Systemic Venous Congestion Research Articles

Clinical profile and outcome of idiopathic restrictive cardiomyopathy.

Idiopathic restrictive cardiomyopathy is a poorly recognized entity of unknown cause characterized by nondilated, nonhypertrophied ventricles with diastolic dysfunction resulting in dilated atria and variable systolic function. Between 1979 and 1996, 94 patients (61% women) 10 to 90 years old (mean, 64 years) met strict morphological echocardiographic criteria for idiopathic restrictive cardiomyopathy, mainly dilated atria with nonhypertrophied, nondilated ventricles. None had known infiltrative disease, hypertension of >5 years' duration, or cardiac or systemic conditions associated with restrictive filling. Nineteen percent were in NYHA class I, 53% in class II, and 28% in class III or IV. Atrial fibrillation was noted in 74% of patients and systolic dysfunction in 16%. Follow-up (mean, 68 months) was complete for 93 patients (99%). At follow-up, 47 patients (50%) had died, 32 (68%) of cardiovascular causes. Four had heart transplantation. The death rate compared with actuarial statistics was significantly higher than expected (P<0.0001). Kaplan-Meier 5-year survival was 64%, compared with expected survival of 85%. Multivariate analysis using proportional hazards showed that the risk of death approximately doubles with male sex (hazard ratio [HR] = 2.1), left atrial dimension >60 mm (HR = 2.3), age >70 years (HR = 2.0), and each increment of NYHA class (HR = 2.0). Idiopathic restrictive cardiomyopathy or nondilated, nonhypertrophic ventricles with marked biatrial dilatation, as defined morphologically by echocardiography, affects predominantly elderly patients but can occur in any age group. Patients present with systemic and pulmonary venous congestion and atrial fibrillation and have a poor prognosis, particularly men >70 years old with higher NYHA class and left atrial dimension >60 mm.

Constrictive pericarditis: Clinical and pathophysiologic characteristics

Constrictive pericarditis is an uncommon disorder with various causes. Although most often idiopathic, it may also occur after cardiovascular surgery, radiation therapy, and tuberculosis, especially in developing countries. The encasement of the heart by a rigid, nonpliable pericardium results in characteristic pathophysiologic effects, including impaired diastolic filling of the ventricles, exaggerated ventricular interdependence, and dissociation of intracardiac and intrathoracic pressures during respiration. Constrictive pericarditis typically presents with chronic insidious signs and symptoms of predominantly systemic venous congestion. Notoriously difficult to diagnose and distinguish from restrictive cardiomyopathy (RCM), the use of cardiac catheterization, echocardiography (transthoracic and transesophageal), central venous (hepatic and pulmonary) and transvalvular Doppler measurements, and magnetic resonance imaging should secure the diagnosis in most cases, eliminating the need for diagnostic thoracotomy. Although medical treatment may temporarily alleviate symptoms of heart failure, patients do poorly without pericardiectomy. (Am Heart J 1999;138:219-32.)

ELEVATION OF cyclic AMP AND cyclic GMP LEVELS BY PHOSPHODIESTERASE3 (PDE3) INHIBITOR ATTENUATES ISCHEMIA AND REPERFUSION INJURY OF CANINE LIVERS.

289 Aim; After reperfusion of ischemic organs (I/R), administration of cyclic AMP (cAMP) improves microcirculation by inhibiting platelet aggregation and cytokine production, while cyclic GMP (cGMP) dose so by relaxation of constricted Ito cells. Using a two-hour total hepatic vascular exclusion model in dogs, we tested our hypothesis that elevation of both cAMP & cGMP levels by PDE3 inhibitor, Amrinone, would attenuate I/R injury of the liver. Method; After skeletonization, the liver was made totally ischemic for two hours by cross-clamping portal vein, hepatic artery, and vena cava (above and below the liver). Veno-venous bypass was used to decompress splanchnic and inferior systemic venous congestion during the procedure. Eighteen beagle dogs were assigned into 2 groups: Group CT, untreated control (n=12); Group AM, treated with Amrinone (n=6); In treated animals, each drug was given intra-venously 0.25mg/kg for 5 min plus continuously 25f g/kg/min for 55 minutes before ischemia. Animal survival rate, hepatic tissue blood flow (HTBF), liver enzymes levels, hepatic tissue cAMP & cGMP were determined. (Table)TableConclusions; Compared to the control, treatments with Amrinone significantly improved animal survivals, augmented hepatic tissue blood flow, and hepatocyte damage. cAMP & cGMP levels were elevated by PDE3 inhibitor administration.

