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Review of recent clinical trials of lipid lowering in coronary artery disease.

Early trials with lipid-lowering therapy in patients with established coronary artery disease revealed favorable trends in cardiovascular events but did not yield significant reductions in total mortality. Recent clinical trials using hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitor ("statin") therapy have shown significant decreases in total mortality, cardiovascular events, hospitalizations, and the need for revascularization procedures, with its usage (1) to lower low-density lipoprotein (LDL) cholesterol after myocardial infarction (secondary prevention); and (2) in high-risk patients without evidence for coronary artery disease (primary prevention). Secondary prevention benefits have been seen for both men and women, in the young and elderly, and among diabetic and nondiabetic patients. The beneficial effects of LDL-cholesterol reduction occur early and are additive to other risk-reduction therapies. Lipid-lowering therapy should be part of the comprehensive treatment of all patients with atherosclerotic vascular disease and patients at high risk.

Anticholesteremic Agents↗

Coronary arteriography and lipid lowering: limitations, new concepts, and new paradigms in cardiovascular medicine.

Coronary arteriography has played a central role in improving our understanding of the mechanisms of unstable coronary syndromes and the benefits of cholesterol lowering. However, coronary arteriography as currently used is outmoded and inadequate for new clinical algorithms based on vigorous lipid and other risk factor control as alternatives to invasive procedures for the primary treatment of coronary artery disease. What is needed is a way of viewing or analyzing noninvasive myocardial perfusion images and coronary arteriograms so as to identify and quantify the extent or severity of diffuse coronary atherosclerosis. Determining the relative contribution of diffuse and segmental narrowing by definitive myocardial perfusion imaging or coronary arteriography would provide the optimal basis for determining the need for revascularization procedures. In the absence of significant segmental stenoses, mild or diffuse disease identified by coronary arteriography would also provide a definitive diagnosis as the basis for lifelong cholesterol-lowering drugs and risk factor modification, even for patients with normal cholesterol levels. Thus, it is important to consider several new concepts for analyzing coronary arteriograms. More physiologically accurate invasive and noninvasive technology allows improved diagnosis and management of coronary atherosclerosis as new paradigms in cardiovascular medicine.

Anticholesteremic Agents↗

Effects of successful parathyroidectomy on altered arterial reactivity in patients with hypercalcaemia: results of a 3-year follow-up study.

OBJECTIVE: Serum calcium was found to be an independent, prospective risk factor for myocardial infarction. We have previously shown that altered arterial reactivity in the course of primary hyperparathyroidism, a disease characterized by hypercalcaemia, may predominantly involve the arterial media and not the endothelium as observed in patients with various stages of atherosclerosis. The present study was performed to test whether successful parathyroidectomy can improve vascular reactivity in patients with primary hyperparathyroidism. SUBJECTS AND DESIGN: Endothelium-dependent, flow-mediated and endothelium-independent, nitroglycerin-induced dilatation were assessed by brachial artery ultrasound (7 MHz) in 18 patients with primary hyperparathyroidism (mean +/- SD; age, 55.1 +/- 12.6) prior to and 3 years after successful parathyroidectomy. RESULTS: Parathyroidectomy resulted in significant decreases of PTH (242 +/- 186 vs. 34 +/- 24 ng/l, P = 0. 0001) and serum calcium levels (2.8 +/- 0.3 vs. 2.4 +/- 0.1 mm/l, P = 0.00001) and in an increase of serum phosphate levels (0.78 +/- 0. 23 vs. 1.17 +/- 0.18 mm/l, P = 0.00001). However, normalization of hormone and electrolyte levels did not lead to an improvement of flow-mediated dilatation (12.1 +/- 3.1 vs. 11.0 +/- 5.4&, P = 0.49) or nitroglycerin-induced dilatation (12.5 +/- 3.1 vs. 13.2 +/- 6.8%, P = 0.68) within the follow-up period. No changes were observed with respect to the risk factor profile, vessel size and blood flow. CONCLUSION: These data suggest that restoration of normocalcaemia by parathyroidectomy cannot improve vascular reactivity in patients with primary hyperparathyroidism but may prevent further progression of vascular disease within this period of time.

