Allergol et Immunopathol 1999;27:5-10.
ORIGINAL ARTICLES
Non invasive assessment of cardiac function in patients with bronchial asthma (BA) or chronic obstructive pulmonary disease (COPD)
G. F. Bagnato*, A. Mileto*, S. Gulli*, S. Piscioneri*, C. Romano*, O. Giacobbe*, R. De Pasquale*, A. Schiava*, S. Gangemi**, A. Forestieri** andF. Purello D''Ambrosio**
*Departement of Internal Medicine. University of Messina, Messina, Italy. **School of Allergy and Clinical Immunology. University of Messina, Messina, Italy.
SUMMARY
Background: most respiratory diseases involve the heart and can lead to acute or chronic pulmonary heart in the most serious cases. The common pathogenetic element is pulmonary arterial hypertension which es secondary to the resistance of the pulmonary circulation together with hypertrophy and/or dilatation of the right ventricle, caused mainly by chronic hypoxia.
Methods and results: in order to verify the effects induced on pulmonary circulation and right heart by BA or COPD the cardiac function was assessed by mono and bidimensional Doppler echocardiography in 10 patients with BA (group A), 10 with COPD (group B) and 10 healthy control subjects (group C).
At the M-mode echocardiography examination no significant difference was observed among the three study groups. By Doppler pw the peak velocity of early tricuspidal flow (VmaxE) was significantly higher in the group A when compared to the group B (p = 0.03).
No subject had pulmonary hypertension. The pulmonary acceleration time (PAT) using pw Doppler technique was similar in groups A and B but it was significantly different when compared to group C (p = 0.006:A vs C; p = 0.03:B vs C).
Conclusions: our results suggest in patients either with BA or COPD, an early involvement of the right heart even if they had a clinical stable condition and no pulmonary hypertension.
Key words: Bronchial asthma. COPD. Pulmonary disease. M-mode echocardiography. PAT. IVRT.
RESUMEN
Antecedentes: La mayoría de las enfermedades respiratorias afectan el corazón y, en los casos más graves, pueden originar neumopatía aguda o crónica. El elemento patogénico común es la hipertensión arterial pulmonar secundaria a la resistencia vascular pulmonar y la hipertrofia y/o dilatación del ventrículo derecho, producidas sobre todo por hipoxia crónica.
Métodos y resultados: Para verificar los efectos inducidos en la circulación pulmonar y corazón derecho por el asma bronquial (AB) o enfermedad pulmonar obstructiva crónica (EPOC), se valoró la función cardíaca por ecocardiografía Doppler mono y bidimensional en 10 pacientes con AB (grupo A), en 10 pacientes con EPOC (grupo B) y en 10 controles sanos (grupo C).
El estudio por ecocardiografía modo M no evidenció ninguna diferencia significativa entre los tres grupos de estudio. Por Doppler pw, la velocidad máxima del flujo temprano por el tricúspide fue significativamente mayor en el grupo A que en el grupo B (p = 0,03).
Ningún sujeto tuvo hipertensión pulmonar. El tiempo de aceleración pulmonar (TAP) utilizando la técnica Doppler pw fue similar en los grupos A y B pero significativamente diferente del grupo C (p = 0,006:A vs C; p = 0,03:B vs C).
Conclusiones: Nuestros resultados sugieren que los pacientes con AB o EPOC tienen una afectación precoz del corazón derecho, incluso cuando su estado clínico es estable y no hay hipertensión pulmonar.
Palabras clave: Asma bronquial. EPOC. Neumopatía. Ecocardiografía modo M. TAP. IVRT.
INTRODUCTION
On one hand the alveolar hypoxemia acts directly on the pulmonary arteriole walls, determining vasoconstriction.
On the other hand, it favours pulmonary hypertension with an indirect mechanism such as compensating polycythemia.
