20-Year Follow-up of Statins in Children

A recent study (IK Luirink et al. NEJM 2019; 381: 1547-56) examined the effects of statin therapy in children with familial hypercholesterolemia (FH) who were followed for 20 years. At baseline, the median age was 13 years in the treated cohort and in their sibling control group.  184 of 214 (86%) of patients with FH were seen in follow-up and 77 of 95 (81%) of siblings.

Key findings:

  • The mean LDL cholesterol had decreased from 237 to 161 mg/dL
  • LDL target of <100 mg/dL was achieved in 37 patients (20%)
  • Mean progression of carotid intima-media thickness over the entire follow-up period was 0.0056 mm/year in patients with FH and 0.0057 mm/year in sibling controls
  • The cumulative incidence of cardiovascular events and death from cardiovascular causes at age 39 years was lower in the treated group compared to  their affected parents: 1% vs. 26% and 0% vs. 7% respectively

Discussion:

“This makes a strong case for not only ‘the lower the better’ but also for ‘the younger the better” as atherosclerotic disease is determined not only by the LDL level but also by cumulative exposure.

My take: This study provides convincing data that statin therapy prolongs health and life in patients with familial hypercholesterolemia.

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Understanding Sodium Intake and Cardiovascular Risk

A recent review (ME Cogswell et al. NEJM 2016; 375: 580-5) helps sort out some of the confusion regarding sodium intake and cardiovascular disease. In brief, the authors point out the excessive sodium intake is clearly linked to heart disease, stroke and death.  The importance has been questioned by some due to a few studies suggesting that low sodium intake could also increase the risk of cardiovascular disease.

The authors note that these studies have shown only weak associations & were likely a matter of reverse causation due to the low sodium group having increased numbers of participants with numerous health issues (eg diabetes, hypertension, chronic illness and cardiovascular disease).

By looking at these results based on “Hill’s Criteria” to assess whether an association is causal, the authors show that the association of low sodium intake and cardiovascular disease indicates that this association is NOT causal.

Hill’s criteria:

  • Strength -degree which the exposure is associated with the outcome
  • Consistency -is this finding observed by different persons, in different places/times
  • Specificity -is observation limited to the exposure and the outcome
  • Temporality -did observation cause the outcome or did the outcome affect changes that lead to observation
  • Biologic gradient -?dose-response noted
  • Plausibility -is there a physiologic basis
  • Coherence -does this association conflict with other known facts
  • Experiment -is the finding affected by actions to prevent the exposure
  • Analogy -does an exposure with a similar physiologic action cause the outcome

The authors note that population exposure to sodium correlates better than individual exposure, perhaps due to measurement issues. Key points:

  • “There is strong evidence of a linear, dose-response effect of sodium reduction on blood pressure.  In addition, the evidence shows that sodium reduction prevents cardiovascular disease.”
  • “Reducing the average sodium intake by just 400 mg per day could potentially avert as many as 28,000 deaths and save $7 billion in health care costs annually in the United States.”
  • “Yet sodium levels are high before food reaches the kitchen or table, and the sodium density of the U.S. diet has changed little despite consumer education encouraging individual behavior change.”

My take: If we are to take advantage of the science to reduce cardiovascular deaths, we need to convince manufacturers and restaurants to reduce sodium.

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Highline Trail, Glacier Nat'l park

Highline Trail, Glacier Nat’l park

How Does Exercise Improve Your Heart?

Probably like a lot of people, I presumed that the main way that exercise improved cardiovascular outcomes was due to beneficial effects on weight, serum lipid levels, and adiposity. However, recent research (Liu X et al. Cell Metab 2015; 21: 584-95) has shown a critical role for microRNA miR-222.  This research is summarized by Hill JA (“Braking Bad Hypertrophy” NEJM 2015; 372: 2160-62).

Key points:

  • “Liu et al provide compelling evidence that miR-222 is up-regulated by exercise and serves to brake pathologic cardiac remodeling and release the heart (“braking the brake”) to grow in a beneficial way”
  • Thus, “exercise triggers a robust and adaptive growth response in the myocardium.”
  • “Current evidence suggests that the heart, in response to stress (eg. exercise) can help it retrace its steps and move toward “good” heart growth.”

Bottomline: “Exercise is a powerful medicine with few noorthopedic side effects.”

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Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications/diets (along with potential adverse effects) should be confirmed by prescribing physician/nutritionist.  This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition.

How Soccer Can Be Bad for Your Health

When people complain that “everything is bad for your health,” they just might be right.  After yesterday’s soccer match, the NEJM posted a link to a 2008 article (N Engl J Med 2008; 358:475-483).  Here’s part of the abstract:

Methods: Cardiovascular events occurring in patients in the greater Munich area were prospectively assessed by emergency physicians during the World Cup. We compared those events with events that occurred during the control period: May 1 to June 8 and July 10 to July 31, 2006, and May 1 to July 31 in 2003 and 2005.