Dynamic cyclic changes in coronary sinus caliber in patients with and without congestive heart failure

M-mode echography of the coronary sinus in the apical 2-chamber view enabled us to measure coronary sinus caliber at specific phases of the cardiac cycle. Coronary sinus narrowing occurs consistently during atrial contraction, but is always absent in atrial fibrillation; in patients with congestive heart failure and systemic venous congestion, this narrowing is significantly attenuated.

Echocardiography of the Inferior Vena Cava, Superior Vena Cava, and Coronary Sinus in Right Heart Failure.

Echocardiographic evaluation of the three major systemic venous channels that drain directly into the right atrium has hitherto received less attention than it deserves. Attention had been paid initially to inferior vena cava dilatation and lack of collapsibility (plethora) as signs of systemic venous congestion. Superior vena cava imaging has not been part of routine echographic evaluation; however, our recent observations on superior vena cava appearance by the right supraclavicular approach provide evidence that dilatation of superior vena cava correlates with that of inferior vena cava as a marker for venous congestion. The coronary sinus caliber, which has been virtually ignored, may also provide echographic signs of systemic congestion, namely, dilatation and lack of normal narrowing during atrial contraction.

INHIBITION OF THROMBOXANE A2 SYNTHETASE BY OKY-046 ATTENUATES ISCHEMIA AND REPERFUSION INJURY OF CANINE LIVERS

37 Protection against ischemia and reperfusion (I/R) injury of the liver is essential to achieve satisfactory outcome after liver transplantation. Although various factors have been proposed to explain the cause of hepatic I/R injury, derangement of eicosanoid metabolism, particularly suppressed production of prostagrandin I 2, and increase of thromboxane A 2 and leukotrienes, has a critical role. These changes have been shown to induce microcirculatory disturbance, neutrophils adherence to endothelial cells, and their activation. Using a 2-hour total hepatic vascular exclusion model in dogs, we tested our hypothesis that the regulation of eicosanoid metabolism by thromboxane A 2 synthetase inhibitor, OKY-046, would attenuate I/R injury of the liver. After skeletonization, the liver was made totally ischemic for two hours by cross-clamping the portal vein, the hepatic artery, the vena cava (above and below the liver). Veno-venous bypass was used to decompress splanchnic and inferior systemic venous congestion during procedure. Sixteen beagle dogs were divided into two groups: five animals were treated with OKY-046 (group OKY), and 11 received no treatment (group CT). In treated animals, OKY-046 was given intravenously at a rate of 50µg/kg/min for 60 minutes before ischemia and 3 hours after reperfusion. Animal survival, hepatic tissue blood flow(HTBF), portal vein pressure(PVP), liver enzymes and lactate levels, systemic hemodynamics, and hepatic tissue ATP level were determined. Histopathologically severity of liver tissue damage and the number of infiltrated polymorphonuclear cells were analyzed. TableTableCompared to the control, all treated animals by OKY-046 exhibited significantly better survivals, higher HTBF, earlier PVP restoration, and less hepatocyte's damage. No bleeding tendency related to the drug administration was noted. Ischemia and reperfusion injury of the liver was markedly attenuated by OKY-046, indicating it as a promising agent for the improvement of liver preservation.

Joint British recommendations on prevention of coronary heart disease in clinical practice

Heart failure is a common condition that is becoming more prevalent.1 2 It could be defined as the inability of the heart to deliver a satisfactory output at normal filling...

