Patent Foramen Ovale and Cryptogenic Stroke in Older Patients

Further information: Congenital Heart Disease in the Adult: Interventional Therapy from Cardiovascular Medicine, 3rd Edn*

In 40% of patients who suffer a stroke, the cause is unidentified by routine diagnostic testing. However, one potential cause of embolic stroke is a patent foramen ovale (PFO) which allows right-to-left intracardiac shunting. Although the association between PFO and cryptogenic stroke has been studied in a population of younger patients (55 years of age or younger), there have been few studies and the association has remained unconfirmed in patients 55 years of age or older.

The present study [1] was conducted to determine if there were an association between the presence of PFO and cryptogenic stroke in patients 55 years of age or older and to compare the findings with those for younger patients. A total of 503 consecutive patients who had suffered a stroke were prospectively examined. The authors compared 227 patients with cryptogenic stroke and 276 control patients with stroke of known cause. There were 131 patients younger than 55 years old and 372 patients older than 55.

The authors found that the prevalence of PFO is significantly greater among patients with cryptogenic stroke than in patients with stroke of known cause for both younger patients (43.9% vs. 14.3%; odds ratio [OR], 4.70; 95% confidence interval [CI], 1.89–11.68; P<0.001) and older patients (28.3% vs. 11.9%; OR, 2.92; 95% CI, 1.70–5.01; P<0.001). A strong association was found between the presence of PFO with concomitant atrial septal aneurysm and cryptogenic stroke as compared with stroke of known origin, both in younger patients (13.4% vs. 2.0%; OR, 7.36; 95% CI, 1.01–326.60; P=0.049) and older patients (15.2% vs. 4.4%; OR, 3.88; 95% CI, 1.78–8.46; P<0.001). Multivariate analysis adjusted for age, plaque thickness, and the presence or absence of coronary artery disease and hypertension showed that the presence of PFO was independently associated with cryptogenic stroke in both the younger group (OR, 3.70; 95% CI, 1.42–9.65; P=0.008) and the older group (OR, 3.00; 95% CI, 1.73–5.23; P<0.001).

The authors concluded that there is an association between the presence of PFO and cryptogenic stroke in both older and younger patients. In evaluating the association between PFO and cryptogenic stroke in the older patient group, the authors noted that the probability of venous thromboembolism formation increases with increasing age and that a combination of the increased formation of thromboembloic material with hemodynamic changes that promote right-to-left shunting could contribute to increased paradoxical embolism in the older patient group.

[1] Handke M, Harloff A, Olschewski M, et al. Patent foramen ovale and cryptogenic stroke in older patients. N Engl J Med 2007;357:2262-68

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Adolescent Overweight and Future Adult Coronary Heart Disease

Further information: Congenital Heart Disease in the Adult: Interventional Therapy from Cardiovascular Medicine, 3rd Edn*

Obesity has become a major health issue in the United States, and there are more that 9 million children and adolescents who are considered overweight. However, the effect of adolescent overweight on future adult coronary heart disease (CHD) is not understood.

The authors of this paper [1] used a computer-based system, the CHD Policy Model that is a computer simulation of CHD incidence, prevalence, mortality, and costs, used to estimate the potential impact of an increasingly overweight US adolescent population on future adult health. Data sources included the US census, the National Health and Nutrition Examination Surveys I, II, III, IV (NHANES), and the Copenhagen School Health Records Register (CSHR) to obtain data for the incidence of myocardial infarction (MI) and cardiac arrest.

Based on the prevalence of overweight adolescents in 2000, the researchers predicted that 30–37% of men and 34–44% of women will be obese by the year 2020 and that by 2035, the prevalence of CHD will increase by a range of 5–16% with more than 100,000 excess CHD cases attributable to this higher incidence of obesity. Researchers found that for boys, the elevated risk was significant at age 7 for both fatal events (adjusted hazard ratio [HR]: 1.10; 95% confidence interval [CI]: 1.06–1.15) and nonfatal events (adjusted HR: 1.05, 95%, CI: 1.03–1.08). Risk increased with age to HR of 1.24 and 1.17, respectively, at age 13. For girls, the elevated risk became significant at age 8 for fatal events (adjusted HR: 1.08, 95% CI: 1.01–1.17) and at age 10 for nonfatal events (adjusted HR: 1.06, 95% CI: 1.02–1.10). It also increased through age 13 to HR of 1.23 and 1.11, respectively.

