Cardiovascular Diseases

1
Cardiovascular Diseases

• Andrew Reisman, MD, ATC
• PHYT-801
• November 3, 2009

2
Objectives

• Review pathophysiology
• Discuss risk factors
• Investigate hypertension
• Exercise response
• Exercise as treatment
• Discuss cholesterol
• Affects and treatment

3
Arteriosclerosis

• Thickening and hardening of the arteries
• Responsible for the majority of deaths in the
  United States
• Atherosclerosis
• Disorder of the larger arteries
• Coronary artery disease (CAD)
• Aortic aneurysm
• Peripheral Vascular Occlusive Disease (PVOD)
• Cerebrovascular Disease (CVD)

4
Mechanism of Injury

• Fatty streaks develop along the intima (innermost
  layer of an artery)
• A proliferation of smooth muscle cells ensues
  leading to a fibrous plaque
• This plaque begins to decrease blood flow
  downstream

5
Mechanism of Injury

• The plaque may then rupture
• Sending a shower of plaque to the smaller vessels
  down stream leading to localized ischemia
• Leading to a local reaction of platelet
  aggregation and clot formation causing regional
  ischemia

6
Categories of Risk Factors

• Category I
• Risk factors for which interventions have been
  proved to reduce the incidence of coronary artery
  disease (CAD) events
• Category II
• Risk factors for which interventions are likely,
  based on our current pathophysiological
  understanding and on epidemiologic and clinical
  trial evidence, to reduce the incidence of CAD
  events

7
Categories of Risk Factors

• Category III
• Risk factors clearly associated with an increase
  in CAD risk, and which, if modified, might lower
  the incidence of CAD events
• Category IV
• Risk factors associated with increased risk but
  which cannot be modified or whose modification
  would be unlikely to change the incidence of
  coronary disease events

8
Category I - Cigarette Smoking

• A linear relationship exists between
  cardiovascular risk and of cigarettes consumed
• Relative risk of a fatal cardiovascular event is
  5.5 times that of a non-smoker
• Smoking accelerates the atherogenic process in
  both a duration- and dose-dependent fashion

9
Category I - Cigarette Smoking

• An average smoker has a life expectancy 3 years
  less than a non-smoker
• A smoker known to be at high risk for CAD has a
  life expectancy 10-15 years less than a
  comparable non-smoker
• Smoking amplifies the effects of other risk
  factors
• Thrombus formation, plaque instability and
  arrhythmias are all influenced by cigarette
  smoking

10
Category I - Cigarette Smoking

• Clinical data accumulated over the last 20 years
  strongly suggests that smoking cessation reduces
  the risk of cardiovascular events
• Risk of MI declines more rapidly than overall
  death from CV disease after smoking cessation
• Greatest proportion of risk reduction occurs in
  the first several months after cessation

11
Category I - Cigarette Smoking

• Patients who continue to smoke after acute MI
  have an increase in the risk of death and
  reinfarction (22 vs 47)
• Continued smoking after bypass grafting is
  associated with a twofold increase in the
  relative risk of death and an increase in
  nonfatal MI and angina

12
Category I - Cigarette Smoking

• Second hand smoke
• Estimated that passive smoking causes almost
  40,000 heart disease deaths yearly in the US
• Third leading cause of preventable death in this
  country

13
Category I - Low Density Lipoprotein (LDL)
Cholesterol

• Total blood cholesterol is conclusively linked to
  the development of CAD
• The majority of this risk is associated with LDL
  cholesterol concentration
• For every increase of LDL by 1, the risk for CAD
  increases by 2-3

14
Category I - Low Density Lipoprotein (LDL)
Cholesterol

• National Cholesterol Education Program (NCEP III)
  guidelines
• Updated 2003
• LDL gt 190 mg/dl very high risk
• LDL 160 - 189 high risk
• LDL 130-159 Borderline High
• LDL 100-129 Above Optimal for CHD risk equivalent
• LDL lt 100 optimal
• Some studies have suggested that LDL levels as
  low as lt80 are recommended for those with a
  history of CAD