Aged↗

Effect of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors on high-sensitivity C-reactive protein levels.

Cardiovascular disease is the leading cause of death among adults in the United States, in Europe, and in much of Asia. Despite advances in primary prevention of coronary artery disease, including early detection and treatment of dyslipidemia, one half of all myocardial infarctions and strokes occur in patients with normal serum cholesterol levels. Observations like this prompt the search for new risk factors and improved identification of individuals at high risk. One proposed risk factor is an elevated level of C-reactive protein (CRP), a marker of inflammation independent of other risk factors. The CRP assay is desirable in terms of standardization and cost. The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) are indicated for the treatment of dyslipidemias, but data support their protective role against cardiovascular disease beyond their effects on lipids. Statins directly affect inflammatory markers, and nearly 2 dozen randomized studies have demonstrated statins' effects on CRP. Because information regarding the role of CRP in cardiovascular disease is compelling but sometimes contradictory and because the need to reduce CRP levels is unclear, the American Heart Association and the Centers for Disease Control and Prevention presented a panel statement on the topic. Ongoing trials will assist in determining the need to reduce CRP levels to lower cardiovascular risk. An understanding of these issues is important for improving the prediction of cardiovascular risk and for intervening to reduce this risk.

Animals↗

Increased AT(2)R protein expression but not increased apoptosis during cardioprotection induced by AT(1)R blockade.

BACKGROUND: The angiotensin II type 2 receptor (AT2R) is considered to be antigrowth and to mediate apoptosis in several cell types. Whether AT2R upregulation, associated with angiotensin II type 1 receptor (AT1R) blockade and cardioprotection after ischemia-reperfusion (IR), might not result in increased cardiomyocyte (CM) apoptosis has not been documented. OBJECTIVES: To determine whether increased AT2R protein expression, during AT1R blockade after acute IR, is associated with no increase in CM apoptosis. MATERIALS AND METHODS: The recovery of left ventricular (LV) mechanical function after acute IR (30 min of ischemia, 40 min of reperfusion) was measured in isolated Langendorff rat hearts following pretreatment with the AT1R antagonist candesartan (CN) (CN 10 nmol/L) for 40 min before ischemia. The authors established with an initial dose-response curve using escalating concentrations of CN that 10 nmol/L abrogated vasoconstriction induced by angiotensin II (0.1 mol/L). AT1R and AT2R protein expression (Western immunoblot), CM apoptosis (terminal deoxynucleotidyl transferase-mediated 2'-deoxyuridine 5'-triphosphate nick end-labelling assay and nuclear morphology) and apoptotic markers (Bax, Bcl-2, caspase-3, p53) were assessed in LV tissue. RESULTS: Compared with IR controls, CN improved peak systolic pressure, LV developed pressure and positive dp/dt, and increased AT2R (not AT1R) protein, but did not change the level of apoptosis or the expression of Bax, Bcl-2, caspase-3 or p53. CN also increased AT2R protein after ischemia alone but did not change CM apoptosis or expression of the markers. CONCLUSIONS: Increased AT2R protein expression during AT1R blockade after IR in the isolated Langendorff rat heart is associated with cardioprotection but no increase in CM apoptosis.

Analysis of Variance↗

[Anesthetic considerations in patients with CAD (author's transl)].

The primary aim during anesthetic management of the patient with coronary artery disease is prevention of imbalance between myocardial oxygen supply and demand. Since oxygen supply is limited by restriction of coronary blood flow, prevention of increases in demand plus maintenance of supply, rather than increases in supply, will achieve this aim. The major determinants of myocardial oxygen demand are mechanical, i.e. (a) left ventricular wall tension, dependent in turn upon systolic pressure and ventricular volumn, (b) velocity of contraction, and (c) heart rate. Systolic pressure, pulmonary capillary wedge pressure, and heart rate monitoring will alert the anesthetist to increases associated with an enhanced oxygen demand. Decreased arterial diastolic and increased pulmonary capillary wedge pressure are associated with decreased supply. By appropriate manipulation of these variables and avoidance of episodes of myocardial ischemia, the perioperative morbidity and mortality rates associated with coronary artery disease may be decreased.

