beat; P <0.01). After cardioversion, the observed improvement in ventilatory efficiency was accompanied by a significant peak end-tidal CO2 increase (from 33 +/- 2 to 37 +/- 2 mmHg; P <0.01) and no changes in dead space-to-tidal volume ratio (from 0.23 +/- 0.03 to 0.23 +/- 0.02; P=not significant). In addition, the ergoreflex contribution to ventilation was remarkably attenuated, and the brachial artery flow-mediated dilatation was significantly augmented (from 0.32 +/- 0.07 to 0.42 +/- 0.08 mm; P <0.01). Ten patients had atrial fibrillation relapse and, compared with values after restoration of regular sinus rhythm, invariably showed worsening of endothelial function, exercise ventilatory efficiency, and muscle ergoreflex contribution to ventilation. In subjects with lone atrial fibrillation, an impairment in ventilatory efficiency appears to be involved in the pathophysiology of exercise limitation, and to be primarily related with a demodulated peripheral control of ventilation.

Aims: Flow-mediated brachial artery vasodilatation is an index of endothelial function. Published literature describes only supine data and no study has been performed during vertical displacement. This subject deserves investigation for two main reasons: humans spend the larger part of their life in the upright position; this position has significant effects on neural vascular regulation., Methods: In 21 healthy men (25 +/- 2 years) the flow-dependent brachial artery vasodilating response to distal circulatory arrest was assessed by Doppler ultrasound imaging, while supine and during 20 degrees and 60 degrees head-up tilting (HUT). In 11 of these subjects the vasodilating response to nitroglycerine was also explored., Results: Absolute and percentage increments in brachial calibre during hyperaemia after deflation of the occluding cuff became increasingly greater at 20 degrees (+0.44 mm) and 60 degrees (+0.92 mm) HUT (P < 0.01), compared with the horizontal position (+0.27 mm), and the arterial dilatation for an increase in flow (0.98 +/- 0.08 and 1.68 +/- 0.06 mm mL(-1) min(-1) x 1000, respectively) was larger (P < 0.01) than occurred while supine (0.41 +/- 0.05 mm mL(-1) min(-1) x 1000). Nitroglycerine-mediated vasodilatation at 60 degrees HUT was similar to that in the supine position., Conclusion: The orthostatic stimulus is associated with an increase of the flow-mediated brachial artery vasodilatation, which is proportional to the degree of displacement. The mechanism of this effect does not consist of changes in nitric oxide sensitivity.

Chronic heart failure (CHF) may impair lung gas diffusion, an effect that contributes to exercise limitation. We investigated whether diffusion improvement is a mechanism whereby physical training increases aerobic efficiency in CHF. Patients with CHF (n = 16) were trained (40 min of stationary cycling, 4 times/wk) for 8 wk; similar sedentary patients (n = 15) were used as controls. Training increased lung diffusion (DlCO, +25%), alveolar-capillary conductance (DM, +15%), pulmonary capillary blood volume (VC, +10%), peak exercise O2 uptake (peak VO2, +13%), and VO2 at anaerobic threshold (AT, +20%) and decreased the slope of exercise ventilation to CO2 output (VE/VCO2, -14%). It also improved the flow-mediated brachial artery dilation (BAD, from 4.8 +/- 0.4 to 8.2 +/- 0.4%). These changes were significant compared with baseline and controls. Hemodynamics were obtained in the last 10 patients in each group. Training did not affect hemodynamics at rest and enhanced the increase of cardiac output (+226 vs. +187%) and stroke volume (+59 vs. +49%) and the decrease of pulmonary arteriolar resistance (-28 vs. -13%) at peak exercise. Hemodynamics were unchanged in controls after 8 wk. Increases in DlCO and DM correlated with increases in peak VO2 (r = 0.58, P = 0.019 and r = 0.51, P = 0.04, respectively) and in BAD (r = 0.57, P < 0.021 and r = 0.50, P = 0.04, respectively). After detraining (8 wk), DlCO, DM, VC, peak VO2, VO2 at AT, VE/VCO2 slope, cardiac output, stroke volume, pulmonary arteriolar resistance at peak exercise, and BAD reverted to levels similar to baseline and to levels similar to controls. Results document, for the first time, that training improves DlCO in CHF, and this effect may contribute to enhancement of exercise performance.