15
(No Transcript)
16
Category I - Low Density Lipoprotein (LDL)
Cholesterol

• Increases in LDL associated with
• Age
• Weight gain
• Diets high in saturated fat and cholesterol ?
• Genetic factors
• Chronic hypothyroidism
• Estrogen deficiency

17
Category I - Low Density Lipoprotein (LDL)
Cholesterol

• Recent studies indicate that therapeutic lowering
  of LDL is highly effective in secondary
  prevention
• Angiographic studies showed delay in progression
  or coronary atherosclerosis and in some cases
  regression of the lesions

18
Category I - Low Density Lipoprotein (LDL)
Cholesterol

• Scandinavian Simvastatin Survival Study (4S)
• Simvastatin (Zocor) reduced coronary mortality
  by 42
• Reduced total mortality by 30

19
Category I - Low Density Lipoprotein (LDL)
Cholesterol

• West of Scotland Coronary Prevention Study
  (WOSCOPS)
• Demonstrated primary prevention benefits of LDL
  cholesterol reduction
• LDL reduction by 1 mg/dl resulted in a 1-2
  decrease in relative risk for coronary artery
  disease

20
Category I - Hypertension

• A continuous relationship between systolic and
  diastolic arterial pressure and cardiovascular
  risk exists
• Mechanism
• Direct vascular injury caused by increases in
  blood pressure
• Effects on the myocardium, including increased
  wall stress and myocardial oxygen demand

21
Category I - Hypertension

• Related to left ventricular hypertrophy (LVH)
• an independent risk factor for CAD including MI,
  CHF, and sudden death
• Framingham Heart Study showed that a regression
  of LVH associated with a substantial risk
  reduction for a cardiovascular event

22
Category I - Thrombogenic Factors

• A number of prothrombogenic factors have been
  identified
• Remember NSAIDs can inhibit platelet function
• Aspirin has been documented to reduce both
  primary and secondary coronary heart disease
  events
• The first medication given to someone having
  angina or an acute MI is ASA

23
Category II - Diabetes Mellitus

• Both Insulin dependent and Type II DM are
  strongly linked with CAD
• Atherosclerosis accounts for 80 of all diabetic
  mortality
• Coronary mortality is increased 3-10X in
  diabetics compared to non-diabetic controls
• 25 of all heart attacks in the US occur in
  patients with diabetes

24
Category II - Diabetes Mellitus

• Diabetes linked to many other conditions so
  difficult to study the effect of diabetes as a
  lone factor
• Coronary Artery Surgery Study (CASS)
• Diabetics had a 57 increase in risk of death
  after controlling for other known factors
• Higher risk of death and other complications noted

25
Category II - Physical Inactivity

• Approximately 12 of all mortality in the US may
  be related to lack or regular physical activity
• Associated with a twofold increase in risk for
  CAD events
• Overall reduction in CAD events persists despite
  a small transient increase in the risk of MI or
  sudden death that occurs during physical activity

26
Category II - Physical Inactivity

• Difficult to quantify the relationship between
  amount of exercise and CAD risk given multiple
  factors affected by exercise
• Direct and indirect mechanism of actions
• Improves myocardial supply/demand relationship
• Lowers triglycerides and raises HDL cholesterol
  levels
• Lowers blood pressure
• Decreases platelet aggregation

27
Category II - High Density Lipoprotein (HDL)
Cholesterol

• Strong inverse relationship between HDL levels
  and CAD risk
• For every 1 mg/dl decrease in HDL there is a 2-3
  increase in relative risk for CAD events
• High HDL levels associated with longevity
• HDL goal gt 60mg/dl
• Given inter-relationships, it has been difficult
  to establish HDL as an independent variable

28
Category II - Postmenopausal Status

• CAD presents about a decade later in women
  compared with men
• Cardiovascular disease is still the leading cause
  of death among US women
• Observed that the protection conferred upon women
  appears to be lost after natural menopause
• Coronary disease risk clearly increases after
  surgical menopause

29
Category II - Postmenopausal Status

• Evidence of the beneficial effects of
  postmenopausal estrogen replacement were derived
  almost entirely from observational studies and
  recent prospective studies have showed an
  increased risk actually exists
• Results of Womens Health Initiative were stopped
  early as increased cardiac risk was actually noted

30
Category II - Postmenopausal Status

• Exogenous estrogen favorably effects both HDL and
  LDL cholesterol levels
• Self selective population of women who choose
  HRT?