Adrenergic beta-Antagonists↗

[Stimulation of reparative processes in myocardial infarction: comparative evaluation of the effects of piracetam and inosine].

A study of 102 patients with primary macrofocal myocardial infarction, admitted to hospital within the first 6 hours after the onset of the disease, and experimental evidence obtained in 110 Wistar rats are reported. In a control group of myocardial infarction patients, collagen synthesis was depressed in the presence of the activation of free-radical lipid oxidation and circulatory hypoxia. Piracetam and inosine treatment was associated with the inhibition of free-radical lipid oxidation and a reduction of hypoxia, those being accompanied by increased collagenogenesis and accelerated postinfarction scar formation. Piracetam, as compared to inosine, had a more marked stimulating effect on the development of compensatory myocardial hypertrophy, thus contributing to rapid recovery of cardiac contractility and reducing manifestations of circulatory insufficiency.

Adult↗

Permanent cardiac pacing in South African Blacks.

Fifty-seven Black patients received permanent cardiac pacemakers at Baragwanath Hospital, Johannesburg, over a 7 1/2-year period. Most patients had established complete heart block (77%), while very few had intermittent conduction disorders or sinus node dysfunction. In most patients the cause of the conduction disease was unknown but was probably primary degeneration of the conducting pathways (Lenègre's disease); 2 patients underwent insertion of a pacemaker after myocardial infarction, 4 had congestive cardiomyopathy and 4 had valve disease and/or had previously undergone valve replacement. Seventeen patients (30%) were hypertensive. The results of cardiac pacing have been very good and the complication rate is low. Cardiac conduction disorders requiring insertion of a permanent cardiac pacemaker are not infrequent in South African Blacks, despite the absence or rarity of coronary artery disease in this population.

Adolescent↗

Point-of-care determination of baseline platelet function as a predictor of clinical outcomes in patients who present to the emergency department with chest pain.

BACKGROUND: Increased platelet reactivity can identify patients at high risk for thrombotic events, but its clinical use has been impractical due to technical limitations. The purpose of the present study is to determine if a point-of-care measurement of platelet function in patients presenting to an emergency room with chest pain can identify those at high risk of adverse cardiac events. METHODS: Platelet function was measured using the Ultegra-RPFA in 201 patients presenting to the emergency department with the primary complaint of chest pain and either known coronary disease or at least one cardiac risk factor. The primary endpoint was any major adverse cardiac events (MACE) [cardiac death, myocardial infarction (MI), re-admission for coronary revascularization] 6 months post-enrollment. RESULTS: Platelet function at baseline ranged from 44 to 315 platelet activation units (PAU) (mean 175+/-6). Seventy-six patients experienced MACE (37.8%) by 6 months post-enrollment. Mean PAU was significantly lower in the group experiencing MACE (166+/-9 vs. 181+/-9; p=0.026). By univariate analysis, admission PAU was a significant predictor of MACE at 6 months (p=0.028). However, when adjusted for age, gender, cardiac risk factors, and a history of coronary artery disease (CAD) using multivariate logistic regression analysis, PAU was no longer significantly predictive of MACE (p=0.268). CONCLUSIONS: Point-of-care testing of platelet function deserves further study for risk assessment and individualized therapy in the future.

Aged↗

The interdependence between electrogram, total electrode impedance and pacemaker input impedance necessary to obtain adequate functioning of demand pacemakers.

