Just about four years ago a series of deaths related to heart conditions intrigued the team from the Atherosclerosis Unit of the Heart Institute (InCor), linked to the University of São Paulo. In all of the cases the heart had stopped beating because the arteries that take oxygen and nutrients to this organ had been obstructed by fat deposits, blocking the flow of blood. One point especially drew the doctors’ attention: of the fifty one people who died as a result of atherosclerosis – fat deposits on the wall of the arteries -, twenty five had not presented one of the main signs of this problem, since their levels of cholesterol in the blood were considered to be healthy. The team, led by the cardiologist Protásio Lemos da Luz then decided to investigate the composition of the arteriosclerosis deposits and, different from that expected, verified that for both the patients with high cholesterol and those with levels within the normal levels, the quantity of fat on the wall of the coronary arteries was the same.
The result of this study, carried out by Délio Braz Junior, helps to redefine the importance of one of the most widely used tests by doctors to determine the risk of a person developing atherosclerosis, the most common cause of cardiac illnesses such as a stroke or vascular problems, an example being a vascular cerebral accident that every year kills around 17 million people throughout the world, 300,000 of them here in Brazil. “The illness develops independently from the cholesterol levels”, says Braz Junior. Protásio adds: “The previous premise was that the higher the level of cholesterol in the blood, the more fat there would be on the wall of the coronary arteries”.
But this was not what they found. The work of the InCor team suggested that though cholesterol is decisive in the formation of the deposits, there are other factors that weigh in this process. One of them – hardly considered by the doctors up until then – is the high concentration in the blood of a protein called homocysteine, which the group demonstrated is also related to the development of atherosclerosis. By analyzing two hundred and thirty six (236) patients at the InCor hospital, the cardiologist José Rocha Faria Neto, today at the Catholic Pontifical University of Paraná, verified that the level of homocysteine in the blood was higher in the patients with fatty deposits in the coronary arteries than among those with a healthy heart, as other research papers had suggested.
Faria Neto also discovered that the higher the level of homocysteine – the normal is between 5 and 15 micro-mols per liter of blood – the worse the shape of the coronary arteries. This is because the elevated concentration alters the endothelium and consequently injures the blood vessels, bringing about the occurrence of inflammation and favoring the formation of fatty deposits.
Protásio alerts: “This isn’t a classical risk factor, but could well trigger or aggravate a coronary illness”. Based on these results, the determination of homocysteine steadily began to integrate itself into the routine cardiovascular examinations, along side the tests of the blood levels of other proteins such as apolipoprotein B and reactive protein C, also associated with inflammation. And these studies carried out over the last decade suggested that an inflammation disseminated in the blood vessels speeds up the formation of fatty deposits in the interior of the veins and arteries.
The new finding from the InCor team is of practical importance: it indicates that if a person does not present the typical risk factors of the illness, it is worth while verifying that person’s level of homocysteine. The treatment is simple: 5 milligrams daily of a vitamin B complex called folic acid are enough to knock down the homocysteine level to values close to the norm and to restore the capacity of the arteries to dilate. These discoveries led the team to reevaluate the weight of the risk factors considered as classic in the formation of fatty deposits – among them high cholesterol, arterial hypertension., physical inactivity, smoking, obesity and diabetes – and to search for non-invasive forms of early detection and treatment of the illnesses of the heart’s arteries.
“The prevention of atherosclerosis is based on combating these risk factors. It so happens that 35% of people with coronary artery disease do not show any of them, and for this reason we need to understand what other mechanisms are involved”, explains Protásio, whose book Endotélio e doenças cardiovasculares [Endothelium and cardiovascular illnesses], jointly written with Rafael Laurindo and Antonio Carlos Chagas, received the Jabuti 2004 Award, instituted by the Brazilian Book Chamber, in the category Natural Sciences and Health.
If some factors now appear to be relative, others have gained in importance. The simple decrease in the level of HDL (high density lipoprotein) – the good cholesterol, as it is called – is already enough to set off an alarm bell on the organism and to induce the formation of fatty plaque characteristic of atherosclerosis. The HDL does not participate in the process of the blockage of the arteries and, in truth, protects the heart against the illness. In normal quantities (above 40 milligrams per deciliter of blood), these lipoproteins impede the slow and silent invasion of the fats, since they remove the cholesterol from the blood and lead it to the liver, where it is eliminated or reused. In reduced quantities, however, its protecting effect diminishes, as the research carried out by Carlos Magalhães, Antonio Carlos Chagas and Desiderio Favarato, under the Protásio’s direction , the director of the InCor Atherosclerosis Unit has attested to.
During six years and three months, one hundred and sixty five (165) people with partial coronary clogging (coronary insufficiency) submitted to surgery at the InCor for a bypass were accompanied by a team and divided into two groups. What differentiated them was their level of HDL. The good cholesterol was below 35 milligrams per deciliter (mg/dL) of blood in one hundred and one (101) men and women, and above this value in sixty- four of the patients operated.
