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21 CARDIOVASCULAKEFFECTS OF CIGARETTE' SMOKE 11 Summary Report of Stud'ies. Carried out in the Card'i!ovascular. D3,visionloitheD'ep~artment ofNtedioine and Thorndike Laboratory at Beth~Israel Hospitali . by. Drs. W.Hi. Abelmann, O.H.L. Bing, F. Maher, B. Rabinowitz and T. Sakurai October, 1978

-1- t I. ,INTRODUCTION An extensi've review of the literature pertinent to cigarette smoking, tobacco smoke,,components of'tobacco smoke and their re]iation ta cardiac functiomand'di'sease has been completed. SeveraL questions were formulated' and a research program has been initiated to: answer some of these. The: questions.include: (A) FTtiat, if any is the effect of acute exposure to rat heart muscle strips to cigarette smoke and its components, such as nicotine, acetaldehyde, carbon monoxide, upon their mechanicali function? -(B) What, if any, are the effects of acute and chronic exposure of intact rats,to:ci.garettesmoke upon the mechanical functiomofrat heart muscle strip&studFiedisubsequently?' (C) What are the effects of smoking standard reference cigarettes, low nicotine cigarettes and'.non-tobacco:cigarettes:upon cardiac and' circulatory functionlin man,,measured non-invasively and invasively in healthy subjects, inipatients with ischentic (arteriosclerotic)' heart diisease, and in patients with cardiomyopathy (heart muscle disease)? (D) Is:cigarette~ smokiing, arrhythmogenic? II . WORK COMPLETED, (1)i The~~ effect of acute:exper~imental' tob~acco~smoke ~ inhalation on~ ~~ the~mechanical responses of isolated rat~cardiac muscle (~7)~~ Rats, exposed to cigarette smoke from 2R1 Kentucky reference cigarettes in special smoking,chambers for ten minute periods each hour for five hours, were sacrificed and the mechanical properties of isolated left ventricular papillary'and columnar carnae preparationsstudi'e~d~. Mean COHb concentrations of smoked animals were 1'3.2±'0.9 volumes percent. No significant difference was found in rats exposed: to tabacco smoke when compared to shams in: 1) cardiac chamber weight or chamber wet-to- dry ratios, 2)i cardiac muscle performance in oxygenated Krebs-Henseleit solution (95X 02, 5% CO ),.3) muscle per£ormance during,60 minutes of hypoxia (95% N2, 5% C023 followed by 30 minutes of reoxygenation, 4)') muscle performance during graded hypoxia with and without glycolytic blockade (iodoacetic acid 10`4M'):, or 5) sensitivity of myocardial performance to isoproterenol. - - (2'), The direct effect of tobaccoismoke onithe intrinsic mechanical propertjieso~ff cardiac,muscle(~6~), . The direct effects of tobacco smoke from Kentucky University Reference cigarette&on the mechanical performance of isolated rat left ventricular muscle preparations were examined. Experiments were carried out w3'.thipreparations contracting isometrically 12'times per minute at 28°C while at the apex of'the leng,thitension curve.:

-2- L'lnder oxygenated condFitions„ tobacco smoke bubbled througlY~ the bath induced'.an initiaL negative inotropic response (myocardi'all depressant effect). With larger volumes of smoke, mitral depression was followed' by recovery toward control values. Late recovery was inhibited' by first passing the tobacco smoke through,a Cambridge filter., Tobacco smoke add'ed prior to 60 minutes of hypoxia followed by 30 minutes of reoxygenation had a dose dependent deleterious effect on per- formance during hypoxia and a subsequent reoxygenatiom. The deleterious effect of smoke during, hypoxia could'largely:be prevented by first passing, the tobaccoismoke through a Cambridge filter. The nicotine present in tobacco smoke could not by itself account for the changes under oxygenated conditions or those seeniduring hypoxia and!reoxy- gennation. It was concluded,.that the gaseous phase of tobacco smoke is respon- sible for negativeinotropjiceffect seenunderoxyrgenated conditions., The action of the particulate phase of the smoke (which i's blocked by the Cambridge filter) appears tolbe responsible for the partial recovery of mechanical performance under oxygenated conditions and the potentt deleterious effects seen during hypoxia and reoxygenation. (3) Effects of nicotine, catecholamines and hypoxia upon cardiac muscle (3) ~,,... Nicotine and isoproterenol interactions on cardiac muscle were examined during 60!minutes of hypoxia and 301minutes of reoxygenation.. Left ventricular trabecular muscles from rats were studied at 2b°C while contracting isometrically 12'/m3.n at the apex of the length- tension curve. - Nicotine at concentrations of 42 (n=9), 160 (n=9) and' 640ug/ml (n-10) increased': tension~andlrate of tension development in a dose d'ependent manner. This respoase was not blocked by propranolol 10r6M (n=18), andli'soproterenol 10-b~ (n=8) demonstrated an additive effect. With,160 and 640ugN/ml, performance during early hypoxia (95% N2, 5X'C02) was enhanced but premature deterioration subsequently appeared and poor recovery was seen on reoxygenation (95% 02, 5% C02)'. This deleterious response was augmented by isoproterenol. Brb];ockade did nott alter responses of nicotine during hypoxia but improved recovery was seen on reoxygenation« Thus, the inotropic effects of nicotine and catecholamines appear to be additive:. This combination of agents seems particularly dele- terious to hypoxic cardiac muscle and may be a factor related to the increased mortality of'cigarette smokers with coronary artery disease. .i'

-3- t (4) Acute hemodynamic effects of cigarette smoking in healthy man assessed by non-invasive techniques (1,4,5',8') Sixteen healthy subjects ages 18 ' to 35 were studied' in the supinee position by means of systolic time intervals and' echocardiography before and after smoking a nicotine reference cig;arette (2.5mg nicotine) and pre- and post-smoking a virtually "'n2cotine free" tobacco:cigarette (<.25 mg nicotine)~ taassess immediate changes in left ventri:cular mechanics and to determine if any differences exist between inhalation of tobacco cigarette smoke with and without nicotine. Smokers (N=12) and'non-smokers (N=4) behaved alike. Both~cfigar- ettes increased heart rate, systolic and diastolic bloodd pressure and' the triple product of systolic blood pressure LVET and HIt (P<.001) prolonged LV'ETc (P<'.001)and decreased PEP and PEP/LVET (P<.005) In~ addition, smoking a nicotine reference„ cigarette increased resting,value of echocardiographically derived left ventricular end-diastolic dimen- sion f'rom48. 8+1.1 to 51.6i1.2 mm(P<.001)' end-systolicdiiameter from, 32.5±1.1 ta 33I.4i1.1 mm- (P<.01) and' augmented ejection fraction fromi 70±2'' to. 73±2 while enhancing mean normalized!circumferential fiber shorteningg from 1.13±.06:to 1.2]:±.06 circ /sec (P<.05) and mean normalizedipos- terior wall velocity from .81+.03 to .88±.03 sec-1 (P<.05) smoking,a nicotine free.tobacco cigarette did not alter end-diastolic dimensionn but decreased end systolic diameter from control of 33.8t'1.0 to 32'.1i01.9' (P<'.01) whil'e increasing ejection fraction 69±2 to.73+2 (P<.05),, an& mean normalized circumferential fiber shortening,1.12t.0'6 to L.26i.09 (P<.05)' as well as mean normalized posterior wall velocity 0.78±.03 to 0.81+.03 (P=NS:). These data indicate,that in the supine position smoking a nicotine reference cigarette acutely increases venous return andiaugments all the determinants of myocardial oxygen consumption - heart rate,, contractility, preload and'afterload and that cigarette smoke in addition maycontain other inotropicand chronotropdcsubstancesyet to beeluc3'.da~ted. (5)~ Effects of chronic inhalationiof cigarette smoke upon rat myocardium : This series has.been extend'edd to a total of 32 subjects (5). The findings in the initial groupof 16 were:essentiahly!confirmed in the larger group. Preliminary,, uncontrolled studies of the effects of' chronicinh~alation of cigarettesmokebly'rats,upon themech~anical pro- perties of papillary muscles studied in vitroirevealed1no significant effects.

