{"id":2339,"date":"2023-04-03T11:47:07","date_gmt":"2023-04-03T11:47:07","guid":{"rendered":"https:\/\/horizon.peachpuff-wolverine-566518.hostingersite.com\/?p=2339"},"modified":"2023-04-03T11:47:07","modified_gmt":"2023-04-03T11:47:07","slug":"cardiovascular-disease-researchers-pinpoint-missing-piece-of-treatment-puzzle","status":"publish","type":"post","link":"https:\/\/scienceblog.com\/horizon\/2339\/cardiovascular-disease-researchers-pinpoint-missing-piece-of-treatment-puzzle\/","title":{"rendered":"Cardiovascular disease: researchers pinpoint missing piece of treatment puzzle"},"content":{"rendered":"

With new findings that the immune system plays a key role in conditions affecting the heart or blood vessels, options emerge for new cures.<\/p>\n

By<\/em><\/strong>\u00a0\u00a0VITTORIA D\u2019ALESSIO<\/p>\n

Cardiovascular disease (CVD) is the leading cause of mortality worldwide, responsible for\u00a032% of all deaths<\/a>. While the illness is triggered to a large extent by an unhealthy lifestyle, a\u00a0flaw in the immune system has recently been found to be another important contributor.<\/p>\n

For reasons that are only partially understood, cells from the body\u2019s inflammatory response sometimes switch from \u201cprotective\u201d to \u201charmful\u201d, encouraging the build-up of fatty deposits on the inside of artery walls and putting people at risk of heart attacks and strokes.<\/p>\n

Fat fight<\/strong><\/p>\n

Scientists are seeking a drug or vaccine, or both, to eliminate this glitch. Their work, if successful, would pave the way for a major new weapon against premature death.<\/p>\n

It would mean that heart doctors like Dr Dennis Wolf in Germany would no longer need to deliver the distressing news to patients \u2013 some as young perhaps as 40 \u2013 that their CVD risk is high even though they eat well, exercise and avoid cigarettes and other dangerous substances.<\/p>\n

\u2018As a clinician, it\u2019s very challenging to explain to people that they are at high risk although they are apparently healthy and they have no sense that something is wrong,\u2019 said Wolf, who is based at the University Hospital in Freiburg.<\/p>\n

He treats patients with heart disease and studies atherosclerosis, a condition that causes a narrowing and hardening of arteries when a dangerous amount of fat builds up.<\/p>\n

Some build-up of arterial fat is inevitable over the course of a lifetime. This becomes problematic only when the fatty layer thickens into clots that can break away and block the flow of blood.<\/p>\n

\u2018For many years, we didn\u2019t have a complete understanding of what drives this disease, but now it\u2019s becoming increasingly clear that high blood lipids and chronic inflammation are both key factors,\u2019 Wolf said.<\/p>\n

Beyond bad cholesterol<\/strong><\/p>\n

The main fat found in arterial plaques is low-density lipoprotein cholesterol (LDL-C) \u2013 a cholesterol sub-type often known as \u201cbad cholesterol\u201d. While cholesterol is needed by the body to produce cell membranes and several hormones, when there\u2019s a malfunction LDL-C accumulates in arteries.<\/p>\n

Traditionally, atherosclerosis was seen as a \u201cstatic\u201d disease of the arterial wall. It was thought that, the more LDL-C people accumulated in their oxygen-rich blood vessels, the thicker the plaque.<\/p>\n

The remedy seemed relatively straightforward: lower bad cholesterol and other circulating fats through lifestyle changes and take lipid-reducing drugs such as statins and good health would be restored.<\/p>\n

But these measures work in only 30-35% of patients \u2013 the remaining 65-70% show little or no improvement to their condition. The reason is that the static model for the disease is flawed.<\/p>\n

\u2018While it\u2019s true that patients with atherosclerosis have cholesterol clogging their arteries, our research shows the condition is in fact ultra-dynamic, with chronic inflammation \u2013 and therefore the immune system \u2013 playing a central role,\u2019 said Wolf.<\/p>\n