After this period, 20.7% of the people with HDL lower than 35 mg/dL had died, as against 6.25% of the second group. Among all of the risk factors evaluated – diabetes, arterial hypertension, elevated triglycerides, smoking and cholesterol level -, the low level of HDL was the only one capable of predicting whether or not a person with atherosclerosis had a greater or lesser chance of survival. This was a clear signal that HDL in reduced quantities deserves more attention that it had been receiving.
Another finding – the result of the evaluation of four hundred and ninety four (494) patients submitted to surgery at the InCor – provided another good reason for the doctors to review their routines in consulting rooms and hospitals: the relationship between triglycerides and HDL. Some studies had indicated that the higher the level of triglycerides the more reduced was the level of the good cholesterol and the higher the possibility of developing atherosclerosis. On evaluating these four hundred and ninety four patients, Protásio’s team realized that this relationship is effective, especially, for indicating the risk of precocious development of the illness above fifty years of age.
The accounting is simple: divide the values considered to be normal for triglycerides (150 mg/dL) by the HDL value (40 mg/dL) and see if you obtain the number 3.75 – the result of this calculation is the so called triglyceride/HDL ration, currently used in the evaluation of patients at the Atherosclerosis Unit. One does not need to understand mathematics to know that when the concentration of triglycerides increases or that of HDL deceases or both occur at the same time, the result of the division also increases. And together with this increase grows the risk of developing atherosclerosis. The InCor researchers have verified as well that there is a direct proportionality between the relationship triglycerides/HDL and the extension of the fatty deposit in the arteries of the heart: the greater the ratio, the more serious the damage to the coronaries, mainly among people below sixty years of age.
The good cholesterol has turned itself into a villain in this story? Actually, not. Even at low levels the HDL continues to extract fat from the blood. The problem is that the level becomes insufficient to collect the fatty substances unused by the cells for the formation of hormones, bile acids and vitamin D. And, just like the food that we consume, the fat also has a validity date. The longer it circulates in the blood, the older it becomes and the more likely it is to bind to veins and arteries
A question of level
On realizing how the low level of HDL was capable of interfering in the survival capacity of the one hundred and one patients who had received the implant of bypass valves, a surgery destined to reestablish the blood circulation of the heart, the InCor team put forward a new hypothesis: in low quantities, the good cholesterol could favor the bringing about of alterations in the endothelium and the development of atherosclerosis. Said and done. Again, it was possible to prove that one only had to have the good cholesterol in inadequate quantities – a problem that affects between 4% and 8% of the population – for the disease to develop or for its evolution to be more favorable. And, this time, the patients evaluated had not presented any other risk factor associated with atherosclerosis.
In his doctoral thesis, Alexandre Benjó showed that people with a level of HDL lower than 40 mg/dL in their blood showed lower capacity in the dilation of their blood vessels. By using ultrasound exams, he evaluated the variation in the diameter of the artery of the arm in thirty patients with a reduced level of good cholesterol and compared the results with eleven healthy individuals. He verified that the dilation of the artery was lower than normal (8% or more) in twenty two (22) of the thirty (30) test cases who had a low level of HDL, a sign that the endothelium had been altered.
The low level of this lipoprotein also turned the removal of a type of fat known as kilomicron slower – this molecule gives rise, in part, to cholesterol and its excess in the blood stream facilitates the formation of the plaque characteristic of atherosclerosis. In order to understand this mechanism, the researchers introduced into the blood plasma an artificial molecule of kilomicron, developed by Raul Maranhão, head of the lipids sector of InCor, and they observed the removal of triglycerides and cholesterol. Faced with this verification that the small quantity of HDL had been associated with an alteration in the endothelium and the slower removal of the surplus kilomicrons in the blood, they decided to test a treatment based on a vitamin B complex called niacin – already in use with the object of increasing the levels of the good cholesterol, however without much substantiation, over a three month period, on half of the twenty two (22) patients who had presented low levels of HDL who received daily doses of 1.5 grams of the vitamin liberated slowly into the organism – one of the undesirable effects of the current therapy with niacin, or nicotinic acid, is a reddening of the skin – and the other half were medicated with a placebo.
There was no improvement in the group that received the placebo, but the malfunctioning in the endothelium was corrected with the use of niacin, although the action upon the HDL been minimal. The vitamin also did not bring about significant changes in the removal of kilomicrons. “The patients took the niacin hoping that their level of HDL would rise, but however a clear demonstration of any effect upon the blood vessels didn’t exist”, Protásio tells. “We showed that the vitamin improves the dilating capacity of the arteries, even without an increase in HDL.” The results have not yet allowed the team to say that the improvement in the functioning of the endothelium is enough to diminish the risk of cardiovascular illnesses. But the researchers imagine that in the long term the effect will be beneficial.
