Paul Ridker | |
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Born | 1959 (age 64–65) |
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Paul M. Ridker (born 1959) is a cardiovascular epidemiologist and biomedical researcher. He is currently the Eugene Braunwald Professor of Medicine at Harvard University and Brigham and Women's Hospital, where he directs the Center for Cardiovascular Disease Prevention. Ridker also holds an appointment as Professor in the Department of Epidemiology at the Harvard T.H. Chan School of Public Health.
Ridker's research has provided proof-of-principle for the inflammation hypothesis of atherosclerosis, the first FDA approved diagnostic test for vascular inflammation, and the first proven anti-inflammatory treatment for coronary artery disease. [1] [2] [3] [4] [5] He is among the most cited researchers in cardiovascular medicine in the world and has an H-index above 220. [6] [7]
Ridker was born in St. Louis, Missouri in 1959. [8] He attended Brown University for his undergraduate studies, graduating with a Bachelor of Science in 1981. He attended Harvard Medical School, where he received his MD in 1986; Ridker completed his residency at Brigham and Women’s Hospital and West Roxbury VA Medical Center in Boston, Massachusetts. In 1992, Ridker earned a Master of Public Health degree at the Harvard T.H. Chan School of Public Health. [6]
Ridker’s translational research combines the tools of epidemiology, vascular biology, and randomized clinical trials to determine the root causes of heart disease, stroke, and diabetes. He is responsible for the clinical development of high sensitivity C-reactive protein (hsCRP), a marker of inflammation, that is used to evaluate the risk of heart attack and stroke, and coined the term “residual inflammatory risk” to describe patients who are at risk due to vascular inflammation rather than high cholesterol levels. Early in his career, Ridker recognized that elevated cholesterol levels were absent in almost half of all heart attack victims and that the pro-inflammatory response detected by hsCRP and the central signaling cytokine Interleukin 6 were responsible for a large proportion of “unexplained risk”. [9] [10] [11]
Ridker is best known for his work developing inflammatory biomarkers and his clinical trials defining anti-inflammatory treatments for cardiovascular disease. In 1997, Ridker showed that elevated levels of hsCRP and interleukin-6 in healthy individuals were a major risk marker for future heart attack, stroke, diabetes, and cardiovascular death, independent of traditional risk factors. [9] [10] [11] Between 1998 and 2005, Ridker showed that individuals with elevated hsCRP but low levels of cholesterol were at substantial risk and that statin drugs used to lower cholesterol also lowered hsCRP and thus had important anti-inflammatory properties. This work, largely funded by the National Institutes of Health, eventually led to the design and conduct of the multi-national JUPITER primary prevention trial which in 2008 demonstrated that individuals with elevated hsCRP levels could reduce by half their risk of future heart attack or stroke by taking statin therapy, even if cholesterol levels were already low. [12]
Critical proof of the inflammation hypothesis of atherosclerosis came when Ridker and his international collaborators focused on the NLRP3 to Interleukin-1b to Interleukin-6 pathway of innate immunity and its role in coronary disease. Toward this end, in 2010, Ridker obtained parallel funding from the National Heart Lung and Blood Institute and from the pharmaceutical industry to design and conduct two multi-national cardiovascular inflammation reduction trials known as CANTOS [13] and CIRT. [14] The CANTOS (Canakinumab Anti-inflammatory Thrombosis Outcomes Study) reported in late 2017 that inflammation inhibition with Canakinumab, a monoclonal antibody targeting interleukin-1-beta, can significantly reduce future risks of heart attack, need for expensive coronary revascularization procedures, and cardiovascular deaths among high-risk heart disease patients with residual inflammatory risk. [15] Canakinumab had no effects on either cholesterol or blood pressure, and thus these data provided the fundamental first proof-of-concept for the inflammation hypothesis of atherosclerosis. [4] [5] CANTOS also demonstrated that the magnitude of inflammation reduction, as measured by on-treatment levels of Interleukin-6, drives the cardiovascular benefit with 36% decreases in cardiovascular death and all-cause mortality among robust Canakinumab responders. [16] [17] In contrast, the federally funded CIRT (Cardiovascular Inflammation Reduction Trial) showed no benefit to low-dose Methotrexate but also no evidence of lowering Interleukin-1b, Interleukin-6 nor CRP. Thus, the positive CANTOS trial and the informative null CIRT trial defined the need to reduce signaling from the NLRP3 to Interleukin-1 to Interleukin-6 in order to lower vascular event rates. These findings were replicated with low-dose Colchicine in the 2019 COLCOT and 2020 LoDoCo2 trials. Ongoing work from Ridker’s group is testing whether direct targeting of Interleukin-6 itself can improve cardiovascular outcomes. [18]
Ridker’s work has had wide biologic implications beyond atherosclerosis and heart disease. By reducing inflammation in the tumor microenvironment, CANTOS also demonstrated highly significant reductions in lung cancer and lung cancer fatality. [19] These data have generated broad interest within the academic and pharmacologic communities resulting in multiple trials studying Interleukin-1 inhibition with or without adjunctive checkpoint inhibition as a novel therapy for non small cell lung cancers. Work from CANTOS has also demonstrated the potential human benefits of targeted Interleukin-1 therapy on anemia, renal failure, and large joint osteoarthritis.