Background: Chronic heart failure (CHF) may be associated with a disordered nitric oxide (NO)-mediated regulation of the pulmonary vessel tone and permeability and of the gas transfer across the alveolar-capillary membrane. Whether enhancement of NO availability is beneficial with regard to these functions has not been explored. Phosphodiesterase 5 inhibitors, such as sildenafil, may provide a tool with which to test this possibility., Methods: In 10 patients with CHF and 10 normal subjects, before and at 60 minutes after sildenafil (50 mg) or placebo, we measured left ventricular ejection fraction, pulmonary hemodynamics, lung diffusion capacity for carbon monoxide and its alveolar-capillary membrane and blood capillary volume subcomponents, and flow-mediated brachial artery dilation (FMD) during reactive hyperemia to distal circulatory arrest (an indirect index of NO-mediated endothelial function)., Results: In patients with CHF, sildenafil caused no variations in ejection fraction, cardiac index, wedge pulmonary pressure, and blood capillary volume; it decreased pulmonary artery systolic (-21.6%) and diastolic (-31.8%) pressure and arteriolar resistance (-36.9%); and it increased lung diffusion capacity for carbon monoxide (+11.2%), diffusing capacity of the alveolar-capillary membrane (+10.6%), and FMD (from +8.3% to +13.4%). All changes were significant at P < .01. None of these effects was observed in healthy subjects. Placebo was ineffective in both patients and control subjects., Conclusion: This study provides the novel information that, in patients with CHF, phosphodiesterase 5 inhibition with sildenafil ameliorates the pulmonary hemodynamics and reduces the impedance of the alveolar-capillary interface, even if left ventricular filling pressure and function remain steady. The associated improvement in FMD at the periphery substantiates the possibility that an enhancement in NO release may underlie these effects.

Tele-echocardiography is not widely used because of lengthy transmission times when using standard Motion Pictures Expert Groups (MPEG)-2 lossy compression algorythms, unless expensive high bandwidth lines are used. We sought to validate the newer MPEG-4 algorythms to allow further reduction in echocardiographic motion video file size. Four cardiologists expert in echocardiography read blindly 165 randomized uncompressed and compressed 2D and color Doppler normal and pathologic motion images. One Digital Video and 3 MPEG-4 compression algorythms were tested, the latter at 3 decreasing compression quality levels (100%, 65% and 40%). Mean diagnostic and image quality scores were computed for each file and compared across the 3 compression levels using uncompressed files as controls. File dimensions decreased from a range of uncompressed 12-83 MB to MPEG-4 0.03-2.3 MB. All algorythms showed mean scores that were not significantly different from uncompressed source, except the MPEG-4 DivX algorythm at the highest selected compression (40%, p=.002). These data support the use of MPEG-4 compression to reduce echocardiographic motion image size for transmission purposes, allowing cost reduction through use of low bandwidth lines.

Background: Peak exercise oxygen uptake (peak VO2) and ventilation to CO2 production (VE/VCO2) slope are established prognostic indicators in patients with chronic heart failure (CHF). A high VE/VCO2 slope, however, does not take into account the level of physical performance as expressed by peak VO2. We hypothesized that the prognostic value of a high VE/VCO2 slope may be improved by normalization for peak VO2 (VE/VCO2/VO2)., Methods: One hundred patients with CHF underwent pulmonary function tests at rest (spirometry and lung diffusion capacity) and maximal cardiopulmonary exercise testing. The prognostic value of VE/VCO2 slope, peak VO2 and VE/VCO2/VO2 was probed prospectively., Results: Twenty-one patients died from cardiac reasons during a mean follow-up of 26 +/- 19 months. Nonsurvivors, compared to survivors, showed a lower peak VO2 (13.6 +/- 4.0 vs 17.5 +/- 4.1 mL x min(-1) x kg(-1), P <.01) and a steeper VE/VCO2 slope (43 +/- 11 vs 31.6 +/- 5.0, P <.01). Nonetheless, in patients whose VE/VCO2 slope exceeded 34 (upper normal limit), there was no correlation with peak VO2 (r = -35, P = not significant). Interestingly 35% of them showed a normal exercise performance (peak VO2 > or =18 mL x min(-1) x kg(-1)). At multivariate analysis, the VE/VCO2 slope showed a prognostic power stronger than that of peak VO2; however, the VE/VCO2/VO2 index retained a prognostic power greater than that of both VE/VCO2 slope and peak VO2. A VE/VCO2/VO2 > or =2.4 signaled cases at higher risk., Conclusions: Discrepancies between VE/VCO2 slope and peak VO2 may generate uncertainty. Normalization of the former by the latter improves outcome prediction and may be considered a simple and effective way for maximizing the clinical applicability of these 2 indicators.