On the basis of current known effects of obesity on cardiovascular risk factors, the projected effect of increased obesity on cardiovascular outcomes included: a) an excess total number of CHD events of 10% in 2020, rising to 14% in 2035 (absolute excess events 550 and 33,000, respectively; b) an excess CHD incidence of 15% by 2035 (40,000 events). However, the estimates would differ greatly if new treatments significantly changed obesity trends, prevention, or treatment of CHD, just as new treatments have significantly changed medicine. Such a reversal of the current trend would make the projections purely speculative.

[1] Bibbins-Domingo K, Coxson P, Pletcher MJ, et al. Adolescent overweight and future adult coronary heart disease. N Engl J Med 2007;357:2371-79

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Serial Measurement of MCP-1 after ACS

Further information: Biomarkers of Inflammation as Surrogate Markers in Dection of Vulnerable Plaques and Vulnerable Patients from Cardiovascular Medicine, 3rd Edn*

The results of the A to Z Trial (Aggrastat to Zocor Trial), an open-label noninferiority trial, were reported in 2001, and results the A to Z Trial, Z Phase Trial (4497 patients), a randomized, double-blind trial, were reported in 2004. The study population of the current report [1] included all patients enrolled in Phase Z with a blood sample available for measurement of monocyte chemoattractant protein-1 (MCP-1) at either baseline or 4 months.

It has been shown in animal models that when MCP-1 expression is increased, atherosclerosis is promoted, and it is inhibited when the gene for MCP-1 is deleted. MCP-1 may contribute to the transition from stable atherosclerosis to ACS. Authors evaluated the measurement of MCP-1 in the large population of the A to Z Trial, Z Phase of patients stabilized after acute coronary syndromes (ACS) to determine whether 1) measurement of MCP-1 in the hospital setting and/or during out-patient follow-up adds to the prognostic value of standard measurement; 2) plasma levels of MCP-1 were modified by intensive statin therapy; and 3) elevated MCP-1 levels could identify patients who derived incremental benefit from intensive statin therapy. MCP-1 was measured at baseline (n=4244), four months (n=3603), and 12 months (n=2950), and correlated with clinical events in the Z phase of the A to Z trial.

Rates of death and the composite end points of death or myocardial infarction (MI); death, MI, or heart failure (HF), and cardiovascular death, MI, readmission for ACS, or stroke increased across baseline quartiles of MCP-1 and among patients with MCP-1 greater than or equal to the pre-specified threshold of 238 pg/ml (P<0.01 for each). After adjusting for standard risk predictors and levels of C-reactive protein (CRP) and B-natriuretic peptide, MCP-1 >238 pg/ml remained independently associated with mortality (hazard ratio [HR] 2.16; 95% confidence interval (CI) 1.54–3.02) and with each composite end point, and increased the C-statistic of the fully adjusted mortality model from 0.76–0.78 (P<0.0001). A value of MCP-1 >238 pg/ml at the 4-month follow-up visit was also independently associated with mortality after 4 months (HR 1.76; 95% CI 1.12–2.76). Elevated MCP-1 levels did not identify patients who derived incremental benefit from intense statin therapy.

The authors concluded that plasma levels of MCP-1 provide prognostic value in both the acute and the chronic period after ACS that is complementary to that of standard clinical variables. Statin influence on MCP-1 is moderate, and MCP-1 is not useful to identify patients who benefit from aggressive statin regimens after ACS.