Electrogram maximum derivatives (DMAX, SMAX) and electrogram amplitudes (AMAX, UMAX) (Figure 2), were studied in 71 cases during permanent pacemaker treatment. During the acute phase, (at first implantation), 29 patients were studied, and during the chronic phase, (at pulse generator replacement), 42 patients were studied. Of these patients, 27 (acute phase) and 36 (chronic phase) were studied for tissue impedance (RT) and interface impedance (Faraday resistance RF and Helmholtz capacity CH). DMAX and SMAX changed from 3.47 +/- 0.33 V/s (mean +/- SEM) to 2.46 +/- 0.23 V/s and 1.93 +/- 0.20 V/s to 1.32 +/- 0.12 V/s; p < 0.02; p < 0.01. AMAX and UMAX remained nearly unchanged from acute to chronic phase. A paired comparison in 13 patients showed almost identical results. Electrograms recorded in patients with bundle branch block showed no statistical difference in DMAX, SMAX, AMAX, and UMAX compared with electrograms recorded in patients with QRS-complexes of normal duration. No correlation was found between rise in myocardial threshold and fall in DMAX and SMAX from acute to chronic phase; p > 0.8, p > 0.5. Patients with coronary heart disease were found to have significantly higher AMAX than patients classified as having rhythm disturbances of primary cause; p < 0.01. Extremely low values of amplitudes and maximum derivatives were found in some patients with myocardial infarctions and cardiomyopathies. No difference existed in DMAX, SMAX, AMAX, and UMAX recorded from electrodes with a 8 mm2 area compared with a 12 mm2 area (p > 0.5). RT was statistically significantly higher on the smaller compared with the larger surface electrodes (p > 0.005). There was a slight but not statistically significant fall in RT from acute to chronic phase (p > 0.2). RF ranged from 2.0-94.6 kohms. There was no statistically significant differences between the 8 mm2 compared with the 12 mm2 electrodes (p > 0.2). CH varied between 0.7 and 37.0 microfarads, with significantly lower values for the smallest electrodes (p < 0.05). In patients with electrograms of borderline amplitudes and maximum derivatives for being sensed, the low CH found with the small tip electrodes, will gave a higher risk of demand failure if the input impedance in the sensing circuit of a demand pacemaker is too low.

Adult↗

[The PreFord Study. A prospective cohort study to evaluate the risk of a cardiovascular event (overall-collective) as well as a prospective, randomized, controlled, multicentre clinical intervention study (high-risk-collective) on primary prevention of cardiovascular diseases in the Ford Motor Company employees in Germany].

The PreFord Study is a multicenter prospective cohort study to evaluate guideline based risk management on primary prevention of cardiovascular diseases. Furthermore a randomised controlled trial (RCT) will be designed to analyse the effect of a special intervention program. 40,000 employees of the Ford Motor Company, Visteon Company and Deutz Company in Germany will be included, monitored for ten years and the following primary endpoints will be investigated: 1. evaluation and comparison of established and newly developed risk-scores, 2. the relative impact of single and combined cardiovascular risk factors on cardiovascular diseases, 3. the influence of a novel occupationally integrated ambulant rehabilitation program in combination with a guideline oriented optimal drug therapy within a high risk group on the primary endpoint: risk reduction by, 4. the influence of this intervention on secondary endpoints: death, myocardial infarction and stroke, combined appearance of angina pectoris and hospitalisation, occurrence of cerebral circulatory disorder and hospitalisation, occurrence of peripheral occlusive arterial disease and hospitalisation and single cardiovascular risk factors and cost-benefit-analysis. Beginning with an cross sectional study there will be a systemic screening of cardiovascular risk profiles, of anthropometric data and different lifestyle-factors. Based on these data participants will be differentiated into three risk-groups according to the risk score of the European Society of Cardiology (risk of a lethal primary acute cardiovascular event: I < or = 1%; II > 1-< 5% and III > or = 5%). In the following longitudinal study different strategies will be applied: Group I: low risk (< 0.5% per year): repetition of the investigation after five and ten years. Group II: middle risk, (0.6% to 1.4% per year), repetition of the investigation every two years, instruction of the patients general practitioner (GP) with respect to a risk factor oriented and evidence based treatment. Group III: high risk, (> 1.5% per year or >15% within the next 10 years) will be randomised into two interventional groups. The first one, the intervention-group "PreFord" will perform an occupational integrated rehabilitation program (2,5-3 hours twice a week, for 15 weeks according to the BAR guidelines) with a following engagement in heart-groups and an annual repetition of the check-ups. The second group, the "classic" intervention-group will be treated evidence based in cooperation with their GP. As a result of this long term interventional study efficient, area wide implementable and economically feasible prevention concepts with special regards to operational healthcare will be developed and evaluated. Core elements will be exercise- and lifestyle-oriented concepts as well as guideline-based pharmacotherapy.