In his work as a clinical trialist, Ridker has designed, conducted, and served as Trial Chair of the Steering Committee of PRINCE, VAL-MARC, PREVENT, LANCET, JUPITER, SPIRE-1, SPIRE-2, CANTOS and CIRT, as well as the ongoing PROMINENT, ACTIV-4B, and ZEUS trials.
High-density lipoprotein (HDL) is one of the five major groups of lipoproteins. Lipoproteins are complex particles composed of multiple proteins which transport all fat molecules (lipids) around the body within the water outside cells. They are typically composed of 80–100 proteins per particle. HDL particles enlarge while circulating in the blood, aggregating more fat molecules and transporting up to hundreds of fat molecules per particle.
Inflammation is part of the biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. The five cardinal signs are heat, pain, redness, swelling, and loss of function.
Atherosclerosis is a pattern of the disease arteriosclerosis, characterized by development of abnormalities called lesions in walls of arteries. This is a chronic inflammatory disease involving many different cell types, and driven by elevated levels of cholesterol in the blood. These lesions may lead to narrowing of the arterial walls due to buildup of atheromatous plaques. At onset there are usually no symptoms, but if they develop, symptoms generally begin around middle age. In severe cases, it can result in coronary artery disease, stroke, peripheral artery disease, or kidney disorders, depending on which body part(s) the affected arteries are located in the body.
Statins are a class of medications that reduce illness and mortality in people who are at high risk of cardiovascular disease. They are the most commonly prescribed cholesterol-lowering drugs.
C-reactive protein (CRP) is an annular (ring-shaped) pentameric protein found in blood plasma, whose circulating concentrations rise in response to inflammation. It is an acute-phase protein of hepatic origin that increases following interleukin-6 secretion by macrophages and T cells. Its physiological role is to bind to lysophosphatidylcholine expressed on the surface of dead or dying cells in order to activate the complement system via C1q.
Cardiovascular disease (CVD) is any disease involving the heart or blood vessels. CVDs constitute a class of diseases that includes: coronary artery diseases, heart failure, hypertensive heart disease, rheumatic heart disease, cardiomyopathy, arrhythmia, congenital heart disease, valvular heart disease, carditis, aortic aneurysms, peripheral artery disease, thromboembolic disease, and venous thrombosis.
In vascular diseases, endothelial dysfunction is a systemic pathological state of the endothelium. The main cause of endothelial dysfunction is impaired bioavailability of nitric oxide,
Asymmetric dimethylarginine (ADMA) is a naturally occurring chemical found in blood plasma. It is a metabolic by-product of continual protein modification processes in the cytoplasm of all human cells. It is closely related to L-arginine, a conditionally essential amino acid. ADMA interferes with L-arginine in the production of nitric oxide (NO), a key chemical involved in normal endothelial function and, by extension, cardiovascular health.
The lipid hypothesis is a medical theory postulating a link between blood cholesterol levels and the occurrence of cardiovascular disease. A summary from 1976 described it as: "measures used to lower the plasma lipids in patients with hyperlipidemia will lead to reductions in new events of coronary heart disease". It states, more concisely, that "decreasing blood cholesterol [...] significantly reduces coronary heart disease".
Mevalonate kinase deficiency (MKD) is an autosomal recessive metabolic disorder that disrupts the biosynthesis of cholesterol and isoprenoids. It is a very rare genetic disease.