Some authors have suggested that even unprolonged alveolar hypoxia can be the cause of chronic pulmonary heart, because even two hours of hypoxia a day can lead to this pathology (1).
Haemodynamic pulmonary alterations have also been found in patients affected by night desaturation of oxyhaemoglobin, secondary to obstruction from sleep apnea (2).
Blood viscosity increases in the pulmonary circle and together with the hypovolemia and tachychardia induced by hypoxemia, makes the flow rate increase, causing hypertension.
Hypoxia in patients affected by COPD is partly attributed to an alteration in the distribution of the ventilation/perfusion ratio in the pulmonary capillaries (3).
In COPD we find more vascular alterations of the pulmonary circulation through hypoxic vasocons-triction whereas in bronchial asthma the bronchial circulation is more involved, due to inflammation and congestion of the bronchial walls (4, 5).
Under normal conditions, the bronchial flow, even though moderate (1% of the cardiac rate flow), can greatly increase when a pathological condition is present.
The term chronic bronchitis has been used for several pulmonary alterations from simple mucous hypersecretion to advanced chronic obstructive broncopneumonia.
During the latter phase, the intrapulmonary airways are constantly obstructed during exhalation, and this causes an increase in resistance to the airflow (6).
It is believed that the primary cause of bronchial obstruction can be attributed to distal air passages of the bronchial tree.
Pulmonary circulation is constantly involved during the advanced phase of disease, and manifests itself with the symptoms of chronic pulmonary heart (7).
CPH appears earlier in bronchitic patients than in those affected by emphysema, and this suggests that the reduction of the pulmonary vascular bed is not a primary pathogenetic factor in COPD pulmonary hypertension. On the contrary, hypoxia, reducing perfusion in the parts of the lung which are badly ventilated is extremely important.
The effect of chronic hypoxia on pulmonary circulation appears to be caused by structural and functional alterations of the vascular endothelium.
From a functional point of view, the pulmonary vessels in patients affected by COPD show a reduced of no capacity for vessel dilatation due to a defect in synthesis and/or release of nitric oxide (8).
Other humoural mediators such as prostaglandines, ANP, leukotriens, PAF, endothelins and neuro-peptides have been extensively studies (9-12).
Endothelins are peptides released by macro-phages, endothelial and epithelial cells which regulate the pulmonary functions, acting as potent bronchial constrictors.
Endothelin-1 (ET-1) in particular causes a prolonged and strong constriction of the vascular (13) and bronchial smooth muscles (14) and therefore could act on pulmonary vascular alterations in COPD and on the physiopathology of asthma attacks (15).
ET-1 is considered to be released due to the following stimulating factors: hypoxia, thrombin, angiotensin 2, vasopressin, interleukins, atrial natriurethic factor and lipopolysaccarides.
However some data in literature show that ET-1 can cause temporary vasodilation.
Immuno-chemical studies show a high con-centration of ET-1 in the bronchial epithelium and vessels of asthmatic patients compared to healthy subjects (16).
A pathogenetic effect of ET-1 in asthma is suggested by an increase in ET-1 in bronchioalveolar wash liquid (BAL) during bronchospasm (17).
When hypoxia persists, the vessel walls undergo a larger structural remodelling, with hypertrophy of the medial and extension of the more distal arteriole smooth muscles.
BA is now defined as a chronic inflammation of the air passages, caused by the activation of various cell populations, including eosinophils and mast cells which support and amplify inflammation by releasing powerful mediators (Pg, Tx, PAF, LTC4 etc.) (18).
In sensitive individuals, this inflammation causes symptoms associated with a variable obstruction of the airways which is often reversible.
During an acute episode of bronchial obstruction, as in BA the most evident cardio-circulatory modification is "paradoxic pulse", i.e. a reduction of systemic arterial pressure (10 mmHg) at the peak of inspiration (19).
Pathogenesis can mainly be traced back to intra-thoracic pressure which stretches the cardiac cavity and vessels, increasing the filling and transmural pressure (i.e. the difference between the pressure inside and outside the vessels).