[1] de Lemos JA, Morrow DA, Blazing MA, et al. Serial measurement of monocyte chemoattractant protein-1 after acute coronary syndromes. J Am Coll Cardiol 2007;50:2117-24

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Ischemic and Thrombotic Effects of Dilute Diesel-Exhaust Inhalation in Men with Coronary Heart Disease

Further information: Coronary Artery Disease: Pathologic Anatomy and Pathogenesis from Cardiovascular Medicine, 3rd Edn*

In an effort to determine the direct effect of air pollution on myocardial, vascular, and fibrinolytic function, a randomized, double-blind, crossover study was conducted on 20 men, aged 21–44 years, with stable coronary artery disease, but prior myocardial infarction (MI) [1].

The men were exposed to filtered air that served as a control and to diluted diesel-exhaust at 300 micrograms per meter cubed, a level comparable to curbside exposure on a busy street. During exposure, myocardial ischemia was quantified by ST-segment analysis using continuous 12-lead electrocardiography. Researchers performed the exposures in a specially built diesel exposure center, and at 2 and 6 hours after exposure, a small amount of the participants’ blood was allowed to flow through a perfusion chamber. Clot formation, coagulation, platelet activation, and inflammatory markers were measured after each exposure. Clot formation was measured by low and high shear rates to recreate flow conditions inside the body’s blood vessels.

Compared to filtered air at 2 and at 6 hours, breathing air with diluted diesel-exhaust increased clot formation in the low shear chamber by 24.2% and by 19.1% in the high shear chamber. An increase in platelet activation was also seen when the number of platelets associated with white blood cells was measured. Platelets, when activated, associated with white blood cells such as neutrophils and monocytes, and diluted diesel-exhaust inhalation increased platelet-neutrophils and monocytes aggregates from 6.5–9.2% and platelet-monocyte aggregates from 21–25% at 2 hours after exposure. Platelet activation at 6 hours was not significant.

Although it is already known that high levels of traffic pollution increase the risk of heart attacks in the immediate days after exposure, the findings in this study provide a potential mechanism that indicates an increased chance of blood clotting that could result in heart attack or stroke. Even brief exposure to dilute diesel-exhaust promotes myocardial ischemia and inhibits endogenous fibrinolytic capacity in men with stable coronary heart disease. It is not clear whether these findings apply to gasoline-powered engines because research has not pinpointed which part of the diesel-exhaust is responsible for the adverse effects. However, the study suggests that the most damaging parts of the exhaust are the particle components. Although the long-term goal of this research is to develop particle traps for vehicles, the most damaging effects may come from particles that are less than 100 nm and thus, very difficult to filter.

[1] Mills NL, Törnqvist H, Gonzales MC, et al. Ischemic and thrombotic effects of dilute diesel-exhaust inhalation in men with coronary heart disease. N Engl J Med 2007;357:1075-82

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Severe Mental Illness and Risk of Cardiovascular Disease

Further information: Coronary Artery Disease: Pathologic Anatomy and Pathogenesis from Cardiovascular Medicine, 3rd Edn*

Although cardiovascular disease (CVD), including coronary heart disease (CHD), stroke, and peripheral vascular disease, is the leading cause of death in the United States and most of the Western countries, the mortality rate has declined over the past 20 years from more than 50% to less than 36% as the underlying cause of death. However, patients with severe mental illnesses (5–10% of the US population), including patients with schizophrenia, bipolar disorder, and depression, lose 25 or more years of life expectancy, with the majority of premature deaths due to CVD and not suicide.

Recent data suggest that the most observed reductions in CVD mortality in the general population have been due to improvements in the treatment of acute events and in long-term secondary prevention rather than in primary prevention. This study addresses the disparities in CVD mortality and prevention efforts between the general population and individuals with severe mental illness. The authors of this commentary article [1] believe that better communication between health-care specialists who care for mentally ill patients and cardiologists, as well as improved education and involvement of primary care clinicians and endocrinologists, is critical to reduce the disparities in the level and quality of treatment services received by individuals with mental illness who require treatment for CVD and CHD risk-equivalent conditions like diabetes, hypertension, and dyslipidemia. Whereas increases in utilization of aspirin, thrombolytics, β-blockers, and ACE inhibitors have contributed to reductions in mortality in the general population, patients with severe mental illness are less likely to receive drug therapies of proven benefit, to undergo cardiac catheteritizations, to receive emergency angioplasties, or to undergo coronary artery bypass surgery because of the misconception that psychiatric issues need to be “resolved” before other health problems can be addressed.

