AJP - Heart AJP: Endocrinology and Metabolism
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Am J Physiol Heart Circ Physiol 294: H1357-H1364, 2008. First published January 11, 2008; doi:10.1152/ajpheart.00866.2007
0363-6135/08 $8.00
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
294/3/H1357    most recent
00866.2007v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via Web of Science (1)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Guazzi, M.
Right arrow Articles by Guazzi, M. D.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Guazzi, M.
Right arrow Articles by Guazzi, M. D.

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

Marco Guazzi,1 Ross Arena,2 and Maurizio D. Guazzi3

1Cardiopulmonary Unit, Cardiology Division, University of Milano, San Paolo Hospital, Milano, Italy; 2Virginia Commonwealth University, Richmond, Virginia; and 3Institute of Cardiology, University of Milano, Milano, Italy

Submitted 24 July 2007 ; accepted in final form 8 January 2008


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
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 ≥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.

gas diffusion; myocardial function; pulmonary edema

ACUTE ALVEOLAR FLOODING, a prognostically severe complication of acute myocardial infarction (AMI) (1, 13, 21, 22, 31, 32, 40, 41, 42, 43), is currently interpreted as the result of an imbalance in hydrostatic forces by severe myocardial damage and left ventricular (LV) dysfunction and/or mitral insufficiency (4, 14, 15, 38). A less striking form of pulmonary edema after AMI is excessive fluid leakage from capillaries to the alveolar interstitium without alveolar space flooding. The pathophysiological correlates of this occurrence have attracted less attention of investigators and have been the subject of limited research. As stressed by Møller and colleagues in a recent review (25), a basic, still-unanswered question is why pulmonary congestion is frequently seen after what appears to be only minor myocardial damage with only mildly reduced LV ejection fraction (EF). These authors alluded to diastolic rather than systolic dysfunction as a primary mechanism. Another possibility, however, might be that factors different from, or additional to hydrostatic forces, are at work. The inflammatory burden carried by the lungs in the case of AMI or the neural/hormonal stimulation elicited by an abrupt coronary occlusion are putatively blamable to damage the microvascular pulmonary endothelial barrier, which is critical in preventing interstitial fluid overflow and deterioration of alveolar-capillary gas diffusion. An animal study (10) has shown that in experimental AMI, even if of small size and with normal cardiac index at rest, the expression of pulmonary endothelial nitric oxide (NO), a basic regulator of the lung vessel motility and permeability, is unequivocally blunted. We considered the issue worthy of investigation in humans and designed this study accordingly. Basic requirements were that in the acute phase of myocardial infarction, LV systolic and diastolic function impairment were least and that a simple and reliable method was available for monitoring the variations in alveolar interstitial fluid content. We deemed that the assessment of the diffusion capacity of the alveolar-capillary membrane could be such a method, because an increase or a decrease in the fluid amount lengthens or shortens, respectively, the diffusion path between alveoli and capillaries (16) and changes in the same direction the conductance of the blood gas barrier.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Patients and controls. Consecutive patients admitted to the coronary unit, for first AMI (typical chest pain, evolving ST elevation >1 mm in contiguous leads, development of abnormal Q waves, or transient elevation of creatine kinase-MB ≥20 U/l), within 4 h of the beginning of symptoms, were eligible under the following criteria: they did not have clinical or chest X-ray evidence of congestive heart failure, aortic valve disease, diabetes (17), pulmonary disease, cardiac hypertrophy, and a pack year index of smoking ≥10; they had not smoked over the last 8 mo; mitral regurgitation, when present, did not exceed grade 2 on a scale from 0 to 5 as evaluated by the area of the regurgitant jet by color Doppler (4) and by the amplitude of the v wave in the wedge pulmonary pressure (WPP) tracing; LV EF was ≥50%; and the mean WPP did not exceed 16 mmHg. The patients' ages were between 40 to 70 yr. One hundred eighteen patients were enrolled in the study. Twenty-five healthy subjects, who were similar in age and physical characteristics to the patients and who were nonsmokers or ex-smokers of at least 8 mo with a pack year index of smoking ≤10, volunteered to serve as controls; they had been admitted to the hospital because of atypical chest pain and had no history of respiratory disease. Physical examination, electrocardiogram, echocardiogram, chest X-ray, and coronary angiography were all normal for the healthy subjects.

The institutional Ethics Committee approved the protocol, and written informed consent was obtained from each subject. The procedures followed were in accordance with institutional guidelines.

