Why Rheumatologists Should Focus on Patients’ Cardiovascular Health

Watching Pablo Sandoval’s belly burst his belt buckle on live TV during a recent Red Sox game got me thinking about the link between obesity and metabolic syndrome.
David Lee/shutterstock.com

Baseball is a great sport. It’s fascinating to watch the evolving duel between pitcher and batter. As the former employs their remarkably powerful and versatile rotator cuff and forearm flexor muscles to hurl blazing pitches, the latter engages their exceptionally honed hand–eye neural link to make contact with the ball. Baseball is the ultimate summertime sport: a slow-moving, drawn-out affair punctuated by the occasional hit or the occasional calamity. Consider what recently occurred when a hefty batter took a massive swing that not only failed to connect with the ball, but resulted in the strong torque forces bursting his belt buckle in front of 49,000 fans. This recent embarrassing mishap brought considerable unwanted attention to the player’s rather portly belly.¹ Fortunately for the batter, the recently acquired Boston Red Sox third baseman Pablo Sandoval, his pants did not fall down.

Mr. Sandoval has struggled with weight issues for most of his career, but when he became a free agent last fall, the Red Sox wasted no time in signing him to a multi-year, $95 million contract. After all, there is a long history of overweight ballplayers being successful at their craft, including the immortal Babe Ruth and the incredibly talented pitcher, C.C. Sabathia. Perhaps the team should have consulted with a nutritionist, because Mr. Sandoval is known to have a penchant for overeating.² The issue of his weight and its effect on his lackluster performance this year dogged him until a few weeks ago when he suffered a season-ending labral tear in his shoulder.

Pablo Sandoval’s story serves as a not-so-gentle reminder of the pervasive nature of the obesity epidemic that, save for Africa, has spread to every corner of the globe. As obesity rates continue to steadily rise, its perils, along with those of its fellow traveler, the metabolic syndrome, have arrived at our clinics and hospital wards in full force. The hazardous triad of the metabolic syndrome—hypertension, dyslipidemia and insulin resistance—were formerly considered to be medical issues that rested solely within the purview of the endocrinologist or the cardiologist. Rheumatologists were preoccupied with other pressing matters, such as dealing with the active inflammation that was steadily destroying our patients’ joints and damaging other critical tissues.

However, the tide began to slowly turn some years ago, as epidemiologic studies bore out what many of us in practice had already observed: a strikingly high number of our patients succumbed to heart disease and other vascular complications. In the earlier days of rheumatology, the debility caused by our illnesses, the necrotic skin, the infected nodules, the scarred lungs, coupled with the frequent use of corticosteroids and the limited repertoire of antibiotics available to combat microorganisms, enabled many infections to become fatal. With better overall medical care, thankfully, deadly infections have become rare and, like the rest of the population, morbidity and mortality related to cardiovascular causes have assumed top billing in the rheumatology clinic.

Cholesterol: A Brief History

From a practical standpoint, it can be challenging for many of us to assume the management of the conditions that contribute to the metabolic syndrome. Yes, we all routinely measure and record blood pressures, but most rheumatology practices are not focused on treating hypertension. For similar reasons, though some of us may keep tabs on a patient’s hemoglobin A1C level, diabetes is a complex disease and its proper management belongs with their endocrinologist or primary care doctor. But getting involved in managing our patients’ hyperlipidemia may be more feasible. First, it is easy to measure and follow a patient’s lipid levels. Second, generic statin drugs are cheap and readily available without the need for prior authorization. Third, we are well versed in managing two of the most common statin-drug-induced side effects, myalgia and elevated liver enzymes.

The association between cholesterol and vascular disease was first established at the turn of the 20th century by the Russian pathologist, Nikolay Anitschkow, MD, who described this link after feeding rabbits a purified cholesterol diet.³ However, his observations were dismissed by critics who were skeptical of the relevance of this model, which relied on an herbivorous creature to serve as a surrogate for carnivorous humans.

When it comes to inflicting havoc on our health, what seems to matter most is whether fat cells are taking up residence in visceral organs, such as the liver, or merely depositing themselves under the skin.

The field lay dormant until the post-World War II era, when the singular efforts of the late John Gofman, MD, professor emeritus of molecular and cell biology at the University of California at Berkeley, transformed our understanding of cholesterol’s critical role.4 A gifted polymath, Dr. Gofman was enlisted in the Manhattan Project, where he isolated 1.2 mg of plutonium, creating the world’s largest existing quantity of this radioactive substance at that time. After the war, he changed careers and focused his attention on cholesterol and its role in cardiovascular disease. Using one of the first analytic ultracentrifuges designed for detailed characterization of proteins and other large biomolecules, he elegantly demonstrated that the key to ultracentrifugal isolation and analysis of cholesterol-bearing lipoproteins was to adjust the density of serum by adding salt and, thereby, float them away from the other, denser sedimenting proteins. This led to the discovery of the three major classes of lipoproteins in human serum: the very low-density (VLDL-C), low-density (LDL-C) and high-density lipoproteins (HDL-C).⁴

Dr. Gofman’s research demonstrated that those in the cholesterol-rich LDL class were the most atherogenic and were highly predictive of cardiac risk. The triglyceride-rich VLDL class was also assigned a causal role in atherosclerosis. Subsequent studies by others definitively established HDL to be a strong inverse predictor of cardiovascular risk, hence the terminology identifying LDL as bad cholesterol and HDL as good cholesterol.

Bolstering the case implicating cholesterol in the pathogenesis of cardiovascular disease were two seminal epidemiological studies. The first, known as the Seven Countries Study, was an intensive compilation of the eating habits of middle-aged men in the U.S., Italy, Greece, Yugoslavia, the Netherlands, Finland and Japan.⁵ This long-term study confirmed that the rates of cardiovascular disease correlated with higher levels of LDL-C. Their observations led to the adoption of the Mediterranean diet among many dieters.