Adult↗

Survival and predictors of death in dialysed diabetic patients.

The objective of this study was to examine diabetic patients at the time of admission to maintenance haemodialysis and to follow them for 36 months in order to define predictors of cardiovascular and non-cardiovascular death. This prospective study comprised all consecutive diabetic patients admitted to 28 German dialysis centres between January 1985 and October 1987; 196 patients were examined, 67 Type 1 (insulin-dependent) diabetic (43 male, 24 female; median age 49 years, range 22-73) and 129 Type 2 (non-insulin-dependent) diabetic patients (54 male, 75 female; 64 years, range 37-82). Outcome measures were death, i.e. myocardial infarction, sudden death, cardiac death of other causes, stroke and non-cardiovascular death. Actuarial survival 36 months after the beginning of dialysis was similar in Type 1 (40%) and Type 2 diabetic patients (43%) despite the age difference. Causes of death were myocardial infarction (18%), sudden death (18%), other cardiac causes (18%); stroke (6%); septicaemia (17%) mostly originating from diabetic foot problems; and interruption of therapy. Survival rates and the proportion dying from cardiac causes were similar in patients with diabetic nephropathy or with other primary chronic renal disease and coincidental diabetes. On dialysis, de novo amaurosis or de novo amputation was not observed in any patient. The strongest predictor of myocardial infarction or sudden death was serum lipids on admission. Duration of hypertension, blood pressure at the time of admission to dialysis, left ventricular hypertrophy or end-diastolic diameter by echocardiography, Sokolow index and average predialysis blood pressure, smoking, interdialytic weight gain and type of dialysis were not predictive of cardiovascular death or death by all causes.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

D-dimer increase after percutaneous transluminal angioplasty and clinical recurrence after primary revascularization in acute myocardial infarction? A pilot study.

It has been reported that the increase of plasminogen activator inhibitor-1 activity immediately after elective coronary angioplasty is related to subsequent clinical recurrence in patients with chronic coronary artery disease. The aims of our study were to evaluate the behavior of plasminogen activator inhibitor-1 and D-Dimer after revascularization in acute myocardial infarction patients treated with angioplasty and stenting and if this behavior is predictive of subsequent clinical recurrence. D-Dimer and plasminogen activator inhibitor-1 activity were evaluated in two groups of patients. Group 1 consisted of 54 consecutive patients undergoing primary angioplasty for acute myocardial infarction and Group 2 consisted of 48 patients undergoing elective angioplasty. Patients underwent control coronary angiography only in the case of clinical recurrence and/or positivity of provocative tests. D-Dimer and plasminogen activator inhibitor-1 baseline levels were significantly higher in group 1 than in group 2 (P<0.0005 and P<0.05, respectively). The percentage of group 1 patients with a post-procedural increase in D-Dimer was significantly higher among those with subsequent clinical recurrence with restenosis (61%) than among those with no recurrence (25%, P<0.05). No difference was observed in group 2. The percentage of group 2 patients in whom no decrease of plasminogen activator inhibitor-1 was observed after angioplasty was significantly higher (83%) among those with subsequent recurrence than among those with no recurrence (38%, P<0.05). This pattern was not observed in group 1. In conclusion, the role of early changes in plasminogen activator inhibitor-1 in predicting clinical recurrence after primary angioplasty in acute myocardial infarction patients is less clear than that observed after elective angioplasty. A significant role seems to be played by a more-marked clotting activation with increased fibrin formation.

Adult↗

Immediate and long-term outcomes of stent implantation for unprotected left main coronary artery disease.