Echocardiographic and Doppler experiments. Two-dimensional and Doppler measurements were performed according to recommendations of the American Society of Echocardiography (35) with a Hewlett-Packard (Andover, MA) Sonos 5500 cardiac ultrasound unit using a 2.5-MHz transducer. Blood pressure and heart rate were monitored simultaneously. LV volume and EF were determined using Simpson's method. Mitral and venous pulmonary (4-mm sample volume placed in the right upper pulmonary vein) flows were evaluated by pulsed Doppler techniques in the apical four-chamber view, and values were calculated from an average of five consecutive cardiac cycles. Pulmonary venous flow was obtained in 87% of cases. Standard presets, optimized to eliminate background noise and enhance tissue signals, and a 5- to 10-mm sample volume placed at the lateral and septal mitral annular margins in the four-chamber view were used to acquire medial and lateral early diastolic mitral annular velocities by tissue Doppler imaging (Ea) and E/Ea values; medial and lateral Ea values were averaged (26). Systolic LV performance was evaluated with EF, systolic wall stress versus endocardial shortening, end-systolic pressure (ESP) versus end-systolic volume (ESV), and the slope of this relationship (Ees). Diastolic function (45) was assessed with Ea, relationship of the WPP versus LV end-diastolic volume (EDV), ratios of E/Ea [an index that has been demonstrated to correlate with mean left atrial pressure (28)] and EDV, ratios of mitral E to mitral A velocity (E/A), ratios of venous systolic pulmonary flow velocity to peak diastolic velocity (S/D), and the deceleration time of mitral E velocity (DT). LV midwall systolic stress (MWSS) and midwall fractional shortening (MWFS) were calculated by preset formulas (36, 44).

Pulmonary function. Forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1), and carbon monoxide diffusing capacity (DLCO) were measured with the Sensormedics 2200 Pulmonary Function Test System (Sensormedics, Yorba Linda, CA) according to reference equations (17). DLCO was determined with a standard single breath technique using a test gas with 0.28% carbon monoxide, 0.3% acetylene, 0.3% methane, and 21% oxygen with the balance made up of nitrogen. Measurements were then repeated using test gases with 40% and 60% oxygen concentrations. The alveolar-capillary membrane conductance (DM) and pulmonary capillary blood volume (Vc) were assessed with the classic method of Roughton and Forster (34), which partitions pulmonary diffusion into the diffusive resistance of the alveolar-capillary membrane and the reactive resistance due to pulmonary capillary blood.

Study design. Soon after patient arrival in the coronary care unit, before coronary angiography and primary percutaneous reperfusion, measurements were performed of the echocardiographic variables and WPP through a double-lumen catheter introduced percutaneously into an antecubital vein and advanced through the pulmonary artery far out into the lung field until its end became impacted in one of the smaller branches; the wedge tracing had a characteristic configuration, and blood withdrawn from the catheter had an oxygen saturation within the systemic arterial range. In patients in whom values of EF and WPP satisfied the eligibility criteria, we proceeded to the assessment of FVC, FEV1, DLCO, and its two subcomponents DM and Vc; in each of these patients, we then infused 150 ml of 0.9% NaCl solution into the main stem of the pulmonary artery over 10 min and estimated the effects on alveolar capillary membrane conductance by repeating DLCO, DM, and Vc measurements after the infusion. Details of this procedure have been described in a previous report (18). Right atrial pressure and WPP were continuously recorded before, during, and after the saline infusion. The catheter was withdrawn after the procedure and was reintroduced percutaneously on day 7 for measurements and infusions. Studies of reproducibility have shown a high level of agreement between consecutive measurements of 1/DM with a correlation coefficient of 0.94 and a coefficient of variation of <5%. Under the present study protocol, we found no evidence of significant carbon monoxide backpressure effects on serial DLCO, DM, and Vc determinations. All procedures were completed within 1 h or less and were repeated, by the same examiners, 7 days after. The same protocol for the evaluation of the lung diffusion capacity and of the effects on it of saline infusion was also applied, before coronary angiography, in patients with atypical chest pain, and results in 25 subjects without angiographic evidence of coronary disease were used as reference values.

Ultrasound images were stored onto a magnetic optical disk and analyzed by an echocardiologist blinded to clinical, hemodynamic, and pulmonary function data. Those performing the pulmonary tests were blinded to the ultrasound results. Patients having an increase of DM >5% or a decrease >5% from admission to 1 wk followup were categorized to have improvement or worsening of the alveolar-capillary interface conductance, respectively; seven patients with variations ≤5% were classified as having DM unchanged. By these criteria, 83 patients were assigned to the improvement group (group 1) and 28 patients were assigned to the worsening group (group 2).

Primary percutaneous coronary reperfusion was performed in all patients but four and was successful in 77% of cases in group 1 and 81% of cases in group 2. The infarct-related artery was determined from ECG, wall motion, and evidence of residual thrombus in the culprit stenosis (the most severe proximal stenosis) at angiography.

All patients continued aspirin (100 mg/day), metoprolol (50–100 mg/day) or atenolol (50 mg/day), ramipril (5 mg/day), and statin during the 1-yr followup. At the end of the first month, echocardiographic variables and alveolar-capillary membrane conductance were evaluated again in each patient. Death from cardiac pump failure and development of acute alveolar edema were the outcome variables and were assessed by clinical databases, a bimonthly return visit at the outpatient clinic, and review of readmission records during followup. In a few cases in which vital or clinical status could not be determined from these methods, the patient's physician was visited and interviewed.