The authors emphasize that systemwide changes as to how patients with severe mental illness are handled in the medical system will take time, and they suggest that improvements in primary prevention offer potential for reducing CVD mortality in patients with mental illness. They also suggest that research should be directed to the evaluation of the antipsychotic and other drug therapies less likely to adversely affect cardiometabolic risk, such as excess weight, dyslipidemia, hypertension, and hyperglycemia in this patient population.

[1] Newcomer JW, Hennekens CH. Severe mental illness and risk of cardiovascular disease. JAMA 2007:298:1794-96

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Effects of Torcetrapib in Patients at High Risk for Coronary Events

Further information: Management of Cholesterol Disorders from Cardiovascular Medicine, 3rd Edn*

Cholesterol ester transfer protein (CETP) promotes the transfer of cholesteryl esters from high-density lipoprotein (HDL) to other lipoproteins, and the inhibition of this protein raises HDL cholesterol levels and decreases low-density lipoprotein (LDL) cholesterol levels. The Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events (ILLUMINATE) study was a randomized, double-blind study of 15,067 high risk cardiovascular patients conducted to determine whether or not the use of torcetrapib, a CETP inhibitor, would reduce major cardiovascular events [1]. This trial ran concurrently with three large trials using ultrasonography and other imaging techniques to determine if the drug could slow the progress of the atherosclerotic burden. The ILLUMINATE trial tested the proposition that torcetrapib would decrease the risk of clinical cardiovascular events.

The trial enrolled 15,067 patients at 260 centers in seven countries. Of these patients, 7534 were assigned to receive atorvastatin plus placebo and 7533 were assigned to the combination arm of atorvastatin and torcetrapib. In patients receiving torcetrapib, at 12 months, there was a 72.1% increase in HDL-C and a 24.9% decrease in LDL-C as compared with baseline P<0.001 for both comparisons. For the primary composite outcome of major cardiovascular events, the hazard ratio (HR) was 1.25 in the torcetrapib group as compared with the atorvastatin-only group (95% confidence interval [CI], 1.09–1.44; P=0.001). HR estimates for the individual components of the composite outcome ranged from 1.35 for hospitalization for unstable angina (P=0.001) to 1.08 for stroke (P=0.74). The trial was terminated December 2, 2006 because the drug was also associated with a 25% rise of potentially deadly heart problems and a 40% rise in deaths. Adverse events were reported in 86.6% of patients in the torcetrapib group and in 83.3% of patients in the atorvastatin-only group (P<0.001). Among events that were significantly more frequent in the torcetrapib group than in the atorvastatin-only group were hypertension, which occurred in 1411 torcetrapib patients and 564 atorvastatin patients, respectively; peripheral edema in 467 and 353 patients, respectively; angina pectoris in 451 and 360 patients, respectively; dyspnea in 313 and 243 patients respectively; and headache in 412 and 296 patients respectively. Serious adverse events were reported more frequently in the torcetrapib group than in the atorvastatin-only group (16.4% vs. 15.0%, P=0.02).

Close examination of the data from each of the trials gives rise to the belief that torcetrapib has a problem with toxicity and that there may be a biochemical explanation that will not be true of other drugs in this class. However, considering that such significant problems occurred in the torcetrapib trials, it will be more difficult for researchers to have the courage to undertake clinical trials testing new drugs of the same class, even though evidence exists that other CETP drugs may be beneficial.

[1] Barter PJ, Caulfield M, Eriksson M, et al. Effects of torcetrapib in patients at high risk for coronary events. N Engl J Med 2007;357:2109-22

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