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/orneural/hormonal/hemodynamic stimulation might injure the microvascular endothelium, eliciting interstitial overflow and altering alveolar-capillary gas diffusion. In 118 patients with AMI ( ejection fraction >= 50% and wedge pulmonary pressure 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

Insulin improves alveolar-capillary membrane gas conductance in type 2 diabetes.

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 \ub1 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 \ub1 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

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 functio

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 CO2 during exercise (i.e. the VE/VCO2 slope) is a strong prognosticator. VE/Vco(2) slope determinants are the dead space-tidal volume (VD/VT) ratio and the arterial CO2 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 CHIF patients (average left ventricular ejection fraction 34 &PLUSMN; 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 Kaptan-Meier approach with Log-rank testing and by multivariate Cox regression analysis, During a mean period of 31.3 &PLUSMN; 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/VCO2 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. rote in the exercise ventilation inefficiency of CHF patients

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

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 patient

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/m2; 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 VO2), ventilation efficiency (ventilation to CO2 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