31
Category II - Obesity

• Linear relationship between body mass and
  mortality
• 20 of Americans between the ages of 25-34 are
  classified as obese
• Approximate 10 of the population becomes obese
  with each succeeding decade to the age of 55

32
Category II - Obesity

• Associated with multiple other risk factors
• Hypertension
• Glucose Intolerance
• Decreased HDL
• Increased Triglycerides
• Hard to sort out effects of obesity vs
  association with other risk factors

33
Category III - Psychosocial Factors

• A variety of psychosocial factors are associated
  with increased coronary heart disease risk
• Given the multiplicity and diversity of these
  risk factors, it is difficult to establish a
  direct relationship between them and
  cardiovascular diseases

34
Category III - Psychosocial Factors

• Type A personality
• Efforts to change behavior have not convincingly
  demonstrated that it changes CAD risk
• Other traits felt related to CAD in observational
  studies
• Depression
• Hostility
• Social Isolation
• Economic insecurity

35
Category III - Psychosocial Factors

• Mechanisms
• Directly through neuroendocrine effects
• Brain catecholamine and serotonin levels
• Indirectly through patients adherence to
  preventive recommendations and compliance with
  therapeutic strategies

36
Category III - Psychosocial Factors

• Major depression after acute MI increases 6-month
  mortality
• Patients without a social support system have a
  threefold increase in 6-month mortality after
  acute MI
• Chronic stress doubles the risk of developing MI

37
Category III - Triglycerides (TGs)

• TG levels uniformly predict coronary heart
  disease in univariate analyses but often lose
  their predictive power when other risk factors
  are added in a multivariate analysis
• HDL levels inversely related to TG levels so some
  feel these should be linked

38
Category III - Triglycerides (TGs)

• Two important nonlipid associations of high TG
  levels
• Abnormalities in various clotting factors
• Syndrome X (Familial dyslipidemic hypertension)
• High TG levels
• Low HDL
• Insulin resistance
• Abdominal adiposity
• Hypertension

39
Category III - Triglycerides (TGs)

• Factors which decrease TG levels
• Weight loss
• Dietary changes
• Decreased ETOH consumption
• Smoking cessation
• Increased physical activity
• Difficult to determine if decreasing TG levels
  act independently from above factors

40
Category III - Triglycerides (TGs)

• Triglyceride levels
• lt200 Normal
• 200-399 Borderline high
• 400-1000 High
• gt1000 Very high
• Some recent advances in targeting TG levels with
  pharmacotherapy

41
Category III - Lipoprotein(a)

• Elevated levels of Lipo(a) recently recognized as
  a potentially significant CAD risk factor
• Acts as a potential inhibitor of fibrinolysis
  allowing for narrowing of vessel walls
• Levels are largely determined through autosomal
  dominant inheritance
• Among patients with premature CAD, 15-20 have
  elevated Lipo(a) levels

42
Category III - Lipoprotein(a)

• Lipoprotein(a) levels increase with
• Age
• African-American heritage
• Female sex
• Levels may possibly be reduced be Niacin
• No prospective interventional trial information
  is available

43
Category III - Homocysteine

• Increased homocysteine levels are associated with
  increased risk of both CAD and peripheral
  arterial disease
• Increased levels of homocysteine associated with
• Deficiency of the catabolic enzyme cystathionine
  B-synthase
• Vitamin B6 and Vitamin B12 (Folate) deficiency
• Aging