The confirmation that the traditional risk factors did not always work to indicate damage to arteries has motivated the InCor team to investigate more efficient alternatives, and if possible, less uncomfortable than the technique most widely used today: the catheter, which consists of inserting a plastic tube into the interior of the blood vessel in order to evaluate its diameter. In another study, Paulo Bertini analyzed the efficiency of the electromagnetic resonance scan for identifying signs of atherosclerosis in the arteries of the heart. Capable of producing images of the internal organs of the body without exposure to high doses of radiation, the resonance scan is not invasive and allows for measuring the internal diameter and the thickness of the coronary walls.
On comparing the coronaries of seven healthy people with those of twenty three (23) patients with atherosclerosis, Bertini observed that the artery walls were much more condensed and rigid among the members of the second group, as reveals a study to be published in the Brazilian Journal of Medical and Biological Research. More importantly, the images from the magnetic resonance scan showed that these alterations in the walls of the blood vessel, not always identified using the catheter and the cinecoronariography, had come about even before the fatty deposit had formed and upset the passage of the blood.
“This technique could help to identify the problem in a very early stage”, explained the group’s coordinator, “when the patient doesn’t as yet show clinical signs of coronary inefficiency such as chest pains”. In an attempt to identify the most efficient and least upsetting examinations, the InCor team is currently evaluating the efficiency of computerized tomography of multiple cuts, a technique capable of detecting the presence of calcium in the fatty plaque, an indication that atherosclerosis has already installed itself and is beginning to advance. “Precocious detection will allow for a slowing down of the evolution of atherosclerosis and to avoid its most serious consequences such as a stroke”, advised Dr. Protásio.
The grape and the wine
The latest wager from the InCor team to protect the heart is grape juice, rich in flavonoids. In the same way as niacin, grape juice was also capable of improving the dilation capacity of the arteries. It is already known that the flavonoids – found in the skin of the grape, in red wine, in chocolate, in teas, nuts fruit dark green vegetables such as water cress – are good because they favor the production of nitric oxide, which increases the dilation of the veins and arteries, and also reduces the production of endothelin, a substance in the endothelium capable of diminishing the thickness of the blood vessels and inducing the formation of fatty plaque on the walls of the arteries, as detailed Drs. Protásio and Silmara Regina Coimbra in an article published in the Brazilian Journal of Medical and Biological Research in September of 2004.
What the study conducted by Dr. Silmara, comparing the ingestion of red wine and grape juice, has now demonstrated is that the beneficial effect upon the endothelium is due to the flavonoids of the fruit itself, and not only to the alcoholic component of the drink. She separated into two groups sixteen (16) patients with a high level of cholesterol and without any other risk factor. The first group received, over a two week period, 250 ml of red wine per day. After a further two weeks, during which they were not submitted to treatment, this group drank daily 500 ml of grape juice for a further fourteen days. The same thing happened with the other people who began by drinking grape juice and afterwards went on to drink red wine. In all of the cases the dilation of the artery of the arm was measured by way of ultra-sound.
Results: the levels of cholesterol continued to be the same, but even at that, the working of the endothelium was re-established. “This result is especially relevant for those people who had been advised against even a moderate consumption of alcohol, such as those with arrhythmia (alterations in the rhythm of the beating of the heart) or cardiac insufficiency (when the heart loses the capacity to pump blood efficiently)”, affirmed Dr. Silmara. The short period of observation, nonetheless, did not allow the team from the Atherosclerosis Unit to be certain that the benefits would last into the future. The encouraging results on the ingestion of grape juice and red wine had already been observed by Dr. Protásio in rabbits submitted to a diet rich in fat: by being herbivores these animals have no way of digesting the fats, and it quickly accumulates in the blood vessels. By the end of three months, the fatty plaque had occupied 69% of the total diameter of the aorta artery of the animals treated with a fatty diet and water. The plaque extended over 47% of the aorta of the rabbits that had consumed the same feed and instead of water had drunk grape juice. And the percentage was even lower among the rabbits that had received red wine: reaching 38% of the diameter of the blood vessels. Adept at simple and effective solutions, the InCor team is following on in search of ways to detect atherosclerosis as early as possible, within a time frame of avoiding grave consequences such as a stroke.
1. Action of red wine upon the sympathetic nerve system (03/09084-0); Modality: Regular Line of Research Assistance; Coordinator: Protásio Lemos da Luz – USP; Investment: R$ 99,199.31.
2. The evaluation of the role of homocysteine as a coronary risk factor in the Brazilian population (98/03168-8); Modality: Regular Line of Research Assistance; Coordinator: Protásio Lemos da Luz – USP; Investment: R$ 133,354.98 (FAPESP)