Results: Acute cardiovascular events were assessed in 4279 patients. On days of matches involving the German team, the incidence of cardiac emergencies was 2.66 times that during the control period…On those days, the highest average incidence of events was observed during the first 2 hours after the beginning of each match.

Conclusions: Viewing a stressful soccer match more than doubles the risk of an acute cardiovascular event.

Take-home point: Some people are not lying when they say they live and die with their favorite team.

The Liver –Front and Center

Before proceeding with today’s post, those who read yesterday’s post may be interested in Atul Gawande’s take on the NEJM checklist publication -here’s the link (from Atul Gawande’s twitter feed): bit.ly/1d6v31z

A recent review “Extrahepatic Complications of Nonalcoholic Fatty Liver Disease” (NAFLD)(Hepatology 2014; 59: 1174-97) seems to position the liver as the center of a multitude of problems rather than one of many associated problems.

It is known that NAFLD increases the risk of end-stage liver disease and hepatocellular carcinoma.  However, the majority of deaths among individuals with NAFLD are attributed to cardiovascular disease and malignancy.  This lengthy review describes in great detail the associations between NAFLD and the risk of developing cardiovascular disease (CVD), type 2 diabetes mellitus (T2DM), chronic kidney disease (CKD), and colorectal neoplasm.  The presence of NAFLD appears to convey an independent increase in risk for these conditions.

Key points:

  • “The aggregated evidence provides strong evidence that individuals with NAFLD are at increased “independent” risk of developing CVD.  The risk of CVD mortality may be greater in subgroups of subjects with NASH and advanced fibrosis, compared to those with simple steatosis.”
  • “USS-defined NAFLD is associated with a 2- to 5-fold risk of developing T2DM after adjustment of several lifestyle and metabolic confounders.”
  • “NAFLD (in particular, biopsy-proven NASH) is associated with a greater prevalence of CKD (20% to 50% of patients). USS-defined NAFLD carries a 1.5- to 2-fold adjusted risk of incident CKD.”
  • “A true causal relationship between and NASH and colorectal cancer cannot be confirmed.”
  • Other potential extrahepatic manifestations: hypothyroidism, polycystic ovarian syndrome, obstructive sleep apnea syndrome, and osteoporosis.

Take-Home Message: NAFLD has independent associations for greater risk of CVD, hyperglycemia, and malignancy.  Whether these associations are simply an epiphenomenon  of more aggressive metabolic syndrome or whether the liver injury primarily causes these additional risks remains unclear.

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Facts, “Misfearing” and Women’s Health

A terrific short perspective article shows how “misfearing” affects health care (NEJM 2014; 370: 595-597).

The author quotes one of her patients who when asked what is the number-one killer of women, replies “I know the right answer is heart disease…but I’m still going to say ‘breast cancer.'”

Key points:

  • “Tornadoes. Terrorist attacks. Homicides.  The big, the dramatic, and the memorable occupy far more of our worry budget than the things that kill with far greater frequency.”
  • “Misfearing” is a term coined by Cass Sunstein “to describe the human tendency to fear instinctively rather than factually”  274. Cass R. Sunstein, “Misfearing: A Reply” – University of Chicago 
  • “When I read Angelina Jolie’s New York Times editorial…She’s beautiful and brave, I thought, and I want to be like her.  The cardiologist in me, however, said, ‘Oh no –will this make it even harder for us to help women believe they’re at risk for cardiovascular disease?'” My Medical Choice by Angelina Jolie – NYTimes.com

A graphic from this perspective article shows that mortality from cardiovascular disease is approximately ten times greater than mortality from breast cancer (if difficult to see, the graphic is available online http://www.nejm.org/doi/full/10.1056/NEJMp1314638?query=featured_home):

Cardiovascular vs. Breast Cancer Mortality in Women

Cardiovascular vs. Breast Cancer Mortality in Women

In pediatric GI, families are often more worried about the treatment than the disease (e.g.. inflammatory bowel disease), despite the fact that the disease is often far more dangerous.

Take home message: (quote from author) “If we want our facts to translate into better health, we may need to start talking more about our feelings.” This is true not just in cardiovascular disease, but in all aspects of medicine.

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Healthy Obesity?

From NY Times,  nyti.ms/1diH2d4 –an excerpt:

The idea that there are obese people who are nonetheless healthy may be a myth.

Although some overweight or obese people have normal cholesterol, glucose levels and blood pressure — elements of so-called metabolic health — a new study suggests that obesity by itself increases the risk for heart disease, stroke, diabetes and death.