Objective: In type 1 diabetes, lung diffusing capacity for carbon monoxide (DL(CO)) may be impaired, and insulin has been shown to be beneficial in cases in which near-normal metabolic control is achieved. An influence of insulin, per se, on the alveolar-capillary membrane conductance is unexplored. We aimed at testing this possibility., Research Design and Methods: We studied 19 life-long nonsmoking, asymptomatic patients with type 2 diabetes and normal cardiac function, whose GHb averaged 6.2 +/- 0.3% with diet and hypoglycemic drugs. DL(CO) and its subcomponents (alveolar capillary membrane conductance [D(M)] and pulmonary capillary blood volume available for gas exchange [Vc]), vital capacity (VC), forced expiratory volume 1 s (FEV(1)), cardiac output (CO), ejection fraction (EF), pulmonary wedge pressure (WPP), and pulmonary arteriolar resistance (PAR) were determined before and within 60 min after infusion of 50 ml saline + 10 IU of regular insulin or after saline alone on 2 consecutive days (random block design). Glycemia was kept at baseline levels during experiments by dextrose infusion., Results: Percent of normal predicted DL(CO) averaged 84.2 +/- 7.9% and in 14 patients was <100%. Insulin infusion, not saline alone, improved (P < 0.01) DL(CO) (12%) and D(M) (14%) and raised DL(CO) to 98% of the normal predicted value. There were no variations in VC, FEV(1,) CO, EF, WPP, or PAR, suggesting that the influences of the hormone on gas transfer were not mediated by changes in spirometry, volumes, and hemodynamics of the lung., Conclusions: Several cases of type 2 diabetes present with increased impedance to gas transfer across the alveolar-capillary membrane, and hypoglycemic drugs do not prevent this inconvenience. Insulin, independently of the metabolic effects, acutely improves gas exchange, possibly through a facilitation of the alveolar-capillary interface conductance.

Heart failure increases the resistance to gas transfer across the alveolar-capillary interface. In different experimental conditions of vascular capillary injury, peculiar anatomical and functional abnormalities of the alveolar unit have been reported and consist of a disruption of its anatomical configuration and of a loss of fluid-flux regulation and gas exchange efficiency (i.e. "stress failure" of the alveolar-capillary membrane). In heart failure, the pathophysiological relevance of these changes has been only recently appreciated. Alveolar-capillary membrane conductance and capillary blood volume are subcomponents of lung diffusion capacity. A reduction of the former with an increase of the latter and consequent impairment of gas exchange are typical of heart failure syndrome. Alveolar-capillary membrane conductance abnormalities have been shown to be a sensitive index of the underlying lung tissue damage, bring an independent prognostic information and play a significant role in the pathogenesis of exercise limitation and ventilatory abnormalities. This review examines the current knowledge on this topic.