PROTECTIVE ROLE OF NITRIC OXIDE IN ISCHEMIA AND REPERFUSION INJURY OF THE LIVER

70 In the liver, nitric oxide (NO) has various actions such as hepatic sinusoidal dilatation and the inhibition of endothelium-neutrophil interaction. Suppressed production of endogenous NO elicited by endothelial injury could be one reason for microcirculatory disturbance and neutrophil-related tissue injury in the liver subjected to ischemia and reperfusion (I/R). Using a two-hour total hepatic vascular exclusion model in dogs, we tested our hypothesis that NO enhancement by administrating the substrate of NO, L-arginine or a novel NO donor, FK409, would attenuate vascular dysfunction and reduce I/R injury of the liver. We also evaluated which sort of enhancement would be more favorable strategy. After skeletonization, the liver was made totally ischemic for two hours by cross-clamping the portal vein, the hepatic artery, and the vena cava(above and below the liver). Veno-venous bypass was used to decompress splanchnic and inferior systemic venous congestion during the procedure. Twenty beagle dogs were assigned into 3 groups Group CT, untreated control(n=10); Group LA, treated with L-arginine (n=5); Group FK, treated with FK409 (n=5). In treated animals, each drug was continuously given for 30 minutes before ischemia and 60 minutes after reperfusion. In total, L-arginine of 200mg/kg was administered intravenously, while FK409 of 600µg/kg was given through a mesenteric vein. Animal survival rate, hepatic tissue blood flow (HTBF), tissue ATP level, and liver enzymes levels in the peripheral venous blood, were determined. Histopathologically, the severity of liver injury and the number of infiltrated polymorphonuclear cells (PMN) in the postischemic tissue were analyzed. Systemic hemodynamics was also assessed using mean arterial pressure (MAP).Table 1Compared to the control, treatments with L-arginine or FK409 significantly improved animal survivals, augmented hepatic tissue blood flow, increased high energy phosphate restoration, lessened hepatocyte damage. Histopathologically, liver injury and PNM infiltration were remarkably reduced in the treated groups. Although any adverse effects were not noticed in the dogs treated with L-arginine, considerable hypotension was observed in Group FK. NO enhancement with L-arginine or FK409 markedly attenuated microcurculatory disturbance and ameliorated ischemia and reperfusion injury of the liver. Due to the adverse effect of FK409, supplementation of L-arginine is considered to be more favorable strategy.

A NOVEL HYDROXYL RADICAL SCAVENGER, NICARAVEN, ATTENUATES ISCHEMIA REPERFUSION INJURY OF THE LIVER

278 Protection of the liver against ischemia and reperfusion (R/I) injury is essential to achieve satisfactory outcome after liver transplantation. Although various factors have been proposed to explain hepatic R/I injury, reactive oxygen substance of the cellular membrane and such cellular components has been considered and to play a crucial role. But enhancement of the defense system by supplementation of various antioxidants has been applied, it has only limited effect due to small range of biological activity and/or restricted distribution of each agents in the biological system. Nicarven (AVS) is a novel hydroxyl radical (• OH) scavenger which has both hydrophilic and lipophilic property and permeates evenly into cellular and extracellular space. Using two-hour total hepatic vascular exclusion model in dogs, we tested our hypothesis that the administration of a novel •OH scavenger would attenuate I/R injury of the liver. After skeltonization, the liver was made totally ischemic for 2 hours by cross-clamping the portal vein, the hepatic artery, and the vena cava (above and below the liver). Veno-venous bypass was used to decompress splancnic and inferior systemic venous congestion. Seventeen beagle dogs were divided into two groups 6 animals treated with AVS (Group A), and 11 with no treatment(Group C). AVS was administered intravenously at a rate of 2mg/kg/min for 60 minutes before ischemia and 3 hours after reperfusion. Animal survival, hepatic tissue blood flow (HTBF), tissue high energy phosphate level and liver enzymes level were determined. Histopathologically, severity of sinusoidal and parenchymal damages, and the number of infiltrated polymorphonuclear cells in the postischemic liver tissue were analyzed. AVS allowed survival of the all animals (6/6, 100%), while only 3 control animals lived for 2 weeks (3/11,27%p<0.01). In addition, treatment remarkably augmented HTBF and reduced hepatocyte injury. Any adverse effect was not observed in the animals treated with AVS.FigureIschemia and reperfusion injury of the liver was markedly attenuated by AVS, indicating it as a promising agent for improved presevation of hepatic graft.

Echocardiographic Aspects of Restrictive Cardiomyopathy: Their Relationship with Pathophysiology.

BACKGROUND AND METHODS: We studied 17 patients with restrictive cardiomyopathy; eight had biventricular restriction (type A), four had left ventricular restriction (type B), and five had only right ventricular restriction (type C). RESULTS: Type A disease was characterized by pulmonary and systemic venous congestion. The restrictive pattern was found in the inlet of both ventricles. Both atria were enormous, with small or normal-size ventricles. Differential diagnosis included constrictive pericarditis and systolic pump dysfunction. Type B restriction disease was characterized by venous pulmonary congestion, pulmonary hypertension, and important dilatation of the left atrium and right cavities with a small or normal-size left ventricle; the restrictive pattern was found only in the affected left ventricle. CONCLUSIONS: The clinical picture resembles that of rheumatic mitral valve disease with right ventricular failure. Type C disease had restriction only in the inlet of right ventricle, with giant right atrium, systemic venous hypertension with low flow, and normal pressure of pulmonary artery and left heart. Differential diagnosis included Ebstein's anomaly of tricuspid valve. The etiology of type A disease was amyloid, endomyocardial fibrosis of ventricles and idiopathic interstitial fibrosis. Asymmetric types were always caused by Davies' disease.

