Ariaratnam Gobikrishna MD
Heart disease and stroke remain the number one cause of death and disability worldwide, claiming more than 16 million lives each year. For decades, doctors have grappled with many factors to understand why some people suffer heart attacks and strokes while others do not. Some of the most groundbreaking discoveries — discoveries that the so-called “influencers” often ignore or misrepresent — have not come from research laboratories, but from families quietly living ordinary lives in isolated villages. These families carry rare genetic mutations that alter how their bodies process fats and cholesterol. Studying them has solved decades of medical mysteries and directly inspired new drugs that could save millions.
Long before genetics revealed hidden protective mutations, families affected by a rare condition called homozygous familial hypercholesterolemia (HoFH) taught doctors a heartbreaking lesson. Children with this disorder had extraordinarily high levels of LDL cholesterol and often suffered heart attacks in childhood or adolescence. While studying these families in the 1970s, Michael Brown and Joseph Goldstein discovered the LDL receptor, the cellular “doorway” responsible for clearing LDL from the blood, and showed that this pathway was absent or severely impaired in affected children. This insight led to the LDL hypothesis and became a turning point in cardiovascular medicine, ultimately paving the way for effective therapies such as statins. For their pioneering work, Brown and Goldstein were awarded the Nobel Prize in Medicine in 1985, transforming our understanding of heart disease and saving countless lives worldwide.
One way LDL receptors fail in these families is not because they are never made, but because they are destroyed too quickly. This destruction is driven by a molecule called PCSK9, which marks LDL receptors for breakdown inside the liver. In these families with unusually high LDL cholesterol, PCSK9 is present in excess, dramatically reducing the number of functioning LDL receptors. For years, scientists wondered whether blocking PCSK9, a fundamental biological pathway, might have dangerous long-term consequences. That concern was answered serendipitously.
In the early 2000s, Dr. Helen Hobbs and her colleagues, while studying participants in the Dallas Heart Study, made a remarkable discovery. Some African American families carried natural mutations in the PCSK9 gene that reduced its quantity or rendered it ineffective. These individuals had lifelong extremely low LDL cholesterol levels and, strikingly, far lower rates of cardiovascular disease, without any apparent health problems. This natural experiment in humans provided the reassurance scientists needed and directly paved the way for the development of PCSK9 inhibitors, a new class of powerful cholesterol-lowering drugs.
A common argument from naysayers is this: if LDL cholesterol has been the central target for decades, why do heart attacks and strokes still occur? The answer begins with perspective. The incidence of cardiovascular disease has, in fact, fallen significantly worldwide — most dramatically in developed countries — and many heart attacks that once occurred in middle age are now postponed into much later life thanks to increased longevity and better prevention. That alone represents a major public health success. Still, there is no doubt that we can and must do better — particularly as the downward trajectory has begun to reverse in the wake of the pandemic, driven by the cumulative effects of unhealthy behaviors and deferred care.
The recurring criticism is that LDL is not the real problem, and that triglycerides or HDL cholesterol are the true culprits. This argument, however, overlooks decades of careful research. These pathways were not ignored; on the contrary, they were intensely studied. What emerged from those efforts was not a simple solution, but something more valuable: clarity about which directions did not work, and why. That clarity again is supported by human genetics.
In normal cholesterol metabolism, fats absorbed from food are packaged into large particles called chylomicrons. These particles are progressively broken down in the bloodstream by an enzyme called lipoprotein lipase. As this process unfolds, chylomicrons are converted into smaller particles such as very-low-density lipoproteins (VLDL), intermediate-density lipoproteins (IDL), and eventually LDL. The smaller VLDL and IDL particles that circulate during this process are known as remnant particles, and they are now recognized to be at least as harmful, if not more, to arteries as LDL itself.
In some Amish families in Lancaster County, Pennsylvania, scientists made a crucial observation. These families carry natural deficiencies in a protein called ApoC-III, which normally inhibits lipoprotein lipase. Without ApoC-III acting as a brake, triglyceride-rich particles are cleared efficiently, leaving very low levels of remnant particles in the blood. These individuals have strikingly low triglyceride levels, but more importantly, they have a significantly lower remnants and incidence of heart disease — without any apparent health disadvantages despite a lifetime of low remnants.
This discovery shifted scientific thinking in a profound way. It suggested that simply lowering triglyceride numbers was not enough. What mattered was reducing the particles that carry triglycerides — the remnants themselves. This insight redirected research away from earlier failures and toward therapies designed to remove these atherogenic vehicles from the bloodstream. Several medications targeting this pathway have now been approved for lipid reduction, and large trials are underway to determine whether they reduce heart attacks and strokes. If successful, they may finally close a gap that has frustrated cardiovascular scientists for decades.
A parallel story emerged from Italy. Families born with naturally low levels of a protein called ANGPTL3 — another inhibitor of lipoprotein lipase — were found to have low remnant cholesterol, low LDL cholesterol, low HDL and a reduced incidence of heart disease. Once again, nature had performed the experiment first. Drugs targeting ANGPTL3 are now being tested to confirm whether this protection translates into fewer cardiovascular events.
Not all genetic lessons, however, were heeded early on — and ignoring some of them came at a cost.
Families in Milan carrying a rare variant known as ApoA-I Milano had very low HDL cholesterol yet experienced fewer heart attacks. Conversely, Japanese families with extremely high HDL cholesterol were found to have no protection, and in some cases higher rates of heart disease. These observations warned that HDL levels alone were not a reliable target.
Similarly, genetic variants that increased activity of PPAR-alpha — a pathway known to lower triglyceride levels — did not confer protection against heart disease when the triglyceride-carrying particles themselves remained. Despite these human clues, pharmaceutical efforts focused heavily on raising HDL or simply lowering triglycerides in the blood. Drugs such as CETP inhibitors, fibrates and multiple fish-oil formulations largely failed to deliver meaningful reductions in cardiovascular events.
A new technological advance is now taking this approach to an entirely different level. Small interfering RNA technology works by shutting down the production of disease-modifying proteins at their source, inside the liver, rather than blocking them after they are made. By selectively silencing specific genes, this approach allows the body to produce far less of the undesirable protein for months at a time, effectively mimicking the lifelong protection observed in naturally protected families.
For example, small interfering RNA therapies targeting PCSK9 can dramatically reduce its production, leading to sustained lowering of LDL cholesterol with injections needed only once every six months. Similarly, therapies aimed at ApoC-III suppress the protein that interferes with triglyceride clearance, allowing effective remnant reduction with dosing as infrequent as once every three months.
A new gene-editing approach aims to permanently silence the PCSK9 gene, essentially replicating the naturally low-LDL state seen in individuals born with PCSK9 loss-of-function variants. The promise is a one-time treatment that could eliminate lifelong cholesterol management. However, the technology is still in its early stages, and questions about cost, durability, and long-term unintended effects remain unresolved.
Taken together, these stories reinforce a central lesson of modern lipidology: numbers alone can mislead. What matters most is which particles deliver cholesterol and fat into the artery wall. The most successful therapies have been those that remove these atherogenic particles at their source — a principle revealed not first in laboratories, but in families whose genes quietly told the truth.