Chronic heart failure (CHF) (hydrostatic stress) and diabetes (basal laminae thickening) share the potentiality of damaging the alveolar-capillary membrane. We investigated 15 control subjects and 3 groups of 15 patients each having type 2 diabetes (Group 1), CHF (Group 2), and diabetes and CHF (Group 3), to probe whether addition of diabetes worsens lung diffusion in CHF and whether insulin counteracts this effect. Compared with control subjects, carbon monoxide diffusing capacity (DL(CO)) and diffusing capacity of the alveolar-capillary membrane at rest were increasingly depressed from Group 1 through Group 3. DL(CO) was lower than predicted in 11 patients each in Groups 1 and 2 and in all patients in Group 3. Regular insulin (10 IU) was ineffective in CHF alone, whereas it improved DL(CO) and diffusing capacity of the alveolar-capillary membrane in diabetes; changes, however, were significantly greater in the patients with both diabetes and CHF (+17.6%, +27.3%) than in those with diabetes alone (+9.2%, +13.1%). Insulin did not affect lung spirometry, volumes, and hemodynamics. Thus, gas transfer is depressed in a number of patients with diabetes or CHF; comorbidity increases the frequency and extent of this disorder. Insulin facilitates diffusion in diabetes, through an influence on alveolar-capillary conductance, and its efficacy is greater in comorbidity; diabetes is more disturbing in patients with CHF and produces a synergistic rather than a simple additive effect.

Transmitral color Doppler early diastolic flow propagation velocity (Vp) has been correlated with the left ventricular (LV) relaxation time constant tau in dilated cardiomyopathy and ischemic heart disease. The aim of this study was to investigate the independent influence of LV systolic function and geometry, and of LV relaxation, on Vp in an unselected outpatient population. We studied 30 normal subjects and 130 patients (hypertensive LV hypertrophy, aortic valve stenosis or prosthesis, hypertrophic cardiomyopathy, coronary artery disease, dilated cardiomyopathy, aortic or mitral valve regurgitation). In all, we noninvasively measured LV geometry, mass, systolic function, wall motion dyssynergy, and diastolic function (abnormal relaxation or restrictive LV Doppler filling patterns). The Vp was similar in normal subjects and in patients (51 +/- 14 vs 53 +/- 25 cm/s). In normal subjects, the determinants of Vp at multiple regression analysis were isovolumic relaxation time, 2-dimensional cardiac index, and mitral E-wave velocity-time integral. In all, the main determinants were LV ejection fraction, percent of segmental wall dyssynergy, and isovolumic relaxation time and age. The Vp was highest in hypertrophic (75 +/- 25 cm/s, p <0.05 vs normal subjects) and lowest in dilated (35 +/- 13 cm/s, p = NS) cardiomyopathy. During multivariate analysis of variance, percent of wall dyssynergy (but not diffuse LV hypokinesia) independently reduced Vp (p = 0.02). The latter was not influenced by the LV filling pattern. Thus, in an unselected clinical population, prolonged relaxation per se does not influence Vp if LV systolic dysfunction and/or wall dyssynergy is absent-the latter factors are important independent determinants of Vp, which is determined by multiple factors.

In chronic congestive heart failure (CHF), backward effects of left ventricular dysfunction alter pulmonary volumes and gas diffusion. Some of these disorders are detected in some patients with diabetes mellitus, possibly due to a microangiopathic process and nonenzymatic glycosylation of lung tissue proteins. We explored the possibility that coexistence of non-insulin-dependent diabetes mellitus (NIDDM) may potentiate the deterioration of lung function in CHF. In 20 normoglycemic patients (group 1) and in 20 patients with NIDDM (group 2), with New York Heart Association class II to III CHF due to idiopathic or ischemic cardiac disease, and in 20 controls (groups were age- and gender-matched), we investigated cardiac function, pulmonary volumes, carbon monoxide diffusion (DL(CO)) and its alveolar-capillary membrane (D(M)) subcomponent, oxygen uptake and dead space-to-tidal volume ratio (pVD/VT) at peak exercise (individualized ramp test), and slope of ventilation-to-carbon dioxide production ratio (VE/VCO(2)) during exercise. Although, compared with reference subjects, both patient groups had similar variations in left ventricular diastolic volume, ejection fraction, and pulmonary wedge pressure; in group 2 lung volumes, DL(CO), D(M), and oxygen uptake were significantly more reduced; in this group there was no overlap of individual results of DL(CO) and D(M) with those in controls; VE/VCO(2) slope and pVD/VT also were significantly increased, and inversely correlated with D(M). Thus, coexistence of NIDDM makes pulmonary dysfunction worse in CHF, and significantly enhances exercise intolerance.