L-Arginine infusion. For mechanistic insights, we investigated whether endogenously synthetized lung capillary NO, a basic regulator of lung vessel tone and permeability (6), may be implicated in the presumed nonhydrostatic interstitial fluid swelling in the acute phase of myocardial infarction. To this end, we investigated the alveolar-capillary interface conductance correlates of NO pathway overexpression with L-arginine in 37 additional patients. Eligibility criteria were those reported above. Hemodynamic, ultrasound, and lung function procedures were also the same. On day 1, DLCO, DM, and Vc were assessed at baseline, after an infusion of saline (150 ml) or L-arginine (200 mg/kg vehicled by 150 ml of saline over 10 min), and again 10 h later after an infusion of saline with or without L-arginine, according to a double-blind crossover design. On day 7, DLCO, DM, and Vc were reassessed at the baseline as well as after saline and L-arginine vehicled by saline infusion with the same modalities as on day 1. Patients having an increase of baseline DM >5% or a decrease of >5% from days 1 to 7 were categorized to have improvement or worsening of the alveolar-capillary membrane conductance, respectively; 3 patients with variations ≤5% were classified as having DM unchanged. According to this, the improvement group (group A) was composed of 24 patients, and the worsening group (group B) was composed of 10 patients. The effects of L-arginine and DM were also tested in 11 healthy control subjects whose age and somatic characteristics were similar to those of the patients.

Statistical analysis. Data are presented as means ± SD. Descriptive parameters were compared by {chi}2-analysis. Data were analyzed by two-way repeated-measures ANOVA with the Neumann-Keuls multiple-comparison procedure. We conducted linear univariate regression analysis to assess the significance of associations between DM and its possible correlates. To determine which of these factors were significant independent determinants of DM, we used multivariate regression analysis.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 GRANTS
 REFERENCES
 
Clinical characteristics. Groups 1 and 2 did not differ with respect to body mass index, gender, blood pressure, or LV mass index, which, in no cases, exceeded 134 g/m2 (9). These variables were similar in control subjects. Mitral regurgitation and drug treatment in groups 1 and 2 were also similar. Patients in group 2 were slightly older and more often had anterior AMI (Table 1).


View this table:
[in this window]
[in a new window]

  		Table 1. Clinical and demographic characteristics of the study cohorts

 
Pulmonary function. Values of FVC and FEV1 exceeded 90% normal predicted in both groups, were comparable with those in controls, and did not show variations at 1-wk measurements (Table 2). The two cohorts of patients were also homogeneous with respect to baseline DLCO and DM. In both cohorts, these variables at admission were significantly lower than in 25 healthy control subjects. At 1 wk, according to the grouping criteria, DLCO and DM were raised in group 1 to values comparable with those in the control group, whereas in group 2, they were further reduced. In group 1 and group 2, Vc was reduced and augmented, respectively. Hematocrit was similar and steady in either group; C-reactive protein, as a marker of inflammation, was also similar at admission and exhibited a comparable decay (Table 2).


View this table:
[in this window]
[in a new window]

  		Table 2. Pulmonary function, hematocrit, and C-reactive protein levels in controls, group 1, and group 2 at admission and at 1 wk and 1 mo after admission

 
Saline infusion. In healthy subjects, saline did not interfere with the alveolar-capillary membrane conductance (Table 3). In contrast, in patients with AMI, after the administration of 150 ml of saline we recorded a significant reduction from baseline of DLCO and DM in both group 1 (DLCO: –5.9% and DM: –6.8%) and group 2 (DLCO: –6.4% and DM: –7.9%; Table 3). One week later, the saline infusion was ineffective in patients with DLCO and DM recovery (group 1) and still interfered with DLCO (–8.1%) and DM (–8.4%) in patients with DLCO and DM worsening (group 2).


View this table:
[in this window]
[in a new window]

  		Table 3. Hemodynamic variables and lung diffusion capacity in controls, group 1, and group 2 at baseline and immediately after 150-ml saline infusion in the pulmonary circulation

 
Systolic performance. Parameters reflecting LV systolic performance were comparable at admission in the two groups of patients (Table 4). EF, ESP/ESV, Ees, and MWFS did not vary after 1 wk, and no significant group differences were evident over this period. When values of MWFS/MWSS were plotted, values for patients having DM improvement were scattered among those of patients having DM deterioration at both admission (Fig. 1, left) and 1 wk later (Fig. 1, right), suggesting that the LV afterload-fiber shortening relationship was similar on either occasion in the two groups.


View this table:
[in this window]
[in a new window]

  		Table 4. LV systolic performance at admission at the 1-wk and 1-mon follow-up

 

Figure 1
View larger version (11K):
[in this window]
[in a new window]

  		Fig. 1. Relationship between midwall fractional shortening (MWFS) and midwall systolic stress (MWSS) in patients in group 1 [diffusing membrance conductance (DM) improved] and group 2 (DM worsened). Values for patients in group 1 were scattered among those of patients in group 2 both at admission (left) and on day 7 (right).