Dual-role cells<\/strong><\/p>\n

As part of the EU-funded\u00a0ANIMATE<\/a>\u00a0project, a five-year initiative that runs through 2024, he has discovered that cells of the immune system \u2013 particularly T cells \u2013 are always found in the fatty plaque lining artery walls.<\/p>\n

This doesn\u2019t automatically mean T cells are involved in causing the disease. What has become apparent, however, is that these cells play a double-edged role in arterial health.<\/p>\n

When atherosclerosis is in its earliest phases, T cells are protective against further plaque formation, recognising the excess of LDL and fighting against it by instructing other cells of the immune system not to overreact.<\/p>\n

But as the condition progresses, what began as a protective autoimmune response converts into a harmful one, encouraging the build-up of more plaque still. At this stage, T cells actually fuel the inflammatory reaction in arteries.<\/p>\n

\u2018We don\u2019t know if this switch in functionality represents a cause or a consequence of the condition.\u2019 said Wolf. \u2018But finding ways to manipulate the immune system with drugs or a vaccine is an attractive proposition.\u2019<\/p>\n

Any future vaccine is likely to work by boosting the number of healthy T cells sending helpful messages to other immune-system cells in a person\u2019s body, thereby increasing natural protection against fatty build-up and countering the effects of T cells that have turned rogue.<\/p>\n

\u2018We know this works in mice \u2013 vaccinated mice develop less atherosclerosis,\u2019 said Wolf. \u2018Now we need to find a way to make this concept work in humans too.\u2019<\/p>\n

Precise targeting<\/strong><\/p>\n

According to Professor Esther Lutgens, an expert in inflammatory and vascular diseases, any future drug would need to be highly targeted. That means it would need to be focused precisely on the cell types that are responsible for atherosclerosis-associated inflammation.<\/p>\n

Lutgens,\u00a0who is principle investigator on the EU-funded\u00a0CD40-INN<\/a>\u00a0project,\u00a0says non-specific anti-inflammatory medication would be only a short-term solution for atherosclerosis.<\/p>\n

\u2018The problem is, this is a condition that needs lifelong treatment and you can\u2019t take strong, random anti-inflammatories \u2013 which block the immune system \u2013 forever or you\u2019ll cure your cardiovascular disease but die from an infection,\u2019 she said.<\/p>\n

CD40-INN, which will end this November after seven years, has been exploring a type of molecule that sits on the surface of macrophages \u2013 another kind of immune system cell \u2013 and influences the way these cells behave.<\/p>\n

These molecules, known as co-stimulatory molecules, are important communicators of the immune system. When turned on, they trigger a chain of cellular commands that results in an inflammatory response; when they are turned off, inflammation is subdued.<\/p>\n

At the project\u2019s outset, it was already known that co-stimulatory molecules nudged cells of the immune system (both T cells and macrophages) in one direction or another. Lutgens wants to untangle the precise mechanisms that lead some cells to switch from protective to harmful.<\/p>\n

Encouraging steps<\/strong><\/p>\n

She and colleagues have identified the co-stimulatory molecule CD40 as a major driver of the inflammatory response that leads to atherosclerosis. Her hope now is to develop a drug that interferes with the actions of this molecule, with a view to preventing both the T cell switch and macrophage activation.<\/p>\n

In animal experiments, Lutgens has already had success: mice injected with a compound that blocked CD40 developed immune cells that protected against plaque build-up.<\/p>\n

\u2018The compound gave proper, powerful immunity against cardiovascular disease,\u2019 she said.<\/p>\n

Unfortunately, this compound can\u2019t be tested in humans because its chemical make-up is a potential danger to them. Nonetheless, Lutgens is far from discouraged.<\/p>\n

\u2018We now have our proof of concept,\u2019 she said. \u2018We just need to patiently screen and eventually develop many, many compounds that might have the same impact as the one that works in mice until we find one that works in humans too but is in no way toxic or harmful.\u2019<\/p>\n

Research in this article was funded via the EU\u2019s European Research Council (ERC). The article was originally published\u202fin <\/em>Horizon<\/em><\/a>, the EU Research and Innovation Magazine.\u00a0<\/em><\/p>\n

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