To be more precise, when the air passages are blocked, the variations in intra-thoracic pressure are more noticeable, determining on one hand an increase in the systemic vein pressure, and on the other impeding the emptying of the left ventricle, due to the increased aortic pressure. This reduces the systolic flow and the strength of the pulse, at the peak of inspiration. In bronchial asthma, the bronchial circulation is important because the bronchial flow and microcirculatory permeability locally increase during broncospasm, and can cause an increased hypersecretion of the bronchial walls (20).
It is therefore evident that hypoxia plays a very important role in the pathogenesis of chronic pulmonary heart.
AIM OF THE STUDY
Considering what we know from literature and our clinical and functional knowledge of BA and COPD, the aim of our study was to discover whether there are any differences in the effects on the pulmonary circulation and the right side of the heart between the two diseases.
BA is a hypoxic disease and this hypoxic condition liberates ET-1, even if it is transitory, which is shown to be higher in the BAL of these patients.
On the other hand, ET-1 can be considered a regulator of pulmonary hypertension which leads to the chronic pulmonary heart.
Therefore it appeared extremely interesting to concentrate our study on bronchial asthma in order to verify if alterations can be shown in pulmonary circulation and in the right side of the heart considering that scientific experience tends to attribute an important role to hypoxia in determining cardiac alterations, also in asthmatic patients who are typically hypoxic, even if for transitory periods.
MATERIAL AND METHODS
We chose theree groups of subjects.
The first group (group A) was made up of 10 subjects (6 M.- 4F.) aged between 25-65 (average age 45) with a clinical history of moderate bronchial asthma. The evaluation was based on the criteria for the diagnosis of asthma by the American Thoracic Society (ATS) (21), and the International Consensus Report.
The patients had suffered from asthma for at least 5 years and their FEV1 was 60-80% of the theorical normal values, and were being treated with steroids and long acting beta-2 agonists.
The second group (group B) we chose was made up of 10 subjects (6M.- 4F.), aged between 25-65 (average age 55), with a clinical history of moderate chronic obstructive bronchitis dating back at least 5 years, diagnosed according to the ATS criteria. In both groups patients conditions were clinically compensated. The third group (group C) was formed by ten healthy control subjects (HS). We excluded patients with systemic ilnesses, bronchiectasis, arterial hypertension and pregnant or breast-feeding women.
First, personal data were collected, and clinical histories recorded, especially noting any association with other chronic diseases, duration of BA or COPD, number of acute episodes or hospitalization for these diseases in the past 12 months, and present therapy.
During the medical examination, cardiac and respiratory rates and arterial pressure were measured, and a standard ECG and M-mode, twodimensional and pulsed color Doppler echocardiography with a Vingmed model CFM 750 3.25 MHz transducer. All subjects underwent standard echo cardiographic study in left lateral position at approximately a 30º angle, with the transducer placed in standard positions and each tracing was recorded at a paper speed of 100 mm/s., following the criteria of the American Society of Echocardiography.
Recording M-mode echocardiography we determined:
The aortic root diameter (Ao mm.).
The left atrial dimension (LA mm.).
The interventricular septum (IVS mm.) and the posterior left ventricular wall (PLVW mm.) thickness at end-diastole.
Left ventricular end-diastolic (Lvd mm.) and end-systolic (Lvs mm.) dimensions.
Ejection fraction (EF %) and fractional shortening (FS %) of l.v.
Using pulsed-wave Doppler echocardiography we recorded in flow velocity curves (mitral-M-, tricuspidal-T-, pulmonary-P-) on strip chart recorder at 100 mm./s. and were calculated:
Isovolumetric relaxation time index (IVRT mm/s.).
Initial filling velocity, representing the early rapid filling (E cm/s.) and late filling velocity, representing the atrial contraction (A cm/s.)
E/A ratio.