Isolated right ventricular infarction

Our experience with 18 cases of isolated right ventricular infarction is reported and the literature is reviewed. Chronic lung disease with right ventricular hypertrophy is an important risk factor. Chest pain is the usual symptom at presentation but some cases can have breathlessness, palpitations or syncope. Some cases can have sinus bradycardia, atrial fibrillation or ventricular tachycardia. Atrioventricular block is rare. Cases with pulmonary artery hypertension, extensive right ventricular infarction due to proximal occlusion of the right coronary artery, right atrial infarction or atrial fibrillation can have hypotension and/or systemic venous congestion. A surface electrocardiogram mainly showing changes in leads conventionally considered to represent left ventricle and right-sided chest leads may not show an infarct pattern in some cases. Echocardiography is, therefore, more reliable in diagnosing this condition. The cautious use of small doses of nitrates and diuretics is not hazardous in the absence of hypotension. High doses of steroids and anti-coagulants can be helpful. The prognosis is usually good, although sudden collapse can occur due to ventricular fibrillation, rupture of the right ventricular free wall or a massive pulmonary embolism.

Are hepatic pulsations in dilated cardiomyopathy with heart failure due to tricuspid regurgitation?

Hepatic pulsations are important clinical manifestations of many cardiac disease states associated with severe systemic venous congestion. These hepatic pulsations are related to transmission of dominant right atrial a or v waves to the liver. For example, systolic pulsations of the liver in patients with primary severe tricuspid regurgitation are due to transmission of a prominent right atrial v wave. 1 Presystolic pulsations are due to transmission of a prominent right atrial a wave, seen in patients with tricuspid stenosis, constrictive pericarditis, restrictive cardiomyopathy and pulmonary hypertension. 2 In patients with dilated cardiomyopathy who present with biventricular failure, a pulsatile liver is generally taken as a sign of secondary tricuspid regurgitation, indicating advanced heart failure. The original description of this clinical finding is difficult to pinpoint, but it is taught to medical students and housestaff, and is mentioned in most comprehensive cardiology texts. 2 This study was prompted by the unexpected observation of a pulsatile liver due to a-wave transmission, as assessed with Doppler studies of hepatic venous flow, in a 59-year-old patient with dilated cardiomyopathy being considered for heart transplantation. After this finding in a selected patient, we conducted this prospective study in patients with dilated cardiomyopathy and biventricular failure to assess specifically the frequency of a- versus v-wave transmission to the liver causing clinically detected hepatic pulsations.

Clinical profile and outcome of restrictive cardiomyopathy in children

The clinical profile and outcome of idiopathic restrictive cardiomyopathy in a group of eight children are reviewed. There were six girls and two boys. Age at presentation was 4.0 ± 2.6 years (range 1.3 to 9.5 years). All patients had evidence of congestive heart failure with systemic venous congestion. Right or left atrial enlargement was the most consistent ECG finding and was present in all patients. Left ventricular shortening fraction was normal in five patients, increased in two, and mildly reduced in one. The most striking echocardiographic feature was severe biatrial dilatation in the presence of normal or near-normal ventricular cavity dimensions. Marked elevation of left ventricular end-diastolic pressure was noted in all seven patients undergoing cardiac catheterization (34 ± 7 torr; range 24 to 40 torr). Right ventricular end-diastolic pressure was elevated but significantly different from left ventricular pressure (18 ± 7 torr; p < 0.01). A characteristic early diastolic dip with a rapid rise to an elevated plateau (square root sign) was present in five of seven patients. Median survival was 1.4 years. Six patients died 0.2 to 7.0 years after they were initially seen. The actuarial survival rate 1.5 years after presentation was 44%, decreasing to 29% at 4 years. Restrictive cardiomyopathy has a worse prognosis in children than in adults. In part this may reflect the more advanced symptoms of congestive failure at initial presentation. Pediatric patients should be considered for early cardiac transplantation.

Anteroseptal myocardial infarction clinically mimicking right ventricular infarction

Acute transmural anteroseptal myocardial infarction with acute left ventricular failure can also raise systemic venous pressure in the absence of right ventricular infarction. Right ventricular infarction, therefore, should not be diagnosed simply by the presence of systemic venous congestion.