Recent clinical trials have demonstrated a better ability of low-molecular-weight heparin, compared to unfractionated heparin, in reducing ischemic cardiac events in patients with acute coronary syndromes without ST-segment elevation. No data are available concerning the in-vivo comparison of enoxaparin and unfractionated heparin on thrombin generation in patients with unstable angina or non-Q-wave myocardial infarction. We measured the plasma levels of prothrombin fragment 1+2 (a marker of prothrombin activation) and thrombin/antithrombin complex (a marker of thrombin generation) in 45 patients with non ST-elevation acute coronary syndromes who were randomized to receive enoxaparin, 3000 IU anti-Xa as an i. v. bolus, followed by 70 IU anti-Xa/Kg every 8 h for 3 days (23 pts. Group 1) or a bolus of 100 IU/kg of unfractionated heparin followed by infusion for 3 days titrated to maintain the aPTT between 70 and 90 s (22 pts, Group 2). Plasma levels of prothrombin fragment 1+2 reduced significantly at 3rd h of treatment in both groups (-42% in Group 1 and -45% in Group 2), reached the lowest plasma concentration at the 24th h and exhibited a slight increase at the 72nd h; no differences were observed between the two groups at any time points. Plasma thrombin/antithrombin complex levels had a similar behaviour: reduced markedly in both groups at the 3rd h (-52% in Group 1 and -46% in Group 2), remained lower during the first two days and slightly rose at 72nd h. No differences between the two groups in plasma levels of this marker were apparent during drug infusion. In Group 1 the aPTT did not show significant changes: in Group 2 the mean value of aPTT doubled the basal value at any time point of determination. Both enoxaparin and unfractionated heparin produced a marked and similar reduction of thrombin generation. Other unknown mechanisms might explain the different clinical effects of the two heparins.

Aims: In congestive heart failure (CHF), pulmonary gas exchange, as evaluated by carbon monoxide diffusion (DLCO), is impaired. ACE-inhibition improves DLCO. Infusion of saline worsens DLCO, because of upregulated sodium and water transport to the alveolar interstitium, which thickens the alveolar-capillary interface and lengthens the diffusion path for gas exchange. We investigated whether enalapril can readjust the capillary permeability to sodium., Methods: In 10 NYHA class II-III CHF patients, we measured DLCO, its two subcomponents (VC, capillary blood volume available for gas exchange, and DM, alveolar-capillary membrane diffusion), left and right ventricular filling pressures, plasma noradrenaline, aldosterone and renin activity, at baseline and following saline infusion in the main pulmonary artery stem, before and after 1 week enalapril treatment (20 mg daily)., Results: Saline (150 ml) significantly reduced DLCO (-9.1%) and DM (-9.8%) and augmented VC (+ 10.7%). Responses to 750 ml saline were somewhat greater and qualitatively similar. Enalapril produced a significant improvement of DLCO and DM at rest as well as after saline, that was not associated with variations in ventricular filling pressures, cardiac output and left ventricular ejection fraction, and was not accounted for by humoral changes., Conclusions: In CHF, ACE-inhibition attenuates the deterioration of pulmonary gas transfer produced by saline infusion, suggesting an ability to readjust the upregulated sodium transport across the pulmonary microvascular endothelium.

Background: Oxidative stress is present in cardiovascular diseases (CVDs), and hyperhomocysteinemia, an independent risk factor for these diseases, may play a role by inducing production of oxygen free radicals., Methods: To evaluate the possible role of homocysteine (Hcy) in inducing oxidative stress in coronary artery disease (CAD), plasma Hcy was measured in 68 consecutive cardiovascular patients, and plasma malondialdehyde (MDA), both free and total (free + bound), was measured in 40 patients with CAD (18 with chronic stable angina and 22 with unstable angina). As controls, we tested 70 healthy volunteers. Hcy was measured by an immunoenzymatic method and MDA, an index of lipid peroxidation, by gas chromatography-mass spectrometry., Results: Plasma Hcy concentrations were significantly higher in cardiovascular patients than in controls (10.2 vs 8.9 micromol/L; P <0.0002), with no significant difference between values in the stable and unstable angina subgroups. Similarly, total MDA was significantly higher in the CAD group than in the controls (2.6 vs 1.3 micromol/L; P <0.00001), again with no significant difference between stable and unstable angina patients. By contrast, free MDA, which was significantly higher in the CAD patients than the controls (0.4 vs 0.2 micromol/L; P < 0.00001), was also significantly higher in the unstable than in the stable angina group (0.5 vs 0.3 micromol/L; P <0.03). However, no correlation was observed among Hcy and free and total MDA., Conclusions: Our findings show that a moderate increase of Hcy is associated with CVD but that Hcy at the detected values cannot be considered completely responsible for oxidative damage. That lipid peroxidation is involved in CAD is shown by our observation of significantly increased plasma free and total MDA concentrations compared with controls. Moreover, free MDA values discriminated between unstable and chronic stable angina, and could thus represent a new diagnostic tool.