 
Diastolic function. At admission, there were no group differences in variables related with LV diastolic function (Table 5). Notably, WPP tightly and significantly (r = 0.89, P < 0.01) correlated with LVEDP, as obtained during coronary angiography. At 1 wk, group 2 but not group 1 showed an increase in DT, E/A, WPP, E/Ea/EDV, WPP/EDV, and left atrial area and a decrease of Ea velocity and S/D ratio. In group 2, the anterior location of the AMI as well as E/A and S/D at day 7 were weakly correlated with DM (anterior AMI, r = 0.33 and P = 0.01; E/A, r = –0.28 and P = 0.03; and S/D, r = 0.30 and P = 0.02), whereas DT (r = –0.53 and P < 0.001), WPP (r = –0.62 and P < 0.001), left atrial area (r = –0.77 and P < 0.01), WPP/EDV (r = –0.67 and P < 0.001), and Ea (r = +0.71 and P < 0.001) were strongly correlated with DM. The multivariate regression model showed that DT, WPP, E/a, WPP/EDV, and left atrial area were significant independent variables, and the association was more evident for left atrial area (β = 0.49 and P < 0.0001) and Ea (β = 0.41 and P < 0.001) compared with DT (β = 0.29 and P = 0.0006) and WPP/EDV (β = 0.25 and P = 0.0007). When WPP versus EDV at admission and on day 7 were plotted (Fig. 2), admission coordinates were not different between the groups; on day 7, EDV was still similar, but WPP was significantly augmented, in group 2, which is consistent with an upward shift of the diastolic pressure-volume relationship in group 2.


View this table:
[in this window]
[in a new window]

  		Table 5. Variables reflecting LV diastolic function at admission and at 1 wk and 1 mo after admission

 

Figure 2
View larger version (9K):
[in this window]
[in a new window]

  		Fig. 2. Mean wedge pulmonary pressure/left ventricular end-diastolic volume coordinates at admission and the corresponding coordinates (arrows) detected after the 1-wk followup. Values are means ± SD. *P < 0.01 vs. admission.

 
Followup. After a month, two patients in group 1 and one patient in group 2 were lost to followup (for family reasons or because they moved to another town). Compared with day 7, lung diffusion capacity and alveolar-capillary membrane conductance (Table 2), LV systolic performance (Table 4), and ultrasound variables reflecting diastolic function (Table 5) were unchanged.

Clinical outcomes are reported in Table 6. During the 1-yr followup, 13 patients in group 2 developed dyspnea and X-ray evidence of lung congestion, and 10 of them had 1 or more episodes of acute alveolar edema. In the same group, there were nine cardiovascular deaths. All these results were significantly greater than in group 1.


View this table:
[in this window]
[in a new window]

  		Table 6. Clinical outcomes

 
L-Arginine infusion. Results of L-arginine infusions are shown in Table 7. Among patients specifically recruited for endogenous NO synthesis overexpression testing with L-arginine, 24 patients (group A) had DM improvement at 1 wk without systolic and diastolic function variations and 10 patients (group B) developed DM worsening and diastolic dysfunction, duplicating the same pattern already described for group 2 in the main study population. On day 1, baseline DM values were similar in groups A and B; in both groups, saline was effective in reducing DM (by 8.0% in group A and by 7.6% in group B). In contrast, when L-arginine was added to saline, DM was raised by 36.3% of baseline in group A and by 34.4% in group B. On day 7, DM was lowered by 6.9% with saline alone and was increased by 55.6% by L-arginine combination in group B; saline was ineffective and L-arginine raised DM by 16.3% in group A. Notably, a comparable increase of DM (+18.5%, P < 0.01) with L-arginine was recorded in 11 normal control subjects of similar age and somatic characteristics. In neither cohort were variations in mean pulmonary arterial pressure and WPP with L-arginine significant.


View this table:
[in this window]
[in a new window]

  		Table 7. Lung diffusion capacity in groups A and B at baseline and after infusion of saline alone and saline with L-arginine

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
The observations of the present study apply to patients with first AMI, with only a mildly depressed EF. In the acute phase, DM values are reduced in these patients compared with values reported as normal in the literature (27) and with results in healthy subjects with similar demographic characteristics. Saline infusion in the pulmonary circulation makes more critical the resistance to gas transfer. Alveolar-capillary membrane function recovers and saline becomes ineffective within a week, unless LV dysfunction supervenes.

Lung interstitial fluid in AMI. Conductance of the alveolar-capillary membrane depends on its functional and structural properties and on the distance separating the alveolar epithelium from the capillary endothelium. The main determinant of the distance is the interstitial fluid, whose amount is regulated by hydrostatic and osmotic forces and by the sodium exchange/water conductance across the pulmonary capillary wall.

