Coffee: A Selected Overview of Beneficial or Harmful Effects on the Cardiovascular System?

With a history that began in 800 A.D., coffee is the most popular drink known and as a result, the issues regarding its physiologic effects deserve attention. Maintaining alertness is a well-known benefit and in addition, the cardiovascular (CV) effects of the active compounds, which include polyphenols and caffeine, must be considered. Genetics are relevant and where slow caffeine metabolism is inherent, the risk of nonfatal myocardial (MI) has been shown to be increased. Overall risk for coronary heart disease (CHD) is not supported and unless there is excessive intake, congestive heart failure (CHF) is not adversely affected; in moderation, there may be some benefit for CHF. There is no apparent increased risk of sudden cardiac death (SCD). Overall, there also appears to be a beneficial inverse association with all-cause mortality, although this is not absolute for extra heavy intake. Benefit in reducing stroke also has supportive evidence. Hypertension is not increased by coffee. Boiled and unfiltered coffee appears to increase plasma cholesterol and triglycerides but for the overall metabolic syndrome, there appears to be benefit. There is also some evidence that paper-filtered coffee results in an increase in some markers of inflammation. Association of coffee with arrhythmias has been a major concern though in moderation it is not a significant overall problem. Therefore, only if a patient were to associate major arrhythmic symptoms with coffee would cessation have to be advised. Where coffee clearly shines from a CV standpoint is in the established decrease in onset of type 2 diabetes mellitus (DM). Any benefit or harm has always been attributed to caffeine as the apparent major component. However, coffee contains a myriad of compounds, including polyphenols. These other substances may be most relevant for potential benefit or harm and some of these may be partially removed or altered by coffee preparation methods such as paper filtration. Multiple studies support this by what appears to be no CV advantage or disadvantage for decaffeinated coffee. The bottom line on coffee, for those who enjoy the brew, is that it is a wonderful beverage with rare associated CV disadvantage and with much to recommend it from an overall CV standpoint.

Reduction of cholesterol in Kentucky--a state at high risk.

Coronary artery disease (CAD) or coronary atherosclerosis mortality rates vary markedly in the different regions of the United States. It has been observed that the states bordering the Ohio and Mississippi Rivers have a dis-proportionately high coronary heart disease death rate. Kentucky is one of the most severely afflicted states, especially the eastern portion that includes the Appalachian region. The high CAD mortality rates in Kentucky are mainly due to a high prevalence of major traditional risk factors for coronary artery disease: elevated cholesterol, heavy cigarette smoking, and hypertension. Physical inactivity is also widespread. Attempts to reverse these risk factors have often failed for multiple reasons. Primary prevention is often not given priority by individuals because they have not, by definition, experienced any cardiac symptoms. Advice by physicians regarding treatments that can promote atherosclerosis regression and secondary prevention is suboptimal. A major campaign to educate patients and physicians about the importance of lowering cholesterol, dietary counseling, exercising, smoking cessation, and other interventions is essential. The ultimate methods of coronary atherosclerosis prevention will be through interventions at the cellular and subcellular levels. While such interventions are not yet available, major risk factor control and marked cholesterol reduction can be achieved and thereby significantly decrease the personal and economic suffering caused by coronary heart disease.

Plasma apolipoprotein B and VLDL-, LDL-, and HDL-cholesterol as risk factors in the development of coronary artery disease in male patients examined by angiography.

To assess the potential use of plasma apolipoprotein B (ApoB) as a risk factor for coronary artery disease, this apolipoprotein was quantified by electroimmunoassay in 161 male patients with angiographically documented coronary atherosclerosis and 72 male patients with normal coronary arteries. In addition to ApoB, the analyzed lipoprotein profile included plasma total cholesterol, plasma triglyceride and VLDL-, LDL- and HDL-cholesterol levels. Age, plasma cholesterol, triglyceride, and VLDL- and LDL-cholesterol were significantly greater (P less than 0.05) for patients with coronary artery disease than for patients with normal arteries. In contrast, there was no difference in the mean levels of HDL-cholesterol between these 2 groups of patients. However, patients with HDL-cholesterol les than 40 mg/dl had a higher rate of coronary artery disease than those with HDL-cholesterol greater than 40 mg/dl (P less than 0.05). The results of multivariate analysis showed that age and plasma cholesterol were the 2 variables most significantly (P less than 0.01) related to the presence of coronary artery disease. However, in a subgroup of patients with plasma cholesterol less than 265 mg/dl, the most reliable variable was ApoB (P less than 0.01). For patients under 50 years of age ApoB and LDL-cholesterol were the most significant variables (P less than 0.05), whereas for patients at 50 years of age or older VLDL-cholesterol was the most significant variable (P less than 0.01). Results of this study indicate that measurement of ApoB may offer important predictive value for coronary artery disease, especially at lower levels of plasma cholesterol. Whether this and other conclusions also apply to general population, remains to be established in future studies.