44
Category III - Homocysteine

• Homocysteine-induced vascular damage may occur as
  a consequence of the amino acids procoagulant
  activities or by direct injury of vascular
  endothelium
• Appears to be unrelated to other CAD risk factors
• The risk of premature occlusive vascular disease
  is 30X greater for those with elevated
  homocysteine levels
• Clinical trials underway to further study
  homocysteine

45
Category III - Oxidative Stress

• Oxidative modification of LDL cholesterol,
  particularly in the vessel wall, accelerates the
  atherogenic process
• Oxidized LDL recruits monocyte macrophages,
  stimulating auto-antibodies, stimulating LDL
  uptake by macrophages and increasing
  intravascular tone and coagulability

46
Category III - Oxidative Stress

• Antioxidants can increase LDL resistance to
  oxidation and are associated with lower CAD risk
• Cambridge Heart Antioxidant Study (CHAOS)
• Vitamin E therapy in patients with CAD reduced
  the rate of no-fatal MI
• Vitamin E, Vitamin C and beta-carotene felt to be
  protective against CAD?
• ? Wrong isomer in pill form Allhope study
• Results inconsistent from various studies and
  more recent data shows increased CAD risk with
  use of antioxidants

47
Category III C- Reactive Protein

• Marker of inflammation
• It is felt that inflammatory changes cause
  rupture of plaque
• Those with borderline cholesterol levels and
  increased CRP levels should be treated more
  aggressively

48
Category III - Alcoholic Beverage Consumption

• Individuals reporting moderate amounts of alcohol
  intake (1-2 drinks daily) have a 40-50 reduction
  in CAD risk compared to individuals who are
  abstinent
• Excessive consumption (gt2 drinks daily)
  associated with increased risk of CAD

49
Category III - Alcoholic Beverage Consumption

• Increased risk may be associated with alcoholic
  cardiomyopathy
• Alcohol also associated with
• Hypertension
• Cardiac arrhythmias
• Alcohol (particularly red wine) associated with
  increased HDL levels
• Only observational studies done to date

50
Category IV- Non-Modifiable Risks

• Age
• CAD increases nearly linearly with age
• Male Sex
• MaleFemale Risk equalizes at age 75
• Incidence of CAD 3X greater in men below age of
  55
• Family History/Genetic predisposition

51
Hypertension
52

• The maintenance of health lies in forsaking the
  disinclination to exertion. Nothing is found
  that can substitute for exercise in any way,
  because in exercise the natural heat flames up
  and all the superfluities are engendered in the
  body, even though the food is of the very best
  quality and is moderate in quantity. And
  exercise will expel the harm done by most of the
  bad regimens that most men follow. Hippocrates
  420BC

53
Hypertension

• Blood pressure is determined by two factors
  Cardiac Output (CO) and Total Peripheral
  resistance (TPR)
• BP CO x TPR
• CO HR X SV
• Note - TPR sometimes referred to as SVR (Systemic
  Vascular Resistance)
• Normal BP lt130/lt85

54
Hypertension

• Hypertension is present in 17-20 of adults
• Prevalence rises with age
• More common in men then women
• More common in African Americans than European
  Americans
• Most cases of hypertension are idiopathic (i.e.
  We dont know why)

55
Hypertension

• Potential identifiable causes of hypertension
• Adrenal tumors (pheochromocytoma)
• Excessive production of glucocorticoids
• ETOH abuse
• Vascular abnormalities
• Pregnancy (Pre-eclampsia/Eclampsia)
• CNS disturbances (CVA)
• Renovascular diseases

56
Health Risks Associated with Hypertension

• Coronary Artery Disease
• Renal disease
• Stroke
• Peripheral Vascular Disease
• Retinopathy
• Death

57
JNC7 ClassificationTreatment Recommendations
Prehypertension SBP 120-139/ DBP 80-89 Stage 1
140-159/90-99 Stage 2 gt 160/gt100
Exercise and Hypertension Position Statement.
MSSE March 2004. 36(3) P. 534.
58
Stages of Hypertension