The interpretation that the reduced membrane conductance in AMI reflects a hydrostatic imbalance due to dysfunction of the LV, although simple and rational, is not fully satisfactory for the following reasons. In this study, LV EF was, by selection, ≥50%, and WPP averaged 14.1 mmHg in group 1 and 13.8 mmHg in group 2. At 1 wk, reversion of DM to normal in group 1 was not associated with any changes from admission regarding cardiac performance and WPP. In AMI patients and not in healthy subjects, 150 ml of saline were effective in worsening the blood gas barrier conductance. Previous studies (18, 33) have shown that the infusion of saline in the pulmonary circulation with contemporary DM measurement is a reliable method to probe sodium transport across the pulmonary capillary endothelium and that, when transport is challenged, even an amount of saline as small as the pulmonary blood capillary volume in a supine individual (150 ml) may significantly depress the membrane conductance (18). After 1 wk, saline had no measurable effect on gas diffusion in patients with DM recovery (group 1) and still impeded gas transfer in those without DM recovery (group 2), prospecting a link between improved DM and restored salt exchange/water conductance.

Taken together, these considerations support the concept that an altered translocation of fluid from the intravascular to alveolar interstitial compartment are not unusual in AMI. Because of the inflammatory burden carried by the lung, as suggested by C-reactive protein levels, and/or of the remarkable neural, hormonal, and hemodynamic alterations that occur with an abrupt interruption of coronary flow, AMI is putatively blamable for deranging physiology of the blood gas barrier. We can only speculate about the factors involved. Because in many patients DM recovered within 1 wk, discussion should be restricted to mechanisms that can hurt the blood gas barrier in a reversible manner (12), such as the following: 1) lung vascular remodeling mediated by alveolar hypoxia through an increase in gene expression of extracellular matrix proteins (2); 2) upregulation of sodium transport across capillaries (8) or downregulation across the alveolar epithelium (29) due to the release of cellular growth factors and proinflammatory cytokines or to circulating microparticles (3); and 3) failure of the capillary membrane to withstand stress (43) imposed by a sudden and transient rise of the pulmonary capillary transmural pressure that accompanies abrupt cessation of coronary flow and raises the endothelium permeability to sodium (16).

Pulmonary NO synthesis. Several animal (39) and human (23) studies have demonstrated an improvement in endothelial function and an increase in NO production (7) in response to oral or intravenous supplementation of L-arginine, the precursor of NO synthesis. Increasing NO substrate availability has also been shown to restore endothelium-dependent relaxation in the pulmonary circulation of hypoxic rats (11) and overcome the pulmonary vasoconstrictor activity of NG-monomethyl-L-arginine, an antagonist of NO synthesis, in normal children (5). On this basis, we utilized supplementation of the NO substrate L-arginine in the lesser circulation to probe a possible involvement of altered NO pathway synthesis in the alveolar-capillary membrane dysfunction produced by AMI. Findings are strongly in favor of a mechanistic role of NO impairment in the impeded gas transfer in AMI, given the ability of L-arginine to bring DLCO and DM back toward normal, to increase DM under normal conditions as well, and, even more impressively, to modulate the endothelial transport of sodium and water. This belief is in agreement with studies showing blunted NO expression in experimental AMI (10) and improved alveolar-capillary interface conductance in heart failure patients in whom the molecular pathway originated from NO is enhanced by phosphodiesterase-5 inhibition (19, 20, 30). NO is a known pulmonary vasodilator, and a confounding effect of reduced impedance to right ventricular ejection cannot be ruled out. However, failure to detect in our patients significant changes in arterial pressure and WPP does not corroborate this possibility.

LV diastolic function. An explanation for the within-group variations and the between-group differences in alveolar-capillary interface conductance might be that changes in hematocrit modified the binding capacity for carbon monoxide or that patients with DM improvement were those in whom inflammation caused by AMI had resolved. These explanations, however, are inconsistent with the similar decay in C-reactive protein levels and the persistent similarity of hematocrit in groups 1 and 2.

The study emphasizes LV relaxation, WPP, Ea, the wedge pulmonary pressure-EDV relationship, and left atrial dimension (25) as remarkable contributors to the enhancement of the alveolar-capillary interface dysfunction in group 2 patients. Although the exact time relationship between DM worsening and diastolic impairment is unknown (data from the interval between admission and day 7 are not available), a cause-and-effect relationship seems reasonable. Whether diastolic deterioration alone augmented the alveolar interstitial fluid and worsened gas diffusion, or whether there was an interaction with the initial injury of the blood gas barrier, is basically unproven. Nonetheless, the shift of DM from a value of 29% lower than in healthy controls at admission to a value of 50% lower at 1 wk and 48% lower at 1 mo is in favor of an additive or synergistic effect. The ability of L-arginine supplementation to improve DM and counteract saline at 1 wk in similar patients and under the same experimental conditions suggests that NO synthesis impairment maintains a role in depressing the blood gas barrier conductance also after supervenience of diastolic dysfunction and hydrostatic imbalance. On this basis, the alveolar-capillary membrane injury in AMI does not seem to be just a reversible epiphenomenon but rather a disorder that in the case of supervenient LV function deterioration persists and interacts with a hydrostatic imbalance in facilitating fluid translocation to the interstitial compartment.

