Cardiovascular Pathology


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Sex: M>F, Uncommon in women of child bearing age (unless other strong risk factors are present). The difference equals out by about age 60 – 70. Estrogen replacement may offer some protection if initiated in younger postmenopausal women, but in some studies postmenopausal estrogen replacement actually increased cardiovascular risk.

Genetics: There is a well-established genetic predisposition to atherosclerosis, probably polygenic & related to the genetics of the other risk factors; i.e. diabetes, hyperlipidemia, hypertension. Parents with no significant atherosclerotic disease well into old age may be your best protection.

The Big Risk Factors

  • Hyperlipemia (increased LDL and decreased HDL cholesterol)

  • Hypertension (blood pressure >130/80 mm Hg or on antihypertensive medication)

  • Cigarette smoking

  • Family history of premature AS (coronary heart disease in 1st degree male relative <55 years old or 1st degree female relative <65 years old)

  • Diabetes mellitus


  • Mostly means hypercholesterolemia – triglycerides are less significant

  • Major  risk due to LDL cholesterol

  • Inverse relationship to HDL cholesterol

  • Exercise and moderate EtOH  HDL

  • Obesity and smoking  HDL

  • Treatable by diet and pharmacologic means


The significant hyperlipidemia subtypes for increased AS risk are types IIa, IIb, and III .

HDL is believed to mobilize cholesterol from AS plaques and return it to the liver for excretion in the bile.

See text for further evidence implicating hyperlipidemia.

Pearl: Cholesterol lowering can actually cause AS plaques to regress to some extent.


  • Risk factor at all ages, but stronger risk factor if past age 45 (even if on antihypertensive meds!)

  • Both systolic and diastolic are important

  • Antihypertensive therapy reduces the incidence of atherosclerosis related events, especially stroke and ischemic heart disease

  • Some evidence now that even “high-normal” BP increases risk (systolic 130 to 139, diastolic 85 to 89) – see NEJM 345:1291-1339, 2001

Cigarette Smoking

Diabetes Mellitus

  • Induces hypercholesterolemia and markedly increases predisposition to atherosclerosis

  • 100X increased risk of gangrene of lower extremities (rare in non-diabetics)

  • Complex mechanisms

Emerging Risk Factors

Note: Atherosclerosis may occur in the absence of any risk factors (i.e. half of heart attacks occur in persons with normal cholesterol), or some persons with risk factors may not have significant disease. Conclusions:

  1. We don’t know everything about the disease.

  2. Genetics is important!

The Metabolic Syndrome

  • Abdominal obesity (waist > 40 inches for men, > 35 inches for women)

  • Atherogenic dyslipidemia (  LDL & triglyceride, small LDL particles,  HDL

  • blood pressure, > 130/85 mm Hg
  • Insulin resistance, fasting glucose >110 mg/dl

  • Prothrombotic & proinflammatory states

  • Treatment involves “therapeutic lifestyle changes” – diet, weight reduction, increased physical activity (see ATP III study in JAMA 285:2485-97, 2001)

  • Look up your risk at

Note: This is not the only online medical app. There are now about 40,000 smartphone/tablet medical apps covering everything from everything from hypertension to depression, and these are largely as yet unregulated (Indpls. Star, 6/24/2012).


  • Homocysteine is known to be toxic to endothelium

  • Children with homocystinuria may develop first MI by age 20 years

  • Homocysteine may be mildly elevated in adult patients without the classic childhood disorder – correlates with increased risk of symptomatic AS
  • Treatment with folate, B6 or B12 may lower homocysteine, but it is controversial whether this lessens mortality from heart attack/stroke per recent large studies


Homocysteine and may interfere with antithrombotic and vasodilator functions (decreases availability of nitric oxide) and increases collagen production.

Inflammation/C-Reactive Protein

  • CRP is an acute phase reactant from the liver – a nonspecific indicator of systemic inflammation
  • CRP levels have a strong value for predicting cardiovascular events independent of serum cholesterol

  • Suggests that inflammation plays a major role in the pathogenesis of AS

  • Diet, weight loss, cessation of smoking all lead to  CRP

  • Statins, other cholesterol lowering drugs, and ASA all  CRP

  • There is some evidence that the strength of CRP as an independent risk factor may have been overestimated; increased WBC may also serve as a marker for systemic inflammation and is a lot cheaper


Dr. Paul Ridker at of Harvard Medical School has received much attention in the lay press as well as academia in the last few years for his publications relating C-reactive protein to cardiovascular risk. See Ridker, et al., NEJM 347:1557, 2002, for an “original” paper, and Ridker, Circulation 107:363, 2003 for a brief review of the CRP topic. In an article in Fortune magazine in October 27, 2003, Ridker’s and others discuss ideas about “anti-aging” for the layman. A recent NEJM article on the “Jupiter” study provides evidence that a statin drug (Crestor) reduces the rate of cardiovascular problems in persons with  CRP even if they have normal cholesterol (see The Wall Street Journal, November 10, 2008, for the business-oriented summary).
There are numerous other markers for AS risk. One recent one is cystatin (google it). This is a marker for renal function (somewhat like creatinine). It is known that patients with renal insufficiency are at higher risk for cardiovascular events. Even low birth weight as been associated with increased risk of AS in later life!

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