Headliners: Environmental Tobacco Smoke: Respiratory Effects Linked to Genetic Susceptibility

Wenten M, Berhane K, Rappaport EB, Avol E, Tsai W-W, Gauderman WJ, et al. 2005. TNF-308 Modifies the Effect of Second-Hand Smoke on Respiratory Illness–Related School Absences. Am J Respir Crit Care Med 172:1563–1568. 
 
Children are at special risk for adverse effects from exposure to secondhand smoke (SHS). Estimated population-attributable risks for SHS exposures in children range from 9% for asthma prevalence to 25% for hospital admissions due to lower respiratory symptoms. According to the Third National Health and Nutrition Examination Survey, 43% of children between the ages of 4 and 11 years are exposed to SHS at home. Now NIEHS grantees Frank D. Gilliland, Rob McConnell, W. James Gauderman, Louis Dubeau, Edward Avol, and Kiros Berhane, with their colleagues at the University of Southern California Keck School of Medicine, have shown that children with a particular genetic makeup are at a substantially greater risk for respiratory illness when exposed to SHS. 
 
Using data from the Children’s Health Study, the team examined school absences for 1,351 fourth grade students from 27 California elementary schools between January and June 1996. They categorized illness-related absences as being due to nonrespiratory or respiratory illness, then divided the latter into upper respiratory illness (runny nose/sneezing, sore throat, earache) or lower respiratory (wet cough, wheeze, asthma). They also gathered information on the students’ health history, including history of asthma, and their exposure to smoking and allergens at home. 
 
The researchers also collected buccal cells from each subject, to determine the student’s tumor necrosis factor (TNF)–α genotype. TNF-α is an important cytokine in the inflammatory response to SHS. The TNF gene has a common variant in the promoter region G-308A that has been associated with TNF-α expression regulation in some studies. 
 
Students who were exposed to SHS at home had a 51% greater risk of having a lower respiratory illness–related school absence compared with unexposed students. The association was clearest in students who had at least one copy of the variant A allele on TNF-308. Students who displayed the AA or AG genotype had a 75% increase in risk of illness-related absences of any kind. Those children possessing the A variant who were exposed to SHS at home had an even more pronounced risk for respiratory illness–related absences, especially absences due to lower respiratory illness. When compared to nonexposed children with the GG genotype, children with the A allele who were exposed to two or more smokers in the home were four times as likely to stay home because of lower respiratory illness. 
 
The researchers postulate that variations in the TNF gene might intensify the body’s inflammatory response to oxidative stress caused by cigarette smoke. They also note that since a significant number of people are exposed to SHS, future studies should focus on identifying genetically susceptible groups so actions can be taken to reduce their exposure.


Background
Coronary flow reserve (CFR) recording by means of transthoracic echocardiography (TTDE) in all the main distal coronary arteries is a challenge for advanced echocardiography. Clinical implications of such a possibility are involving an improved indication for invasive exams and for revascularisation, the evaluation of coronary flow after revascularisation, the new generation of stress-echo testing (CFR plus wall motion) and the non-invasive followup of patients [1][2][3][4][5][6][7][8].
Several studies concerning coronary flow and CFR recorded in the Left Anterior Descending coronary artery (LAD) and few in the Posterior Descending coronary artery (PD) have been published so far [9][10][11][12], and the measurement of CFR by TTDE was validated, by comparing it with intracoronary Doppler recordings (DW) in the same patient and in the same vessel, in some studies [13][14][15][16].
However, only few papers concerning the distal Left Circumflex coronary artery (LCx) have been published [17][18][19]. Technical difficulties may pose feasibility challenges to LCx recording like the supposed lack of a reference structure to identify the position of the distal branches of LCx on the lateral left ventricle wall or the poor lateral resolution of current equipments accounted for. Moreover, a comparison of TTDE with DW for LCx is still lacking.
In the present study we compared CFR measurements obtained by TTDE with those obtained with intracoronary DW in five patients.