Diastolic dysfunction in group 2 might have resulted from the contribution of age (3, 16), stunning (24, 37), and predominance of an anterior site of AMI (with anterior AMIs, which are generally larger, a persistent demand of increased performance put on the controlateral area to maintain stroke volume and an inability to meet this demand would facilitate impaired relaxation and compliance).

Clinical perspectives. This study reinforces the concept that, despite only mildly reduced LV EF, the AMI outcome may be unfavorable (25) and liability to alveolar flooding may be enhanced in a considerable proportion of patients developing diastolic dysfunction and LV filling pressure elevation (25). Although the final achievement of DM was not assessed and changes in LV function that apply to late alveolar edema are unknown, the study adds another piece of knowledge to the pathophysiology of congestive heart failure in AMI. In fact, it shows that an impaired alveolar-capillary membrane sodium exchange/water conductance may have a role in the fluid translocation to the interstitial compartment and prelude the development of alveolar flooding. This may lead to new opportunities of reducing risk and improving outcomes and attribute a predicting significance to serial assessments of the blood gas barrier conductance.


   GRANTS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
REFERENCES
 
This work was supported by the Monzino Foundation and by a grant from Piera Almini Radice in memory of Bruno Radice.


   FOOTNOTES
 

Address for reprint requests and other correspondence: M. Guazzi, Cardiopulmonary Unit, Cardiology Division, Univ. of Milano, San Paolo Hospital, Via A. di Rudinì 8, Milano 20142, Italy (e-mail: marco.guazzi{at}unimi.it)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