Pulmonary systolic arterial pressure (APA mmHg).
Pulmonary acceleration time (PAT m/s.).
Right ventriculary ejection time (RVET m/s.).
PAT/RVET ratio.
The parameters were recorded at a speed of 50 mm/s and evaluated by two different operators for three consecutive cardia cycles.
All the subjects underwent respiratory function tests by spirometry, and PEF, FEV1 and FVC were measured.
Haemogas tests and chest X-rays were also carried out. The data we obtained underwent statistical analysis with parameter tests (ANOVA) and non-parameter tests (wilcoxon test). A value of p < 0.05 was considered significant.
RESULTS
Electrocardiograms carried out on patients affected by BA and COPD showed significant alterations. Monodimensional eco-scan did not show significant differences between patients with BA, bronchitis or normal subjects (table I).
| Table I M-mode echocardiography | |||
| BA | COPD | HS | |
| LA | 35.9 ± 3.6 | 35.8 ± 4.8 | 29.9 ± 6.9 |
| Lvd | 46.9 ± 7.1 | 49.8 ± 5.7 | 48.8 ± 2.6 |
| Lvs | 33.2 ± 7.2 | 34.3 ± 5.6 | 32.2 ± 1.7 |
| IVS | 12.5 ± 3.2 | 13.6 ± 3.2 | 9.5 ± 1 |
| PLVW | 9.3 ± 1.6 | 10.7 ± 2.1 | 9.1 ± 1.1 |
| EF | 65.3 ± 8.4 | 66.5 ± 10.7 | 67.6 ± 3.7 |
| FS | 30.2 ± 6.3 | 31 ± 6.9 | 31 ± 2.7 |
| AO | 32.3 ± 3.2 | 34.6 ± 4.9 | 30.1 ± 2.3 |
| Table II Doppler pw | ||||
| BA | COPD | HS | ||
| Mitral VmaxE | 68.1 ± 14.7 | 65.3 ± 9.5 | 74.3 ± 11 | |
| Mitral VmaxA | 70.8 ± 12.8 | 68.7 ± 12.7 | 68.6 ± 16.2 | |
| Mitral E/A ratio | 0.9 ± 0.2 | 0.9 ± 0.2 | 1.06 ± 0.1 | |
| IVRT | 62 ± 25.3* | 78.7 ± 19.5 * | 41.6 ± 16 | |
| Tricuspidal VmaxE | 64.3 ± 12.7* | 51.37 ± 10.5 | 57.2 ± 9.4 | |
| Tricuspidal VmaxA | 59.8 ± 13.1 | 50 ± 11.2 | 52.8 ± 10.7 | |
| Tricuspidal E/A ratio | 1.08 ± 0.38 | 1.4 ± 0.18 | 1.1 ± 0.42 | |
| PAP | 15.6 ± 6.4 | 20 ± 6.6 | 18 ± 7.18 | |
| PAT | 96.6 ± 46* | 96.2 ± 19.9* | 130 ± 43.8 | |
| RVET | 291.1 ± 105.3 | 293.7 ± 34.6 | 306 ± 103 | |
| PAT/RVET ratio | 0.32 ± 0.15 | 0.35 ± 0.11 | 0.42 ± 0.14 | |
| *p < 0.05 vs HS. | ||||
Dopplers pw (table II) of the mitral valve (Fig. 1) showed an alteration of the rapid ventricular filling in both groups of asthmatic and bronchitic patients, although some indeces do not reach an important significance.
Figure 1--Doppler pw IVRT.
For example, the E/A ratio, which is one of the most evaluated data during the diastolic phase, is inverted, even though it does not reach a statistic significance in our case study. The E wave-index of rapid ventricular filling does not reach a statistical significance and is globally reduced compared with normal subjects. Only IVRT, which is also an index of the diastolic function like the previous data, is more sensitive in our study, and has a significant statistical difference.