Objectives: We sought to compare the protective efficacy of enalapril and losartan on lung diffusion in chronic heart failure (CHF)., Background: In CHF, hydrostatic overload causes disruption of the alveolar-capillary membrane and depression of carbon monoxide diffusion (DCO); enalapril improves DCO through mechanisms still undefined; and saline infusion in the pulmonary circulation worsens DCO, putatively because of an upregulated sodium transport to the alveolar interstitium. We investigated whether enalapril modulates sodium handling and whether losartan shares the same properties., Methods: In 29 patients with CHF, DCO, its membrane diffusion subcomponent (DM) and right atrial and pulmonary wedge pressures were monitored during saline infusion, in the control condition, during enalapril therapy (20 mg/day) for two weeks and after crossover to losartan (50 mg/day) for two weeks (first 20 patients), or after the combination of enalapril with aspirin (325 mg/day) for one week (last 9 patients)., Results: Saline, 150 ml, lowered DCO (-7.9%; p < 0.01) and DM (-9.9%; p < 0.01) without hydrostatic variations. Responses to 750 ml of saline were qualitatively similar. After treatment with enalapril, baseline DCO (p < 0.01) and DM (p < 0.01) were augmented; after sodium loading, the percent reductions of DCO (p < 0.01) and DM (p < 0.01) were comparable to those before it, resulting in higher absolute values. This suggests that the greater the gas conductance improvement with enalapril, the lower the impedance with saline. Losartan was ineffective on gas transfer at rest and under salt challenge. Aspirin counteracted the benefits of enalapril., Conclusions: In CHF, enalapril protects lung diffusion, possibly through a prostaglandin-mediated modulation of sodium overfiltration to the alveolar interstitium; losartan does not share this ability.

Purpose: Patients with stable heart failure often wish to spend time at altitudes above those of their residence. However, it is not known whether they can safely tolerate ascent to high altitudes or what its effects on work capacity may be., Subjects and Methods: We studied 14 normal subjects and 38 patients with clinically stable heart failure, 12 of whom had normal workload [peak exercise oxygen consumption (VO(2)) greater than 20 mL/min/kg], 14 of whom had slightly diminished workload (peak VO(2) 20 to 15 mL/min/kg), and 12 of whom had markedly diminished workload (peak VO(2) less than 15 mL/min/kg) at baseline. All performed cardiopulmonary exercise tests with inspired oxygen fractions equal to those at 92, 1,000, 1,500, 2,000, and 3,000 m, and maximum achieved work rates (mean +/- SD) were measured., Results: All subjects completed the trial; no test was interrupted because of arrhythmia, angina, or ischemia. Maximum work rate decreased in parallel with increasing simulated altitude. The percentage decrease was greater for patients with heart failure and was most marked among those with the lowest workload at baseline. Maximum achieved work rate declined by 3% +/- 4% per 1,000 m in normal subjects, by 5% +/- 3% (P <0.01) in patients with heart failure with normal workload, by 5% +/- 4% (P <0.01) in patients with slightly diminished workload, and by 11% +/- 5% (P <0.01 vs normal subjects and vs the other patients with heart failure) in patients with markedly reduced workload., Conclusion: Patients with stable heart failure who ascend to higher altitudes should expect to have a reduction in maximum physical activity in proportion to their exercise capacity at sea level.