Patients population and TTDE
Five patients (age 60 ± 9 years, 5 males, 2 with previous inferior myocardial infarction -patient 1 and 2), having a good echocardiographic window for the lateral wall, scheduled for coronary arteriography, were studied after informed consent was given. The 2 tests (TTDE and DW) were performed on different days and in random order within 48 hours in a blind fashion. Recordings of TTDE were obtained with a conventional echo-machine (Sequoia 256, Acuson-Siemens) equipped with its standard harmonic low-frequency probe (3Vc). A four-chamber view (4-C) was used for guiding TTDE recordings by adjusting frequency, limit of Nyquist (reduced to 40 cm/ sec and more) and filtering of guiding color flow mapping (fig 1, 2). No contrast agent was used. Coronary flow signal search was made before by color-Doppler in the 2D view and then by pulsed Doppler. Plane of guiding 2D view was tilted and the region zoomed as necessary. The sample volume of pulsed Doppler was placed on the epicardial layer of the lateral wall in the basal and mid portions, avoiding the far apical portion where a signal recorded could belong to a Diagonal artery coming from LAD. The only reference structure relied was the lateral wall itself where Obtuse Marginal (OM) arteries (distal LCx) are running. No angle correction was used. When the typical coronary diastolic forward flow pattern along the lateral wall of the left ventricle was recorded, CFR was calculated by giving adenosine infusion (140 γg/Kg/min for 3 to 6 min) from the ratio of post-to-pre peak diastolic velocity ( fig. 3A-B, 4A-B, 5A-B, 6A-B, 7A-B).

Coronary arteriography and DW recording
After performing diagnostic coronary angiography, a 0.014" angioplasty Doppler guide wire (Flow Wire, Jomed) trough a 6 Fr guiding catheter was advanced in the target coronary branch 1 to 2 cm distal to the last stenosis (i.e. the first LCx branch with a diameter ≥ 2 mm running toward the lateral wall) or, if no angiographically detectable stenosis was present, in the proximal segment of the target branch. When a position where a clearly defined and stable velocity signal was found and recorded, 40 γ of adenosine were injected intracoronary and the maximum increase of flow velocity was recorded to calculate CFR. Adenosine injection was repeated three times and data averaged. Percent of coronary artery area stenosis was calculated by offline quantitative coronary angiography (QCA-CMS vers. 5.1, Medis, Nuenen, The Netherlands)

Statistical analysis
Continuous data are presented as mean ± Standard Deviation. A sample linear regression analysis with Pearson's coefficient was used to assess the relationship between Plan of section of LCx branches made by the four-chamber view   CFR values obtained with invasive (DW) and non-invasive (TTDE) methods.

Discussion
The non-invasive recording of the coronary flow by means of TTDE is an important progress of echocardiography in the field of coronary artery disease. The evaluation of CFR in the LAD and PD territory by TTDE already found a clinical application in the practice in some centres. Important applications are involving the status of the coronary circulation after myocardial infarction or coronary revascularisation [2,3,5,15] and the clinical use of the on-developing new generation of stress-echo [20,21]. As stated, from a physiological point of view, the largest part of informa-tions comes from recording the flow from a distal segment of the coronary artery. This explains why CFR measured by transesophageal echocardiography on the proximal coronary arteries does not correspond to the status of the distal coronary circulation.
LCx distal CFR recording has been reported until now in few papers only [17][18][19] with a described feasibility of about 80%; however, a comparison with DW method is still lacking.
In the present paper we recorded the flow reserve from the arteries running along the basal and mid lateral wall. These arteries are the OM branches of LCx if the recording is made on the basal or mid lateral wall in a 4-C plane. In fact, the plane of the Diagonal branches of LAD is lying superiorly (fig 1). No reference structure other than the lateral wall itself is necessary to be followed to record the distal LCx, in our opinion. Following these rules, in our patients, we could observe a good comparability in CFR Patients 5 measurements between TTDE and DW either in terms of profile of the Doppler spectrum and in the values of CFR. The borderline statistical significance ought to be due to the sample tininess.
We underline that the present study was neither a feasibility one nor it was its target to assess the improvement of feasibility by using contrast agents. This is why we enrolled non-consecutive patients. To add informations around CFR, particularly in the region of the lateral wall, would be very helpful in assessing the presence of global ischemic response to vasodilators in the course of stress test, as long as this region has a low sensitivity for wall motion marker alone. However, further large studies are needed to precisely assess the applicability of LCx CFR calculation by TTDE in the clinical practice in order to completely evaluate, through a non invasive method, the functional status of coronary circulation.

Limitations
A problem raised in TTDE flow recordings of distal LCx is that one is not certain about which of the vessel on the lateral wall (OM1, OM2) is recorded. However, this is the same for LAD recordings when sometimes a Diagonal branch is recorded in the position of distal LAD. And, in any case, a result of an impaired CFR might be a clinically relevant pushing drive for a furtherwork-up.
For technical reasons only few patients were studied here and larger series are necessary to substantiate our pilot observation.