Researchers analyzed 12 studies that had together followed more than 61,000 adults, most for at least 10 years. About 9 percent of the subjects were obese and metabolically healthy — that is, they had normal LDL, HDL and total cholesterol, along with healthy blood pressure and blood sugar levels. The report was published online last week in Annals of Internal Medicine.

Compared with metabolically healthy people of normal weight, the obese group had a 24 percent increased risk for fatal and nonfatal cardiovascular events like heart attack and stroke, and for death by any cause.

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What is resistin?

Resistin is a cysteine-rich protein which is often elevated in chronic renal disease and has been associated with increased risk for cardiovascular disease (CVD) (J Pediatr 2012; 161: 276-80).  It is expressed primarily in macrophages and stimulates the production of interleukin 6, and tumor necrosis factor α (TNF-α).

The cited study examined whether resistin was associated with renal function and inflammatory markers in 319 children from the Chronic Kidney Disease in Children (CKiD) cohort.  The CKiD study is a longitudinal observational study from 46 pediatric nephrology centers in North America.  For this study, the glomerular filtration rate (GFR) had to between 30-90 mL/min/1.73 m-squared.

Findings:

  • Serum resistin was significantly associated with elevated inflammatory cytokines IL-6, IL-10, and tumor necrosis factor.
  • Resistin levels were negatively correlated with GFR.  The authors state that decreased clearance may not be the only reason for higher resistin levels as chronic kidney disease is a state of chronic inflammation and resistin may be involved in these processes.
  • Resistin also was independently associated with pubertal status

Who needs aspirin?

Despite a lot of good press for aspirin with regards to prevention of cardiovascular events and cancer prevention, determining who should take aspirin is quite tricky.  This blog entry will discuss the vascular rationale and a subsequent post will tackle the potential of aspirin for colorectal cancer prevention.

At this time, the cardiovascular disease (CVD) rationale includes preventing myocardial infarction [MI] and stroke.  These are the main determinants of risk/benefit for taking aspirin.  In 2009, guidelines from US Preventive Services Task Force (USPSTF) for taking aspirin were published (Ann Intern Med 2009; 150: 396-404).  The following link can be used to access this article:

http://www.uspreventiveservicestaskforce.org/uspstf09/aspirincvd/aspcvdrs.pdf

The recommendations include the following:

Men <45:  Not encourage aspirin for MI prevention

Women <55: Not encourage aspirin for stroke prevention

Men 45-79:  Encourage aspirin when CVD benefit.  Benefit likely if:

  • 45-59 years, 10 -year CVD risk ≥4%
  • 60-69 years, 10-year CVD risk ≥9%
  • 70-79 years, 10-year CVD risk ≥12%
To calculate 10-year CVD risk: http://www.mcw.edu/calculators.htm
Risk factors: age, high blood pressure, diabetes, smoking, history of CVD, total cholesterol level, and HDL cholesterol level

Women 55-79:  Encourage aspirin when stroke benefit.  Benefit likely if:

  • 55-59 years, 10 -year stroke risk ≥3%
  • 60-69 years, 10 -year stroke risk ≥8%
  • 70-59 years, 10 -year stroke risk ≥11%

To calculate 10 -year stroke risk: http://my.clevelandclinic.org/p2/stroke-risk-calculator.aspx

Risk factors: age, high blood pressure, diabetes, smoking, history of CVD, atrial fibrillation, and left ventricular hypertrophy

In addition, it is noted that aspirin is NOT recommended when other NSAIDs are being administered or if history of GI ulcers/risk of serious GI bleeding.

While these recommendations are a useful starting point and the risk calculators are fascinating, the absolute benefit of aspirin remains unclear.  A recent article on this subject indicates that aspirin may not improve mortality (Arch Intern Med. 2012;172(3):209-216. doi:10.1001/archinternmed.2011.628).  This article reviewed nine large randomized placebo-controlled studies, each with at least 1000 participants.  In total, more than 100,000 patients were described in these studies.  While CVD events were reduced by 10%, there was no reduction in mortality for cardiovascular disease (OR 0.99) or for cancer (OR 0.93) among aspirin takers over a mean of 6 years.  Most of the reduction in CVD events were due to a lower rate of non-fatal MI (OR 0.80).  In addition, there was an increase in significant GI bleeding among patients taking aspirin (OR 1.31)

Due to these results, the authors conclude that routine use as primary prevention is not warranted; “treatment decisions need to be considered on a case-by-case basis.”

Additional reference:

  • Arch Intern Med 2012;172:217-218.  Aspirin Therapy in Primary Prevention: Comment on “Effect of Aspirin on Vascular and Nonvascular Outcomes”