• Prehypertension
• TPR fails to compensate for changes in CO (should
  decrease)
• Usually due to impaired baroreceptor function
• Systolic BP 120-139
• Diastolic BP 80-89

59
Stages of Hypertension

• Stage I (mild)
• Most common form
• Increased CO and decreased TPR
• Systolic BP 140-159
• Diastolic BP 90-99

60
Stages of Hypertension

• Stage II (Moderate)
• Decreased CO and increased TPR
• Increased afterload leads to LVH
• Systolic BP 160-179
• Diastolic BP 100-109

61
Stages of Hypertension

• Stage III (Severe)
• Development of diastolic dysfunction
• Systolic BP 180-209
• Diastolic BP 110-119

62
Stages of Hypertension

• Stage IV (very severe)
• CO can no longer respond to exercise or other
  demands
• Marked LVH exists
• CHF and peripheral edema common
• Systolic BP gt210
• Diastolic BP gt120

63
Acute Effects of Dynamic Exercise

• Initial response is a linear increase in SBP
  secondary to an increase in cardiac output
• TPR decreases as blood vessels in exercising
  muscles dilate
• SBP increases less than expected due to decrease
  TPR
• DBP stays constant or may even decrease

64
Chronic Effects of Dynamic Exercise

• Reduction of SBP by 7-12 mmHG
• Reduction of DBP by 5-10 mmHG
• Increase in LV diameter
• Thickening of ventricular walls
• Higher VO2 Max

65
Acute Effects of Isometric Exercise

• Dramatic Increase in Systolic and Diastolic Blood
  Pressure
• Increased CO due to Increase HR
• Increased TPR due to compression of blood vessels
  in exercising muscle
• Increase of SBP to 200-300 mmHG have been observed

66
Chronic Effects of Isometric Exercises

• Concentric LVH
• Decreased CO
• Diastolic Function remains preserved
• No long term effect on BP

67
Searching for an answer

• Lifestyle interventions
• Exercise
• Weight Reduction
• Sodium restriction
• Alcohol restriction
• Relaxation Techniques

68
The Devils in the Details

• For people with labile or mild hypertension,
  review whether they are using any natural or
  herbal supplements
• Ephedrine is a frequent ingredient in power or
  anti-allergy supplements and this may increase
  BP
• Check for use of anabolic steroids, particularly
  in an adolescent population

69
In Support of Exercise

• Multiple studies have confirmed that exercise
  decreases SBP and DBP as an independent variable
• Unfortunately, this change lasts only as long as
  the subject continues to exercise with return to
  baseline over the course of 3-6 months of
  inactivity.

70
Mechanism of Effect

• Decreased sympathetic tone
• direct measurement of efferent postganglionic
  muscle sympathetic nerve activity before and
  after a 10 week endurance training activity
  showed a reduction in sympathetic nerve activity.
• Reduction in Renin-Angiotensin Activity
• Baroreceptor Sensitivity
• Changes in myogenic structure

71
Which Exercises are Effective

• Endurance exercise activities have proven to be
  most effective in reducing hypertension
• Three sessions per week
• Little further decrease in BP with workout
  frequency of 5-7 day per week
• Duration from 30 - 90 minutes
• 50-60 minutes most effective

72
Which Exercises are Effective

• 40 - 60 of VO2 Max shown to be most effective
• Actually had a better response than those who
  exercised at gt60 of VO2 Max
• Involvement of large muscle groups through
  activities such as walking, jogging, cycling, and
  swimming

73
Which Exercises are Effective

• Circuit training is also felt to be effective in
  lowering BP
• Work loads should be between 40-50 of RM
• 1 to 2 sets of each exercise with 1 minute rest
  between sets
• 8-10 repetitions per set
• Avoid holding breath (valsalva) during weight
  training
• Some feel that data is inconclusive at this time