Left main coronary artery (LMCA) disease is now uniformly treated with coronary artery bypass grafting (CABG). However, some patients with LMCA disease do not receive CABG because of high operative risks. The advent of stent implantation has permitted a non-operative improvement in myocardial blood flow in many patients with single- and multi-vessel coronary artery disease. However, the outcomes of stent implantation for unprotected LMCA disease are still unclear. Stent implantation was performed for unprotected LMCA disease in 13 patients; eight patients had high operative risk and five patients had refused CABG. The primary success rate was 100% (13/13 patients). One patient (8%) developed a non-Q-wave myocardial infarction after LMCA stenting. Repeat angiography was obtained in five patients (38%) with recurrent angina, and three patients (23%) received repeated percutaneous transluminal coronary angioplasty (PTCA) for LMCA restenosis. In the follow-up period of 18+/-3 months, 12 patients (92%) remained in satisfactory condition with no further need for surgical intervention. One patient (8%) ultimately required CABG, and she died after CABG at 3 months after LMCA stenting. In conclusion, although CABG remains the standard treatment for LMCA disease, the present study demonstrates that stent implantation is a safe and clinically beneficial revascularization procedure for unprotected LMCA disease in patients who have high operative risk as well as those who refuse CABG.

Aged↗

[The PROSPER Study (PROspective study of pravastatin in the elderly at risk)].

Statins reduce coronary and cerebrovascular mortality and morbidity in middle-aged individuals. Until recently, their efficacy and safety in elderly people had not yet been firmly established. PROSPER was a controlled, randomised study involving 2,804 men and 3,000 women aged 70-82, with a history of, or risk factors for cardiovascular disease. Their baseline cholesterol level was 135-350 mg/dl; they were randomised to either 40 mg pravastatin per day, or matching placebo. Average follow-up was 3.2 years. The primary endpoint was a composite of coronary death, non-fatal myocardial infarction, and fatal or non-fatal stroke. Pravastatin lowered LDL-cholesterol (-34%), and reduced the incidence of the primary endpoint (-15%; CI 95%: 3-26%; p = 0.014). Coronary death and non-fatal myocardial infarction risk was also reduced (-19%; p = 0.006), and mortality from coronary disease fell by 24% (p = 0.043). The risk for stroke, however, was unaffected (p = 0.8), whereas the incidence of transient ischemic attacks was reduced by 25%, which was (marginally) insignificant (p = 0.051). Pravastatin had no effect on cognitive functions or incapacity. New cancers were more frequent amongst pravastatin-treated individuals (+25%; p = 0.020). However incorporation of this new data in a meta-analysis of all pravastatin and all statin trials revealed no overall increase of cancer risk.

Aged↗

Prognostic significance of ST-T segment alterations in patients with non-Q wave myocardial infarction.

OBJECTIVE: To determine whether, among patients with non-Q wave myocardial infarction, the characteristics of the segment ST-T shifts at presentation in the diagnostic electrocardiogram can identify those with more severe coronary artery disease and predict a poor clinical outcome. DESIGN: Prospective controlled clinical trial. SETTING: Primary referral medical centre. PATIENTS: 93 patients (mean (SD) 62.0 (7.5) years) were studied: 41 with non-Q wave myocardial infarction and T wave inversion and 52 with ST segment depression. Cardiac events and mortality rates were assessed over 42 months. Age, sex, risk factors, creatinine kinase MB isoenzyme peak, and left ventricular function were comparable. RESULTS: 31 patients with T wave inversion myocardial infarction (94.6%) had total occlusion of the infarct related artery, compared with 12 patients with ST segment depression myocardial infarction (26.7%) (P < 0.05). When compared with patients with T wave inversion, patients with ST segment depression had a higher incidence of cardiac events during the first month and in the 41 subsequent months: 9.6% and 30.8% v 0% (P < 0.01) and 9.8% (P < 0.02), respectively. For the same observation periods, the mortality rates in patients with T wave inversion were 4.9% and 7.3%, and in patients with ST segment depression they were 5.8% and 9.6%, respectively. CONCLUSION: These data suggest that during a non-Q wave myocardial infarction the presence of ST segment depression is related to higher rates of short and long term cardiac events when compared with T wave inversion--possibly because of a higher incidence of residual stenosis of the infarct related artery.

Cardiac Catheterization↗