   REFERENCES
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 

  1. Baicu CF, Zile MR, Aurigemma GP, Gaash WH. Left ventricular systolic performance, function, and contractility in patients with diastolic heart failure. Circulation 111: 2306–2312, 2005.[Abstract/Free Full Text]
  2. Berg JT, Breen EC, Fu Z, Mathieu-Costello O, West JB. Alveolar hypoxia increases gene expression of extracellular matrix proteins and platelet-derived growth factor-B in lung parenchyma. Am J Respir Crit Care Med 158: 1920–1928, 1998.[Abstract/Free Full Text]
  3. Boulanger CM, Scoazek A, Ebrahimian T, Henry P, Mathieu E, Tedgui A, Mallat Z. Circulating microparticles from patients with myocardial infarction cause endothelial dysfunction. Circulation 114: 438–444, 2006.[Free Full Text]
  4. Bursi F, Enriquez-Sarano M, Nkomo VT, Jacoben SJ, Weston SA, Meverden RA, Roger VL. Heart failure and death after myocardial infarction in the community. The emerging role of mitral regurgitation. Circulation 111: 295–301, 2005.[Abstract/Free Full Text]
  5. Celermaier DS, Dollery C, Burch M, Deanfield JE. Role of endothelium in the maintenance of low pulmonary vascular tone in normal children. Circulation 89: 2041–2044, 1994.[Abstract/Free Full Text]
  6. Cooper CJ, Landzberg MJ, Anderson TJ, Charbonneau F, Creager MA, Ganz P, Selwin AP. Role of nitric oxide in the local regulation of pulmonary vascular resistance in humans. Circulation 93: 226–271, 1996.
  7. Creager MA, Gallager SJ, Girard XJ, Coleman SM, Dzau VJ, Cooke JP. Long-term L-arginine supplementation improves small-vessel endothelial function in humans. J Clin Invest 90: 1248–1253, 1992.[Web of Science][Medline]
  8. De Pasquale CG, Arnolda LF, Doyle IR, Grant RL, Aylward PE, Bersten AD. Prolonged alveolocapillary barrier damage after acute cardiogenic pulmonary edema. Crit Care Med 31: 1060–1067, 2003.[CrossRef][Web of Science][Medline]
  9. Devereux RB, Lutas EM, Casale PN, Kligfield P, Eisenberg RR, Hammond IW, Miller DH, Reis G, Alderman MH, Laragh JH. Standardization of M-mode echocardiographic left ventricular anatomic measurements. J Am Coll Cardiol 4: 1222–1230, 1984.[Abstract]
  10. Driss AB, Devaux C, Henrion D, Duriez M, Thuillez C, Levy BI, Michel JB. Hemodynamic stresses induce endothelial dysfunction and remodelling of pulmonary artery in experimental compensated heart failure. Circulation 101: 2764–2770, 2000.[Abstract/Free Full Text]
  11. Eddahibi S, Adnot S, Carville C, Blouquit Y, Raffestin B. L-Arginine restores endothelium-dependent relaxation in pulmonary circulation of chronically hypoxic rats. Am J Physiol Lung Cell Mol Physiol 263: L194–L200, 1992.[Abstract/Free Full Text]
  12. Elliot AR, Fu Z, Tsukimoto K, Prediletto R, Mathieu-Costello O, West JB. Short-term reversibility of ultrastructural changes in pulmonary capillaries caused by stress failure. J Appl Physiol 23: 1150–1158, 1992.
  13. Figueras J, Peña C, Soler-Soler J. Thirty day prognosis of patients with acute pulmonary oedema complicating acute coronary syndromes. Heart 91: 889–893, 2005.[Abstract/Free Full Text]
  14. Finsen AV, Christensen G, Sjaastad I. Echocardiographic parameters discriminating myocardial infarction with pulmonary congestion from myocardial infarction without congestion in the mouse. J Appl Physiol 98: 680–689, 2005.[Abstract/Free Full Text]
  15. Gomez AM, Guatimosims S, Dilly KW, Vassort G, Lederer WJ. Heart failure after myocardial infarction. Altered excitation contraction coupling. Circulation 104: 688–693, 2001.[Abstract/Free Full Text]
  16. Guazzi M. Alveolar-capillary membrane dysfunction in heart failure. Evidence of a pathophysiological role. Chest 124: 1090–1102, 2003.[CrossRef][Web of Science][Medline]
  17. Guazzi M, Brambilla R, De Vita S, Guazzi MD. Diabetes worsens pulmonary diffusion in heart failure, and insulin counteracts this effect. Am J Respir Crit Care Med 166: 978–982, 2002.[Abstract/Free Full Text]
  18. Guazzi M, Agostoni P, Bussotti M, Guazzi MD. Impeded alveolar-capillary gas transfer with saline infusion in heart failure. Hypertension 34: 1202–1207, 1999.[Abstract/Free Full Text]
  19. Guazzi M, Tumminello G, Di Marco F, Fiorentini C, Guazzi MD. The effects of phosphodierterase-5 inhibition with sildenafil on pulmonary hemodynamics and diffusion capacity, exercise ventilation efficiency and oxygen uptake kinetics in chronic heart failure. J Am Coll Cardiol 44: 2339–2348, 2004.[Abstract/Free Full Text]
  20. Guazzi M, Samaja M, Arena R, Vicenzi M, Guazzi MD. Long-term use of sildenafil in the therapeutic management of heart failure. J Am Coll Cardiol 50: 2136–2144, 2007.[Abstract/Free Full Text]
  21. Harrison JK, Califf RM, Woodlief LH, Kereiakes D, George BS, Stack RS, Ellis SG, Lee KL, O'Neil W, Topol EJ, the Study Group TAMI. Systolic left ventricular function after reperfusion therapy for acute myocardial infarction. Circulation 87: 1531–1541, 1993.[Abstract/Free Full Text]
  22. Hellermann JP, Jacobsen SJ, Gersh BJ, Rodeheffer RJ, Reeder GS, Roger VL. Heart failure after myocardial infarction: a review. Am J Med 113: 324–330, 2002.[CrossRef][Web of Science][Medline]
  23. Kaye DM, Ahlers BA, Autelitano DJ, Chin-Dusting JPF. In vivo and in vitro evidence for impaired arginine transport in human heart failure. Circulation 102: 2707–2712, 2000.[Abstract/Free Full Text]
  24. Lee KL, Woodlief LH, Topol EJ, Weaver WD, Betriu A, Col J, Simoons M, Aylward P, Van der werf F, Califf RM. Predictors of 30 day mortality in the era of reperfusion for acute myocardial infarction. Results from an international trial of 41 or 21 patients. GUSTO-I Investigators. Circulation 91: 1659–1668, 1995.[Abstract/Free Full Text]