74
Review of stages of Hypertension

• High Normal BP
• Systolic BP 130-139
• Diastolic BP 85-89
• Mild (Stage I)
• Systolic BP 140-159
• Diastolic BP 90-99
• Moderate (stage II)
• Systolic BP 160-179
• Diastolic BP 100-109

• Severe (stage III)
• Systolic BP 180-209
• Diastolic BP 110-119
• Very Severe (stage IV)
• Systolic gt210
• Diastolic gt120

75
Exercise Prescriptions

• For People with Pre-Hypertension and Stage I
  Hypertension
• Dynamic exercises safe and effective as a first
  line attempt at controlling blood pressure
• Work at 40-60 of VO2 Max for 50-60 minutes three
  times a week
• May need to start at a shorter time and increase
  to 50-60 minutes over a few weeks

76
Exercise Prescriptions

• Combine with other lifestyle modifications
• Monitor blood pressure response over the next 2
  months and institute other therapy options as
  warranted
• Avoid isometric activities

77
Exercise Prescriptions

• For people with Stage II hypertension
• Exercise can be used as an adjunct to
  pharmacological therapy
• Make sure blood pressure is controlled prior to
  instituting an exercise regimen

78
Exercise Prescriptions

• Once an exercise program has been instituted,
  monitor response regularly as the dose of
  antihypertensive medications may be able to be
  decreased
• Again, avoid isometric exercises but dynamic
  exercises have been proven to be safe

79
Pharmacotherapy

• There are many classes of medications which are
  used on a regular basis to treat hypertension and
  other cardiovascular conditions
• All of these medications can have an effect on
  the exercise response

80
Pharmacotherapy

• Diuretics
• Medications which act directly upon the kidney to
  lead to an increased volume loss (diureses)
• Diuretic therapy allows a near normal cardiac
  response to exercise
• Acutely, there is a decreased plasma volume --gt
  decreased SV --gt decreased CO and therefore
  decrease BP without any effect on TPR
• Short term use decreases maximal exercise
  performance and endurance

81
Pharmacotherapy

• Diuretics (continued)
• Need to watch for electrolyte imbalances which
  may lead to cramping, rhabdomyolysis (due to
  hypokalemia), or cardiac arrhythmias
• Not recommended for endurance athletes who are
  prone to dehydration
• Should be avoided in adolescent athletes as
  hypertension in this group generally due to
  increased sympathetic tone

82
Pharmacotherapy - Diuretics

• Diuretics are generally inexpensive and well
  tolerated
• Can increase triglyceride levels and interfere
  with glucose lowering medication

83
Pharmacotherapy - Diuretics

• Thiazide Type
• Chlorothiazide (Diuril)
• Hydrochlorothiazide (HCTZ)
• Chlorthalidone (Hygroton)
• Metolazone (Zaroxolyn)
• Carbonic Anhydrase Inhibitor
• Acetazolamide ( Diamox)

• Loop
• Furosemide (Lasix)
• Bumex ( Bumetanide)
• Torsemide (Demadex)
• Potassium Sparing
• Amiloride ( Midamor)
• Spironolactone (Aldactone)
• Triamterene (Dyrenium)

Many times, different types are combined into one
pill
84
Pharmacotherapy

• Central Alpha Agonists
• Act centrally to block sympathetic stimulation
  leading to decreased plasma norepinephrine at
  rest and during exercise
• Can blunt the sympathetic response during
  exercise
• CO normalizes with chronic use allowing for
  normal cardiac response to exercise

85
Pharmacotherapy

• Central alpha agonists (continued)
• Excellent choice for young athletes as
  hypertension often due to increased sympathetic
  tone
• Should be avoided in older patients as confusion
  can result
• Side effects include sedation, dry mouth, and
  depression

86
Pharmacotherapy

• Central alpha agonists (continued)
• Clonidine (Catapres)
• PO
• Transdermal patch
• guanabenz (Wytensin)
• guanfacine (Tenex)
• methyldopa (Aldomet)