Recognition and treatment of left ventricular diastolic dysfunction

B ASED ON EXTENSIVE research, it has become possible to focus on individual factors that cause or contribute to the clinical syndrome of congestive heart failure. These factors include the effects of ischemia and hypertrophy, changes in the peripheral circulation, alterations in reflex and neurohumoral function, the interdependent function of the right and left ventricles, and of signal importance to the clinician, the difference between systolic and diastolic dysfunction of the left ventricle.‘-” This article will discuss the distinction between systolic and diastolic dysfunction (Fig 1) and will answer three clinically relevant questions. What is diastolic dysfunction? How is it diagnosed? How is it treated? Diastolic dysfunction of the left ventricle (LV) is defined as an impaired capacity to accept blood or fill without a compensatory increase in left atria1 pressure. In its mildest form, diastolic dysfunction may appear as a slow or delayed pattern of relaxation and filling, with little or no elevation of LV diastolic pressure (there is generally little or no systolic dysfunction); thus, in patients with LV hypertrophy or coronary disease, an alteration in diastolic filling can serve as a sensitive and early indicator of disease.‘re2’ Diastolic dysfunction may also appear as overt congestive heart failure, even in the presence of normal or near-normal systolic function.22*23 In some ways diastolic dysfunction is similar to mitral stenosis; in this case, however, impaired filling is due to a reduced effective mitral orifice area. Thus, the concept of diastolic dysfunction as a mechanism underlying heart failure is similar to the description of “backward failure” as originally proposed by Hope.24 In recent years, clinicians and physiologists alike have reexamined their concepts about the pathophysiology of heart failure. The major focus has been to clarify the distinction between diastolic dysfunction (or failure) and systolic dysfunction. Simply stated, systolic dysfunction is the inability of the myofibrils to shorten against a load; thus, the left ventricle loses its ability to eject blood into a high-pressure aorta. Diastolic dysfunction implies that the ventricle can not accept blood at low pressures; ventricular filling is slow, delayed, or incomplete unless atria1 pressure increases. Consequently, pulmonary and/or systemic venous congestion develops. Thus, the signs and symptoms of pulmonary and/or systemic venous congestion are not necessarily the result of systolic dysfunction, instead they are related to alterations in diastolic properties of the LV chamber. These properties may consist of changes in the passive (or “static”) diastolic properties of the LV and/or changes in the “active” processes of relaxation and filling.

Schistosomal glomerulonephritis: is it more prevalent in hepatosplenic patients when cor pulmonale is present?

S. mansoni infection can produce damage in several organs, in some due to immunological altera­ tions such as the development of glomerulopathy2 and in others, at least in great part, due to vascular obstruction related to egg deposition, such as chronic cor pulmonale 1. Both situations are essentially obser­ ved in patients with the hepatosplenic form of the parasitic infection. There are reports in the literature suggesting that a chronic increase in renal vein pressure may favour the development of glomerulopathy and/or nephrotic syndrome, such as has been described in chronic congestive pericarditis, renal vein thrombosis or chronic congestive heart failure3 4 5. Even though the increase in renal vein pressure may not be a cause of glomerulopathy, there is some agreement that it could exacerbate a previously exis­ tent proteinuria3. In chronic cor pulmonale due to S. mansoni infection, besides the immunological alte­ rations related to the parasitic infection, there is frequently heart failure, with severe systemic conges­ tion. It would be logical to assume, then, that patients with hepatosplenic schistosomiasis and cor pulmonale should have more frequent (or, perhaps more intense) glomerulopathy or proteinuria than similar patients without cor pulmonale. To investigate this question, a total of 20 (twenty) patients with hepatosplenic schis­ tosomiasis and cor pulmonale (Group I) were compa­ red with 20 others with schistosomal hepatospleno­ megaly without cor pulmonale (Grupo II), matched ac­ cording to ager and sex. All cases had been autopsied at the University Hospital of Federal University of Bahia. Schistosomal cor pulmonale was defined as hypertrophy of the right ventricle (> 0 .5 cm thickness), with a normal left ventricle, pulmonary arteritis with multiple granulomas around eggs of the parasite, and systemic venous congestion. In each group, 10 (ten) patients were male and 10 (ten) female with an average of 15.3 ± 14.2 years for Group I and 26.5 ± 14.3 for Group II. There was no significant difference in the occurrence of arterial hypertension, microscopic hematuria nor the nephrotic syndrome (Table 1).