  25. Møller JE, Pellikka PA, Hillis GS, Oh JK. Prognostic importance of diastolic function and filling pressure in patients with acute myocardial infarction. Circulation 114: 438–444, 2006.[Free Full Text]
  26. Mottram PM, Marwick TH. Assessment of diastolic function: what the general cardiologist needs to know. Heart 91: 681–695, 2005.[Free Full Text]
  27. Murray JF, Nadel JA. Textbook of Respiratory Medicine (2nd ed.). London: WB Saunders, 1994, p. 897.
  28. Nagueh SF, Middleton KJ, Kapelen HA, Zoghbi WA, Quiñones MA. Doppler tissue imaging: a non-invasive technique for evaluation of left ventricular relaxation and estimation of filling pressures. J Am Coll Cardiol 30: 1527–1533, 1997.[Abstract]
  29. Olivera WG, Ridge KM, Sznajder JI. Lung liquid clearance and Na+,K+-ATPase during acute hyperoxemic and recovery in rats. Am J Respir Crit Care Med 152: 1229–1234, 1995.[Abstract]
  30. Opie LH, Commerford PJ, Gersh B, Pfeffer MA. Controversies in ventricular remodelling. Lancet 367: 356–367, 2006.[CrossRef][Web of Science][Medline]
  31. Persson H, Linder-Klingsell E, Eriksson SV, Erhardt L. Heart failure after myocardial infarction: the importance of diastolic function. A prospective clinical and echocardiographic study. Eur Heart J 16: 496–505, 1995.[Abstract/Free Full Text]
  32. Poulsen SH, Jensen SE, G{phi}tzsche O, Egstrup K. Evaluation and prognostic significance of left ventricular diastolic function assessed by Doppler echocardiography in the early phase of a first acute myocardial infarction. Eur Heart J 18: 1882–1889, 1997.[Abstract/Free Full Text]
  33. Puri S, Dutka DP, Baker L, Hughes JM, Cleland JGF. Acute saline infusion reduces alveolar-capillary gas conductance and increases airflow obstruction in patients with left ventricular dysfunction. Circulation 99: 1190–1196, 1999.[Abstract/Free Full Text]
  34. Roughton FJW, Forster FE. Relative importance of diffusion and chemical reaction rate of exchange of gases in human lung, with special reference to true diffusing capacity of blood in the lung capillaries. J Appl Physiol 11: 290–302, 1957.[Abstract/Free Full Text]
  35. Schiller NB, Shah PM, Crawford M, DeMaria A, Devereux R, Feigenbaum H, Gutgesell H, Reichek N, Sahn D, Schnittger I, Silverman NH, Tajik J. Recommendations for quantitation of the left ventricle by two-dimensional echocardiography. American Society of Echocardiography Committee on Standards, Subcommittee on Quantitation of Two-Dimensional Echocardiograms. J Am Soc Echocardiogr 2: 358–367, 1989.[Medline]
  36. Shimizu G, Hirota Y, Kita Y, Kawamura K, Saito T, Gaasch WH. Left ventricular midwall mechanics in systemic arterial hypertension: myocardial function is depressed in pressure overload hypertrophy. Circulation 83: 1676–1684, 1991.[Abstract/Free Full Text]
  37. Solomon SD, Glynn RJ, Greaves S, Ajani U, Rouleau JL, Menapace F, Arnold JM, Hennekens C, Pfeffer MA. Recovery of ventricular function after myocardial infarction in the reperfusion era: the healing and early afterload reducing therapy study. Ann Intern Med 134: 451–458, 2001.[Abstract/Free Full Text]
  38. Spencer FA, Meyer TE, Gore JM, Goldberg RJ. Heterogeneity in the management and outcomes of patients with acute myocardial infarction complicated by heart failure. The national registry of myocardial infarction. Circulation 105: 2605–2610, 2002.[Abstract/Free Full Text]
  39. Sun D, Messina EJ, Koller A, Wolin MS, Kaley G. Endothelium-dependent dilation to L-arginine in isolated rat skeletal muscle arterioles. Am J Physiol Heart Circ Physiol 262: H1211–H1216, 1992.[Abstract/Free Full Text]
  40. Vasan RS, Larson MG, Benjamin EJ, Evans JC, Reiss CK, Levy D. Congestive heart failure in subjects with normal versus reduced left ventricular ejection fraction: prevalence and mortality in a population-based cohort. J Am Coll Cardiol 33: 1948–1955, 1999.[Abstract/Free Full Text]
  41. Vasan RS, Levy D. Defining diastolic heart failure. A call for standardized diagnostic criteria. Circulation 101: 2118–2121, 2000.[Free Full Text]
  42. Velazquez EJ, Pfeffer MA. Acute heart failure complicating acute coronary syndromes. A deadly intersection. Circulation 109: 440–442, 2004.[Free Full Text]
  43. Wu AH, Parsons L, Every NR, Bates ER. Hospital outcomes in patients presenting with congestive heart failure complicating acute myocardial infarction. A report from the Second National Registry of Myocardial Infarction (NRMI-2). J Am Coll Cardiol 40: 1389–1394, 2002.[Abstract/Free Full Text]
  44. Yu CM, Lin H, Yang H, Kong SL, Zhang Q, Lee SWL. Progresison of systolic abnormalities in patients with "isolated" diastolic heart failure and diastolic dysfunction. Circulation 105: 1195–1201, 2002.[Abstract/Free Full Text]
  45. Zile MR, Brutsaert DL. New concepts in diastolic dysfunction and diastolic heart failure: part I: diagnosis, prognosis, and measurements of diastolic function. Circulation 105: 1387–1393, 2002.[Free Full Text]




This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
294/3/H1357    most recent
00866.2007v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via Web of Science (1)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Guazzi, M.
Right arrow Articles by Guazzi, M. D.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Guazzi, M.
Right arrow Articles by Guazzi, M. D.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Visit Other APS Journals Online
Copyright © 2008 by the American Physiological Society.