Background: We investigated the lung contribution to circulating noradrenaline (NA) homeostasis. Evaluation of the transpulmonary NA gradient, related to the NA amount entering the lungs, is potentially important, mainly regarding clinical conditions, such as congestive heart failure (CHF), that are associated with excessive circulating NA., Materials and Methods: 15 moderate (group 1) and 15 severe (group 2) CHF patients, and 10 normal individuals had determination of NA transpulmonary gradient in the baseline and during rise (exercise, in normals and group 1) or fall (withdrawal from plasma by ultrafiltration, in group 2) of plasma NA., Results: NA gradient (pg mL(-1)) at rest was 30 +/- 3 in normals, 21 +/- 6 in group 1 and 5 +/- 8 in group 2. Increase of NA concentration in the mixed venous blood with exercise was paralleled by depression of the transpulmonary gradient. Pulmonary arteriovenous difference disappeared when NA entering the lungs averaged 1300 pg mL(-1). In group 2, ultrafiltration lowered NA in the mixed venous blood from 1225 +/- 213 to 718 +/- 182, which caused transpulmonary gradient to increase from 5 +/- 8 to 22 +/- 9., Conclusions: Transpulmonary gradient of NA diminishes when NA entering the lungs increases, and 1300 pg mL(-1) in the pulmonary artery is, both in patients and normal subjects, the level at which gradient disappears; which likely reflects cessation of NA uptake or achievement of a balance between lung uptake and production. This may have physiological and pathological implications.

Objectives: We aimed to assess the differences in the adaptive response of patients with hypertrophic cardiomyopathy (HCM) compared with normal subjects, as well as any association with increased susceptibility to the test., Background: Diastolic function contributes importantly in the adaptation of the normal heart to head-up tilting. This mechanism may be disturbed by an impaired relaxation in HCM., Methods: Twenty-one male patients with HCM (46 +/- 6 years old) and 22 healthy men (44 +/- 8 years) were studied using Doppler echocardiography after 1 and 10 min of head-up tilting at 20 degrees, 40 degrees and 60 degrees., Results: In control subjects, tilting was associated with 1) a predominance of diastolic pulmonary venous flow and early left ventricular (LV) filling (atrium functioning as an open conduit); 2) right ventricular (RV) shrinkage; and 3) no LV dimensional variations. In patients with HCM, tilting was associated with 1) a prevalence of systolic pulmonary venous flow (atrium functioning as a reservoir in which filling depends on atrial relaxation and compliance) and late diastolic transmitral flow (atrium working as a booster pump); 2) LV shrinkage; and 3) no RV dimension variations. These mechanisms did not prevent stroke volume (SV) from decreasing at 40 degrees and 60 degrees in both groups. Because of a lower increase in heart rate (HR), a reduction in cardiac output (CO) was greater in patients with HCM. The responses were similar after 1 and 10 min of tilting in control subjects, whereas in patients, blood pressure (BP), SV and LV dimension fell more after 10 min., Conclusions: Adaptation of the normal heart to tilting is based on a ventricular interaction and LV diastolic properties; HCM relies on left atrial diastolic and systolic functions. An inadequate HR reaction to a fall in BP and SV in HCM (depressed reflexogenic activity) contributes to making CO more vulnerable by greater and more prolonged displacements.

