Pulmonary hypertension in heart failure with preserved ejection fraction: a target of phosphodiesterase-5 inhibition in a 1-year study.

BACKGROUND: The prevalence of heart failure with preserved ejection fraction is increasing. The prognosis worsens with pulmonary hypertension and right ventricular (RV) failure development. We targeted pulmonary hypertension and RV burden with the phosphodiesterase-5 inhibitor sildenafil. METHODS AND RESULTS: Forty-four patients with heart failure with preserved ejection fraction (heart failure signs and symptoms, diastolic dysfunction, ejection fraction ≥50%, and pulmonary artery systolic pressure >40 mm Hg) were randomly assigned to placebo or sildenafil (50 mg thrice per day). At 6 months, there was no improvement with placebo, but sildenafil mediated significant improvements in mean pulmonary artery pressure (-42.0±13.0%) and RV function, as suggested by leftward shift of the RV Frank-Starling relationship, increased tricuspid annular systolic excursion (+69.0±19.0%) and ejection rate (+17.0±8.3%), and reduced right atrial pressure (-54.0±7.2%). These effects may have resulted from changes within the lung (reduced lung water content and improved alveolar-capillary gas conductance, +15.8±4.5%), the pulmonary vasculature (arteriolar resistance, -71.0±8.2%), and left-sided cardiac function (wedge pulmonary pressure, -15.7±3.1%; cardiac index, +6.0±0.9%; deceleration time, -13.0±1.9%; isovolumic relaxation time, -14.0±1.7%; septal mitral annulus velocity, -76.4±9.2%). Results were similar at 12 months. CONCLUSIONS: The multifaceted response to phosphodiesterase-5 inhibition in heart failure with preserved ejection fraction includes improvement in pulmonary pressure and vasomotility, RV function and dimension, left ventricular relaxation and distensibility (structural changes and/or ventricular interdependence), and lung interstitial water metabolism (wedge pulmonary pressure decrease improving hydrostatic balance and right atrial pressure reduction facilitating lung lymphatic drainage). These results enhance our understanding of heart failure with preserved ejection fraction and offer new directions for therapy. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. UNIQUE IDENTIFIER: NCT01156636.

PDE5 inhibition with sildenafil improves left ventricular diastolic function, cardiac geometry, and clinical status in patients with stable systolic heart failure: results of a 1-year, prospective, randomized, placebo-controlled study.

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.

Six months of Sildenafil therapy improves heart rate recovery in patients with heart failure.

Previous research has demonstrated an increase in large vessel stiffness in patients with heart failure (HF). Furthermore, heart rate recovery (HRR) may be negatively impacted by increased arterial stiffness secondary to altered baroreceptor discharge. The purpose of the present study was to determine if chronic phosphodiesterase 5 (PDE5) inhibition with Sildenafil, previously shown to improve arterial stiffness, favorably impacts HRR in patients with HF. Forty male subjects (age: 65.3+/-7.3 years, baseline ejection fraction: 37.1+/-7.4%, 15 non-ischemic HF/25 ischemic HF) participated in this study. Subjects received Sildenafil (25 mg, 3 times/day) for six months. Symptom-limited exercise testing was performed at baseline and six months with a lower extremity ergometer. Heart rate recovery was defined as HR at maximal exercise minus HR at 1 min recovery. No adverse effects were reported throughout the study period. Paired t-testing revealed that HRR was significantly improved following six months of Sildenafil therapy (baseline: 17.5+/-3.5 bpm vs. Post: 20.6+/-3.2 bpm). The results of the present study indicate that chronic Sildenafil therapy significantly increases HRR, an important prognostic marker, in patients with HF. A plausible mechanism for the improvement of HRR is the previously demonstrated impact Sildenafil has on arterial stiffness and therefore baroreceptor function.

Evolving changes in lung interstitial fluid content after acute myocardial infarction: mechanisms and pathophysiological correlates.

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.

Long-term use of sildenafil in the therapeutic management of heart failure.

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.

Exercise oscillatory breathing and increased ventilation to carbon dioxide production slope in heart failure: an unfavorable combination with high prognostic value.

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.

Exercise metaboreflex activation and endothelial function impairment in atrial fibrillation.

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 exercise performance in lone atrial fibrillation or associated with hypertension or diabetes: different results with cardioversion.

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.

Alveolar-capillary membrane conductance is the best pulmonary function correlate of exercise ventilation efficiency in heart failure patients.

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.

Effects of orthostatic stress on forearm endothelial function in normal subjects and in patients with hypertension, diabetes, or both diseases.

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.

Exercise ventilation inefficiency and cardiovascular mortality in heart failure: the critical independent prognostic value of the arterial CO2 partial pressure.

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.

The effects of phosphodiesterase-5 inhibition with sildenafil on pulmonary hemodynamics and diffusion capacity, exercise ventilatory efficiency, and oxygen uptake kinetics in chronic heart failure.

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.

Influences of sildenafil on lung function and hemodynamics in patients with chronic heart failure.

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.

Clinical validation of different echocardiographic motion pictures expert group-4 algorythms and compression levels for telemedicine.

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.

Exercise hyperventilation, dyspnea sensation, and ergoreflex activation in lone atrial fibrillation.

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.

Improvement of alveolar-capillary membrane diffusing capacity with exercise training in chronic heart failure.

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.

Insulin ameliorates exercise ventilatory efficiency and oxygen uptake in patients with heart failure-type 2 diabetes comorbidity.

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.