Hepatic dysfunction and cardiovascular abnormalities. Occurrence in infants, children, and young adults.

In infants and children, the effect of heart failure and/or cyanotic heart disease on the liver has not been well documented, nor has there been any comparison between the degree of liver dysfunction and hemodynamic factors. Sixty-five patients with cardiovascular abnormalities were examined. Hepatic function, as indicated by laboratory data and histologic liver studies, was compared with the following categories of cardiovascular dysfunction: hypoxemia, systemic venous congestion, and low cardiac output. If any one of these factors was present, or any combination, abnormalities of liver function were usually noted. Patients with both hypoxemia and systemic venous congestion had marked hepatic dysfunction. Those with low cardiac output had the most severe abnormalities. Serial studies indicated that liver function correlated with cardiac status.

Biventricular hypoplasia with myocardial fiber hypertrophy and disarray

A 25 year old woman with effort intolerance and systemic venous congestion since childhood, and restrictive ventricular filling and severe atrioventricular (A-V) valve regurgitation at cardiac catheterization died after valve replacement surgery. At autopsy, the atria were enlarged and thickened; both ventricles were small. In some areas the right ventricular wall was only a few myofibers thick. The myofibers of both ventricles were hypertrophied, and there was widespread fiber disarray in the left ventricular free wall, the interventricular septum and, focally, the right ventricular free wall. Because the ventricles were not enlarged or thickened despite myocardial fiber hypertrophy and severe chronic A-V valve regurgitation, and the myofiber disarray was widespread, this is a very unusual case of biventricular hypoplasia and dysplasia.

The renin-angiotensin-aldosterone system in rabbits with congestive heart failure produced by aortic constriction.

Severe constriction of the suprarenal abdominal aorta of 3-kg rabbits to 3.7+/-0.2 mm2 and maintenance of a daily sodium intake of 10 mE q by infusion of 0.9% sodium chloride resulted in a progressive increase in central ear arterial pressure to 106+/-3 (SEM) mm Hg (control=79+/-1). This was accompanied by a progressive increase in left ventricular end-diastolic pressure to 22+/-2 mm Hg (control=3+/-1), plasma renin activity to 21+/-5 ng of angiotensin/hour per ml (control=5+/-1), plasma aldosterone concentration to 99+/-23 pg/ml (control=14+/-4), and plasma sodium concentration to 142+/-1 mEq/liter (control=136+/-1). Urinary excretion of sodium decreased to 3.9+/-0.7 mEq/day and marked fluid retention occurred. We also found that these changes were accompanied by a decrease in hematocrit to 24+/-2% (control=40+/-1), formation of 36+/-9 ml of fluid in the thoracic cavity, 33+/-9 ml of ascites, pulmonary congestion and edema, hepatic congestion, and enlargement and hypertrophy of both the left and right ventricles. All rabbits died of ventricular failure at a time that was partly related to the degree of aortic constriction and that ranged from 2 to 12 days. The model we have established is chronic, highly reproducible, easy to produce, and inexpensive, and resembles the clinical syndrome of right and left congestive heart failure in man. Furthermore, the studies provide evidence for an important role of the renin-angiotensin-aldosterone system in the fluid retention that leads to pulmonary and systemic venous congestion after suprarenal aortic constriction.

Mortality in relation to smoking: 20 years' observations on male British doctors.

In 1951 the British Medical Association forwarded to all British doctors a questionnaire about their smoking habits, and 34440 men replied. With few exceptions, all men who replied in 1951 have been followed for 20 years. The certified causes of all 10 072 deaths and subsequent changes in smoking habits were recorded. The ratio of the death rate among cigarette smokers to that among lifelong non-smokers of comparable age was, for men under 70 years, about 2:1, while for men over 70 years it was about 1-5:1. These ratios suggest that between a half and a third of all cigarette smokers will die because of their smoking, if the excess death rates are actually caused by smoking. To investigate whether this is the case, the relation of many different causes of death to age and tobacco consumption were examined, as were the effects of giving up smoking. Smoking caused death chiefly by heart disease among middle-aged men (and, with a less extreme relative risk, among old men,) lung cancer, chronic obstructive lung disease, and various vascular diseases. The distinctive features of this study were the completeness of follow-up, the accuracy of death certification, and the fact that the study population as a whole reduced its cigarette consumption substantially during the period of observation. As a result lung cancer grew relatively less common as the study progressed, but other cancers did not, thus illustrating in an unusual way the causal nature of the association between smoking and lung cancer.