The second took place in Framingham, Mass., a tidy suburb of Boston situated about 20 miles west along the Massachusetts Turnpike from where I sit. With the ongoing support of the National Heart, Lung, and Blood Institute and Boston University, the Framingham Heart Study investigators have been meticulously collecting and analyzing the blood and the electrocardiograms of this town’s citizenry since 1948, and the results have helped shape our approach to cardiovascular disease. Notable findings include the confirmation of the adverse effects of smoking, and the role that diet, cholesterol and truncal obesity play in the development of cardiovascular disease.⁶

Lowering the LDL cholesterol has become a mainstay of cardiovascular risk management. … [But] when it comes to reducing LDL-C, how low is low enough?

Lowering the LDL cholesterol has become a mainstay of cardiovascular risk management. Statins are the most popular class of drug in the U.S., with approximately one of every four adults prescribed one. A recently published study confirmed the lifesaving benefits of lowering cholesterol levels even in patients with intermediate cardiac risk factors. In this double-blinded study of more than 12,000 male subjects over the age of 55, treatment with rosuvastatin resulted in a 24% reduction of cardiovascular events compared with placebo, whereas the addition of antihypertensive therapy to their regimen did not significantly reduce these events.⁷

These findings raise the question: When it comes to reducing LDL-C, how low is low enough? The identification of the PCSK9 protease and its role in LDL-C synthesis in hepatocytes sparked a race among several biopharmaceutical companies to identify those loss-of-function mutations in affected subjects that resulted in remarkable degrees of hypocholesterolemia.⁸ Would you consider an LDL-C measuring 15 mg/dL to be sufficiently low? Amazingly, these levels have been observed in family cohorts lacking functional PCSK9 proteases, and not surprisingly, their cardiovascular risks are fairly negligible. We will wait to see whether similarly slashed cholesterol levels will be achieved with the use of the new class of PCSK9-inhibiting drugs.

The Lipid Paradox

Of course, rheumatology would not be the wonderfully challenging discipline that it is by simply following the script. Sometimes, the rules of medicine don’t apply here. Consider the lipid paradox, the term used to describe what happens to patients with clinically active rheumatoid arthritis (RA) who may face heightened risks for cardiovascular morbidity and mortality at the time of maximal joint inflammation, even as they demonstrate reduced levels of total cholesterol, HDL-C and LDL-C. As their RA improves following immune suppressive treatment, these values begin to rise unexpectedly.⁹ This observation was confirmed by another great longitudinal study based in a single American county. The Rochester, Minn., Epidemiology Project measured and followed the lipid profiles of 577 patients with RA from five years before until five years after diagnosis. Despite having lower rates of statin use, the patients with RA displayed a greater mean reduction in total cholesterol (10%) and LDL-C (17%) during the five years preceding diagnosis compared with the control population, after adjustment for age, gender and calendar year.¹⁰ So can a rising LDL-C value be a sign of improving health? Another rheumatologic enigma to say the least!

The lipid paradox may also extend to the location of excess body fat. Fat cells are not created equally. Researchers are beginning to embrace the concept of good fat and bad fat. Although the release of inflammatory molecules from visceral fat is considered to be a key factor in the development of the metabolic syndrome, these adverse effects are either not observed or are much less pronounced in adults with only excess subcutaneous fat.¹¹ When it comes to inflicting havoc on our health, what seems to matter most is whether fat cells are taking up residence in visceral organs, such as the liver, or merely depositing themselves under the skin. For example, the relatively rapid metabolic improvement noted following bariatric surgery likely reflects the post-operative loss of visceral fat, because in most cases, it occurs prior to any significant loss of subcutaneous fat and body weight.

A Final Paradox

From an evolutionary standpoint, is there any advantage for a host to be afflicted with the metabolic syndrome? Perhaps.

In one study, a high-fat diet induced the metabolic syndrome, but also protected the CD-1 mouse strain from the lethality associated with Trypanosoma cruzi infection, dramatically decreasing mortality by 65%.¹² It is conceivable that at an earlier point in evolution, the metabolic syndrome conferred a substantial benefit to our survival as a species, as our early ancestors warded off a raft of infectious challenges. Over time, this benefit has been far overshadowed by the syndrome’s downsides.

But all may not be lost. There may be one more lipid paradox to consider. Despite meeting clinical criteria for type 2 diabetes and metabolic syndrome, hibernating animals demonstrate no pathologic consequences of their brief bout with obesity. After shedding their extra fat during the winter fast, animals are able to immediately enter into the reproductive cycle. Nor are the ill effects of circumannual obesity transient; in one Swedish study, atherosclerotic lesions were entirely absent from the major vessels of obese, insulin-resistant hibernators despite marked hyperlipidemia.¹³ Similarly, obese hibernators fail to develop the smoldering inflammation that characterizes human obesity, despite similar metabolic parameters. The absence of pathology despite remarkably similar metabolic states suggests that transient obesity and insulin resistance are not necessarily pathologic and may, in fact, be part of an adaptive, evolutionarily conserved response to excess nutrient storage.

That may be the solution! Consider the option of hibernating this fall. With the anticipated pandemonium of the upcoming U.S. general election, imagine if we could hibernate just like our ursine cousins. Pack in those calories, party like it’s 1999, and then take a nap. A very long nap. Yes, you can have your cake and eat it, too.

Simon M. Helfgott, MD, is associate professor of medicine in the Division of Rheumatology, Immunology and Allergy at Harvard Medical School in Boston.

References

1. Foltin L. Pablo Sandoval swung so hard he busted his belt. Fox Sports. 2016 Apr 9.
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