This index is altered in asthmatic and bronchitic patients respect to normal subjects (p = 0.005 A vs C; p = 0.0006 B vs C), (Fig. 1). Tricuspidal Doppler examinations show that the behaviour in asthmatic and bronchitic patients is the opposite to normal subjects. There is a significant increase in tricuspidal VmaxE (p: 0.03 vs B), which shows the rapid ven-tricular filling, whereas in bronchitic patients the diastolic filling values are more or less the same as in the control subjects (Fig. 2). Alterations of VmaxA (slow ventricular filling index) are also present, although they are not statistically significant. The parameters showing the right ventricle systolic function i.e. the time it takes for the pulmonary valve to reach the maximum speed of aperture. We found that the behaviour was similar in bronchitic, asthmatic and normal subjects (p: 0.006 a vs C; p: 0.03 B vs C) (Fig. 3).
Figure 2--Doppler pw WmaxE.
Figure 3--Doppler pw PAT.
DISCUSSION
We can conclude that integrated heart scans have shown initial alterations of the pulmonary circulation in bronchitic and asthmatic patients. These alterations show an equal involvement in the right side of the heart in both groups, although in asthmatic subjects the increased venous return to the right side of the heart could partially compensate for the haemodynamic deficit. We believe it is important to underline that the clinical conditions of all the patients we examined were satisfactory, and this shows that the effects of the cardiocirculatory function are determined not only during acute broncospasm but also when the clinical condition is silent.
It appears important to point out that we were able to demonstrate an organic and functional involvement of the inter-ventricular sect, charac-terized by a statistically significant delay in the isovolumetric relaxation time (IVRT), index of diastolic damage to the left ventricle, not only in COPD subjects, as expected, but also in asthmatic patients. The alteration is probably secondary to a functional and organic involvement of the inter-ventricular sect, which is a structure that belongs to both ventricles, occurring during advanced stages of respiratory pathologies.
We also found a global reduction of the E-wave, even if it was not statistically significant, occurring in correlation with rapid filling or compliance factors. We also found a significant reduction in the pulmonary acceleration time (PAT), secondary to structural and functional alterations of the vascular endothelium in asthmatic vs. normal subjects (p = 0.006). These data are extremely interesting, because they show the involvement of the pulmonary circulation in subjects affected by bronchial asthma, since a reduced AT indicates significant damage of the right ventricle. This could be explained by the fact that systolic damage (indirect index of pulmonary hypertension) shows up earlier than diastolic damage, due to the particular characteristics of the pulmonary circulation. This is because there are fewer compensating factors respect to the diastolic phase (increase of intra-thoracic pressure, influence of respiratory muscles), and unlike what happens in systemic arterial hypertension, where diastolic damage occurs earlier than systolic damage. Tricuspidal Doppler scans also showed a significant increase in the rapid ventricular filling flow rate (VmaxE: p = 0.03 vs bronchitic patients). These modifications can be attributed to different physiopathological conditions of asthmatic patients, who have reduced intra-thoracic (and intra-pleuric) pressure, which causes the cardiac cavity to expand during inspiration. This increases the venous return to the right side of the heart, and explains why asthmatic subjects compensate better than bron-chitic subjects, at least in the initial phase. All the data obtained appears to agree with the idea that asthmatic subjects undergo initial alterations of their pulmonary circulation which in clinical practice could remain silent due to the particular characteristics of the disease. This is rather obvious, because the stu-dy was carried out on patients whose pathologies were moderate, and lacked the real morphological changes found in a chronic pulmonary heart, which is the end point of all pathologies which involve pulmonary circulation. These alterations appear to be particularly important, and add factors of cardiac risk to patients who suffer from chronic hypoxia and who use drugs. Therefore all asthmatic subjects should be monitored for cardiac disease.
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Correspondence:
Gianfilippo Bagnato
Via S. Sebastiano, 27
98100 Messina. ITALY