The effects of dexamethasone on metabolic activity of hepatocytes in primary monolayer culture.

The effects of dexamethasone on multiple metabolic functions of adult rat hepatocytes in monolayer culture were studied. Adult rat liver parenchymal cells were isolated by collagenase perfusion and cultured as a primary monolayer in HI/WO/BA, a serum free, completely defined, synthetic culture medium. Cells inoculated into the culture medium formed a monolayer within 24 hr. Electron microscopy showed that the cells in primary culture had a fine structure identical to liver parenchymal cells in vivo, including the observation of desmosomes and bile canaliculi in intercellular space. There was significant gluconeogenesis by the cells 24 hr postinoculation but it had decreased markedly by 48 hr. There was a marked induction of tyrosine aminotransferase (TAT) by dexamethasone, which was maintained for up to 72 hr postinoculation of cells. The transport of alpha-aminoisobutyric acid into the cells in monolayer culture was stimulated by dexamethasone and was dependent on the concentration of dexamethasone. Albumin synthesis and secretion by the cells was measured by a quantitative electroimmunoassay. Albumin production was shown to increase linearly over an incubation period of 24 to 48 hr postinoculation. Dexamethasone depressed the albumin synthesis. The effects of dexamethasone are slow, and at times require more than 6 hr to show variation from the control, indicating that dexamethasone is not a single controlling hormone. Possibly it functions in a cooperative and coordinating role in the regulation of cell metabolism.

Transmural myocardial infarction with the prolapsing mitral-leaflet syndrome and normal coronary arteries.

Clinical and electrocardiographic evidence of transmural myocardial infarction developed in two patients (a woman, age 38, and a boy, age 17) with prolapsing mitral-leaflet syndrome. Both had normal coronary angiograms and normal plasma lipid levels. Left ventricular angiography showed dyskinetic areas in both patients. Coronary artery embolism or prolonged coronary artery spasm may have been the underlying mechanism of production of myocardial infarction.

Rat high density lipoprotein subfraction (HDL3) uptake and catabolism by isolated rat liver parenchymal cells.

Rat liver parenchymal cell binding, uptake, and proteolytic degradation of rat 125I-labeled high density lipoprotein (HDL) subfraction, HDL3 (1.10 less than d less than 1.210 g/ml), in which apo-A-I is the major polypeptide, were investigated. Structural and metabolic integrity of the isolated cells was verified by trypan blue exclusion, low lactic dehydrogenase leakage, expected morphology, and gluconeogenesis from lactate and pyruvate. 125I-labeled HDL3 was incubated with 10 X 10(6) cells at 37 degrees and 4 degrees in albumin and Krebs-Henseleit bicarbonate buffer, pH 7.4. Binding and uptake were determined by radioactivity in washed cells. Proteolytic degradation was determined by trichloroacetic acid-soluble radioactivity in the incubation medium. At 37 degrees, maximum HDL3 binding (Bmax) and uptake occurred at 30 min with a Bmax of 31 ng/mg dry weight of cells. The apparent dissociation constant of the HDL3 receptor system (Kd) was 60 X 10(-8) M, based on Mr = 28,000 of apo-A-I, the predominant rat HDL3 protein. Proteolytic degradation showed a 15-min lag and then constant proteolysis. After 2 hours 5.8% of incubated 125I-labeled HDL3 was degraded. Sixty per cent of cell radioactivity at 37 degrees was trypsin-releasable. At 37 degrees, 125I-labeled HDL3 was incubated with cells in the presence of varying concentrations of native (cold) HDL3, very low density lipoproteins, and low density lipoproteins. Incubation with native HDL3 resulted in greatest inhibition of 125I-labeled HDL3 binding, uptake, and proteolytic degradation. When 125I-labeled HDL3 was preincubated with increasing amounts of HDL3 antiserum, binding and uptake by cells were decreased to complete inhibition. Cell binding, uptake, and proteolytic degradation of 125I-labeled HDL3 were markedly diminished at 4 degrees. Less than 1 mM chloroquine enhanced 125I-labeled HDL3 proteolysis but at 5 mM or greater, chloroquine inhibited proteolysis with 125I-labeled HDL3 accumulation in cells. L-[U-14C]Lysine-labeled HDL3 was bound, taken up, and degraded by cells as effectively as 125I-labeled HDL3. These data suggest that liver cell binding, uptake, and proteolytic degradation of rat HDL3 are actively performed and linked in the sequence:binding, then uptake, and finally proteolytic degradation. Furthermore, there may be a specific HDL3 (lipoprotein A) receptor of recognition site(s) on the plasma membrane. Finally, our data further support our previous reports of the important role of liver lysosomes in proteolytic degradation of HDL3.