The microvascular pulmonary endothelium barrier is critical in preventing interstitial fluid overflow and deterioration in gas diffusion. The role of endothelium in transporting small solutes in pathological conditions, such as congestive heart failure (CHF), has not been studied. Monitoring of pulmonary gas transfer during saline infusion in CHF was used to probe this issue. Carbon monoxide diffusion (DL(CO)), its membrane diffusion (D(M)) and capillary blood volume (V(C)) subcomponents, and mean right atrial (rap) and mean pulmonary wedge (wpp) pressures after saline or 5% D-glucose solution infusions were compared with baseline in 26 moderate CHF patients. Saline was also tested in 13 healthy controls. In patients, 750 mL of saline lowered DL(CO) (-8%, P<0.01 versus baseline), D(M) (-10%, P<0.01 versus baseline), aldosterone (-29%, P<0.01 versus baseline), renin (-52%, P<0.01 versus baseline), and hematocrit (-6%, P<0.05 versus baseline) and increased V(C) (20%, P<0.01 versus baseline), without changing rap and wpp. Saline at 150 mL produced qualitatively similar results regarding DL(CO) (-5%, P<0.01 versus baseline), D(M) (-7%, P<0.01 versus baseline), V(C) (9%, P<0.01 versus baseline), rap, wpp, aldosterone (-9%, P<0.05 versus baseline), and renin (-14%, P<0.05 versus baseline). Glucose solution (750 mL), on the contrary, increased DL(CO) (5%, P<0.01 versus 750 mL of saline) and D(M) (11%, P<0.01 versus 750 mL of saline) and decreased V(C) (-9, P<0.01 versus 750 mL of saline); aldosterone (-40%), renin (-41%), hematocrit (-3%), rap, and wpp behaved as they did after saline infusion. In controls, responses to both saline amounts were similar to responses in CHF patients regarding aldosterone, renin, hematocrit, rap, and wpp, whereas DL(CO), D(M), and V(C) values tended to rise. Hindrance to gas transfer (reduced DL(CO) and D(M)) with salt infusion in CHF, despite an increase in V(C) and no variations in pulmonary hydrostatic forces, indicates an upregulation in sodium transport from blood to interstitium with interstitial edema. Redistribution of blood from the lungs, facilitating interstitial fluid reabsorption, or sodium uptake from the alveolar lumen by the sodium-glucose cotransport system might underlie the improved alveolar-capillary conductance with glucose.

Background: Chronic heart failure causes disturbances in ventilation and pulmonary gas transfer that participate in limiting peak exercise oxygen uptake (VO(2p )). The beta-adrenergic receptor blocker carvedilol improves left ventricular (LV) function and not VO(2p). This study was aimed at investigating the pulmonary response to changes in LV performance produced by carvedilol in patients with chronic heart failure., Methods: Twenty-one patients with New York Heart Association class II to III heart failure were randomly assigned (2 to 1) to carvedilol (25 mg twice daily, n = 14) or placebo (n = 7) for 6 months. Rest forced expiratory volume (FEV(1)), vital capacity, total lung capacity, carbon monoxide diffusing capacity, its alveolar-capillary membrane component, pulmonary venous and transmitral flows (for monitoring changes in LV end-diastolic pressure), LV diastolic and systolic dimensions, stroke volume, ejection fraction, and fiber shortening velocity were measured at baseline and at 3 and 6 months. VO(2p), peak ratio of dead space to tidal volume (VD/VT(p)), ventilatory equivalent for carbon dioxide production (VE/VCO(2)), and VO(2) at anaerobic threshold (VO(2at)) were also determined., Results: FEV(1), vital capacity, total lung capacity, carbon monoxide diffusing capacity, and the alveolar-capillary membrane component were impaired in chronic heart failure compared with 14 volunteers and did not vary with treatment. Carvedilol reduced end-diastolic pressure, end-diastolic diameter, and end-systolic diameter and increased ejection fraction, stroke volume, and fiber shortening velocity without affecting VO(2p), VO(2at), VD/VT(p), or VE/VCO(2) at 3 and 6 months. Placebo did not produce significant changes., Conclusions: In chronic heart failure carvedilol ameliorates LV function at rest and does not significantly affect ventilation and pulmonary gas transfer or functional capacity. These results suggest that improvement in cardiac hemodynamics with carvedilol does not reverse pulmonary dysfunction. Persistent lung impairment might have some role in the failure of carvedilol to improve exercise performance.

Exercise-induced hemoconcentration is a useful mechanism, particularly in heart failure, because it increases oxygen content of blood, perfusing the working muscles; in 50 normal subjects and 50 patients with congestive heart failure, hemoglobin at peak exercise increased by 7 +/- 3% and 5 +/- 3%, respectively. Hemoconcentration was due to fluid flux out of the vascular bed, likely through oncotic forces related to intracellular lactate accumulation and not to red blood cell recruitment from other organs (spleen), because hemoglobin increase, as a percentage, was similar to plasma protein increase.