-4- III. WORKIMPRCIGRESS. (1) Effects~of acetaldehyde upon the mechanical function of rat myocardium 9 Acetaldehyde, demonstrable in cigarette smoke and also in bloodland tissues after intake of ethanol, has been impZicated'as a potential cardiac toxim. Using,isometricallycontracting,isol!ated rat papillary muscle, the effect of acetaLdehyde upon the performance of cardiac muscle is being studied., Acetaldehyde is given d'irectly into the Krebs-Henseleit bathh in increasing dosage (l mg/dl to,100 mg/dl), and' isometric contraction is recorded'every five minutes. About twenty studies have been carried, out so far. Compared to the control group, acetaldehyde d'ecreases PT (peak tension)and RT1/2 (relaxation time index)', but slightly increases RT (resting tension) at highiconcentration (1:00 mg,/'dl),. At the ]iower 'leveli (Y0mg!,/'dl orliess),, more comparab~leto clinical situations, acetaldehydeseems to have no detectable effect on this model. At 50 mg/dl level, the effect is equivocal, but some iincrease in PT has been observed. Adjuvant effects of propranolol and/or reserpine are now under study. Prel!iminaryresultssuggestthatpropranollol does'notb]lock th~e de-pressive effect of acetaldehyde. Acetaldehyde concentrations are being measured by a gas-chromato- gfiaphic method. The!effectiv~ehal!f life~ iniabath at 2$oGhasbeen determined as: 3'01minutes.. (2), Acute hemod'}mamic effects of cigarette smoking in patientss with heart d'~isease A study of'the effects of cigarette smoking upon the heart and' circul'ation of patients with ischemic heart disease and patients with cardiomyopathy, as assessedinon-invasively by means of echocardiog,raphy and'systolic time:intervals, is:in progr_ess. Three patients~have been studiedifully so far. A study of the hemodynamic effects of cigarette smoking upon the systemic and coronary circulation has been approved by the Human Studies . Committee and has been initiated. i .

r -5- IV. PUBLICATIONS 1. Rabinocvitz„ B., Laguard'a, R.„ Huber, G.L. and Abelmann, W.H'.: Systolic time intervals in the study of cardiovascular effects of'cigarette smoking. Clin. Res. 23:202A, 1975'., 2'. Maher, F.A.,, Bing, O.H.L., Pereira, W., Aranella, L.S', and Abelmann„ W.H.: Effects of acute tobacco smoke inhalatiom on the intr3nsic mechani'ca]J properties of cardiac muscle. C1in. Res. -23:195A, 1975. 1 3'. Maher, F'.A,, AbeTmann,W.H. , Arenellal„ L.,S. and Bing, C,H.L «: Nicotine, catecholamines and hypoxic cardiac muscle. Circulation 52:11-211, 1975. 4. Rabinowitz, B.D., Thorp, K.A., and Abelmannl, W'.H.: Acute hemo- * dynamic effects of cigarette smoking in man assessed by systolic time intervals and echocardiography. Clin. Res., 25:246A, 1977. 5. Sakurai, T., Rabinowitz, B,.D., Thorp,,K., Huber, C. andiAbelmann, 6: , W.H.: Acute hemodynamic effects of'cigarette smoking in man assessed by non-invasive techniques.., Abstracts, VIII World Congress of Cardiology, Tokyo, Japan,,, p. 402„ 19I7'8. . .. ?~.;.. Maher, F.A., Bing, O.H.L., Huber, G.L., Arenella, L. and Abelmann, W.H.: The direct effect of'tobacco smoke on the 'a'+. intrinsic mechanical properties of cardiac muscle. Environmental Research. (In Press) 7. Maher,, F'.A., Bing, O.H.L., Huber, G.L., Arenellal„ L. and Abelmann, W.H.,:. The effect of'acute experimental tobacco smoke inhalation on the mechanica]l responses of iso,latedirat cardiac muscle. (Submitted for publication): 8'. Rab inowi'tz, B.D., Thorp, K.A. and'~ Abelmann, W.H. : The acute cardiovascular effects of cigarette smoking assessed by non- invasive techniques. (Subm3tte~d forPublication).