Catabolism of canine apolipoprotein A-I: purification, catabolic rate, organs of catabolism, and the liver subcellular catabolic site.

The catabolic site(s) of plasma lipoproteins and apolipoproteins has not been established. We have purified one of the major apolipoproteins and explored its catabolic rate and its site of catabolism. Apolipoprotein (Apo) A-1 was purified by column chromatography of canine high-density lipoprotein (HDL) subfraction, HDL3, which was totally delipidated; the purified Apo A-1, molecular weight 28,000, had only one precipitin line to either anti-Apo A-1, or anti-Apo HDL3 serum. Apo A-I was then iodinated, its catabolic rate measured, and the various organs and the subcellular sites of liver involved in the catabolism were investigated. The T 1/2 of 125I-Apo A-I in HDL3 was 3.33 +/- 0.08 days and in plasma 3.52 +/- 0.17 days. The disappearance curve of radioactivity recovered in density fractions d less than 1.110 and d greater than 1.210 Gm. per milliliter was the same as that in HDL3, suggesting identical Apo A-I catabolism in each density class. The liver and kidney absorbed more radioactivity than did the spleen, heart, lung, and intestine. In subcellular fractions of liver, radioactivity was predominantly recovered in the light mitochondrial fraction. There was a statistically significant correlation between the acid phosphatase relative specific activity and the relative specific radioactivity in each subcellular fraction examined at several time intervals after the injection of 125I-Apo A-I. Direct organelle isolation and demonstration of labeled apoplipoprotein uptake indicate that liver lysosomes may play an important role in the catabolism of Apo A-I, as may those of the kidney.

Proteolysis of canine apolipoprotein by acid proteases in canine liver lysosomes.

Canine liver lysosomes were purified by sucrose discontinuous density gradient centrifugation and then ruptured by sonication to obtain the soluble fraction. This soluble lysosomal fraction, which contained a 25-fold increase in acid phosphatase activity per mg of total protein when compared with the original homogenate, was incubated with a subfraction (1.110 less than d less than 1.210 g/cm3, HDL3) of canine high density lipoproteins (HDL) at pH 3.8. HDL3 proteolysis by lysosomal proteases, measured as the release of peptides and amino acids by the ninhydrin reaction, followed hyperbolic curves with straight lines (r = 0.99) obtained on Lineweaver-Burk plots. Km calculated from the Lineweaver-Burk plot was 635 mug of HDL3 protein per 0.5 ml of incubation mixture. Optimum HDL3 proteolysis was observed from pH 3.8 to 4.5. Incubation with the other subcellular organelle fractions did not result in HDL3 proteolysis. To evaluate the effects of enzyme inhibitors, iodoacetate, p-chloromercuribenzoate (both specific for the endopeptidase, cathepsin B (EC 3.4.22.1)) and pepstatin (specific for the endopeptidase, cathepsin D (EC 3.4.23.5) were tested. Iodoacetate and p-chloromercuribenzoate inhibited HDL3 proteolysis 100% and bovine serum albumin proteolysis 65%. Pepstatin inhibited HDL3 proteolysis 45% and bovine serum albumin proteolysis 70%. The in vitro data presented support the hypothesis that hepatic lysosomes play an important role in HDL3 catabolism in the dog. Furthermore, results obtained from enzyme inhibition studies suggest that a specific lysosomal endopeptidase, cathepsin B, may play the key role in HDL3 proteolysis.