Canakinumab, sold under the brand name Ilaris, is a medication for the treatment of systemic juvenile idiopathic arthritis, active Still's disease, including adult-onset Still's disease, gout flares. It is a human monoclonal antibody targeted at interleukin-1 beta. It has no cross-reactivity with other members of the interleukin-1 family, including interleukin-1 alpha.
The JUPITER trial was a clinical trial aimed at evaluating whether statins reduce heart attacks and strokes in people with normal cholesterol levels.
A silent stroke is a stroke that does not have any outward symptoms associated with stroke, and the patient is typically unaware they have suffered a stroke. Despite not causing identifiable symptoms, a silent stroke still causes damage to the brain and places the patient at increased risk for both transient ischemic attack and major stroke in the future. In a broad study in 1998, more than 11 million people were estimated to have experienced a stroke in the United States. Approximately 770,000 of these strokes were symptomatic and 11 million were first-ever silent MRI infarcts or hemorrhages. Silent strokes typically cause lesions which are detected via the use of neuroimaging such as MRI. The risk of silent stroke increases with age but may also affect younger adults. Women appear to be at increased risk for silent stroke, with hypertension and current cigarette smoking being amongst the predisposing factors.
Varespladib is an inhibitor of the IIa, V, and X isoforms of secretory phospholipase A2 (sPLA2). The molecule acts as an anti-inflammatory agent by disrupting the first step of the arachidonic acid pathway of inflammation. From 2006 to 2012, varespladib was under active investigation by Anthera Pharmaceuticals as a potential therapy for several inflammatory diseases, including acute coronary syndrome and acute chest syndrome. The trial was halted in March 2012 due to inadequate efficacy. The selective sPLA2 inhibitor varespladib (IC50 value 0.009 μM in chromogenic assay, mole fraction 7.3X10-6) was studied in the VISTA-16 randomized clinical trial (clinicaltrials.gov Identifier: NCT01130246) and the results were published in 2014. The sPLA2 inhibition by varespladib in this setting seemed to be potentially harmful, and thus not a useful strategy for reducing adverse cardiovascular outcomes from acute coronary syndrome. Since 2016, scientific research has focused on the use of Varespladib as an inhibitor of snake venom toxins using various types of in vitro and in vivo models. Varespladib showed a significant inhibitory effect to snake venom PLA2 which makes it a potential first-line drug candidate in snakebite envenomation therapy. In 2019, the U.S. Food and Drug Administration (FDA) granted varespladib orphan drug status for its potential to treat snakebite.
Evacetrapib was a drug under development by Eli Lilly and Company that inhibits cholesterylester transfer protein. CETP collects triglycerides from very low-density lipoproteins (VLDL) or low-density lipoproteins (LDL) and exchanges them for cholesteryl esters from high-density lipoproteins (HDL), and vice versa, but primarily increasing high-density lipoprotein and lowering low-density lipoprotein. It is thought that modifying lipoprotein levels modifies the risk of cardiovascular disease. The first CETP inhibitor, torcetrapib, was unsuccessful because it increased levels of the hormone aldosterone and increased blood pressure, which led to excess cardiac events when it was studied. Evacetrapib does not have the same effect. When studied in a small clinical trial in people with elevated LDL and low HDL, significant improvements were noted in their lipid profile.
Jean-Claude Tardif is the Director of the Research Center at the Montreal Heart Institute and Professor of Medicine at the University of Montreal. He received his medical degree (MD) in 1987 from the University of Montreal and specialized in cardiology and research in Montreal and Boston until 1994. Dr. Tardif holds the Canada Research Chair in personalized medicine and the University of Montreal endowed research chair in atherosclerosis. He is also the Scientific Director of the Montreal Health Innovations Coordinating Center (MHICC).
Testosterone and the cardiovascular system are the effects that the male hormone testosterone has on the cardiovascular system.
The BaleDoneen Method is a risk assessment and treatment protocol aimed at preventing heart attack and stroke. The method also seeks to prevent or reduce the effects of type 2 diabetes. The method was developed by Bradley Field Bale and Amy Doneen.
Nehal N. Mehta, is an American cardiologist at the National Heart, Lung, and Blood Institute (NHLBI) in Bethesda, Maryland where he studies the role of innate immunity and inflammation in the development of cardiovascular and metabolic diseases.