87
Pharmacotherapy

• Alpha1-receptor blockers
• Decrease TPR by blocking postsynaptic alpha1
  arteriolar smooth muscle receptors
• Allows for a normal physiologic response to
  exercise
• Reduces afterload

88
Pharmacotherapy

• Alpha1-receptor blockers (Continued)
• Good choice for those involved with isometric
  activities
• Can be used as an adjunct to nitrates in patients
  with heart failure
• Frequently used in older men with Benign
  Prostatic Hypertrophy (BPH)
• Orthostatic hypotension is a frequent
  complication

89
Pharmacotherapy

• Alpha1-receptor blockers (Continued)
• Prazosin (Minipress)
• Terazosin (Hytrin)
• Doxazosin (Cardura)

90
Pharmacotherapy

• Beta-Blockers
• Reduce Cardiac Output without effecting TPR (mild
  initial increase returns to baseline)
• Useful in patients with
• ASCVD
• Increases exercise duration without anginal
  symptoms
• fewer incidents of ST-segment depression
• Hypertensive subjects with an excessive response
  to exercise
• Intermittent exertion sports

91
Pharmacotherapy

• Beta-Blockers (continued)
• Leads to an impairment of exercise tolerance in
  individuals without ASCVD
• Blunts decrease in LDL cholesterol and increase
  in HDL cholesterol generally associated with
  exercise
• Associated with and increase in serum K
• Avoided in patients with susceptibility to
  reactive airway disease

92
Pharmacotherapy

• Beta-Blockers (continued)
• Muscle glycogenolysis decreased causing
  hypoglycemia with endurance events
• Use of free fatty acids impaired
• Can impair thermoregulation
• Increased muscle fatigue early on in therapy
• Impotence

93
Pharmacotherapy

• Beta-Blockers (continued)
• Non-selective beta-blockers relatively
  contraindicated in athletes
• Cardioselective beta-blockers are slightly better
  tolerated but still dramatically blunt exercise
  response
• Beta-blockers with intrinsic sympathomimetic
  activity (ISA) thought to be the best tolerated
  with a decreased effect on heart rate and TPR

94
Pharmacotherapy
Beta-Blocking Agents by Cardioselectivity and ISA

• Cardioselective
• Atenolol (Tenormin)
• Metoprolol (Lopressor)
• Carteolol (Cartrol)
• Penbutolol (Levatol)
• Betaxolol (Kerlone)
• Bisoprolol (Zebeta)
• With ISA
• Acebutolol (Sectral)

• Noncardioselective
• Nadolol (Corgard)
• Propranolol (Inderal)
• Carvedilol (Coreg)
• Sotalol (Sotacor)
• Timolol (Blocadren)
• With ISA
• Alprenolol (Aptin)
• Oxprenolol (Trasicor)
• Pindolol (Visken)

95
Pharmacotherapy

• ACE Inhibitors and ARBs
• Angiotensin Converting Enzyme (ACE) inhibitor and
  Angiotensin Receptor Blockers
• ACE produced by lung tissue
• Drug of choice in many athletes as it has the
  lowest incidence of side effects
• Does not impair hemodynamic response to exercise
• Decreases TPR

96
Pharmacotherapy

• ACE Inhibitors and ARBs (continued)
• Mechanism of action
• Angiotensinogen converted to angiotensinogen I
• Conversion of angiotensinogen I to
  angiotensinogen II by angiotensin converting
  enzyme (ACE) inhibited
• Angiotensinogen II is a potent vasoconstrictor
  and leads to production of aldosterone which
  leads to increased blood volume

97
Pharmacotherapy

• ACE Inhibitors and ARBs (continued)
• Need to watch for interactions with NSAIDs and
  hyperkalemia with theses classes of medications
  (i.e. Avoid additional potassium replacement in
  fluids)
• Reports of postural hypotension in athletes
  following intense endurance exercises.
• Most frequent side-effect is a chronic cough
• Not found with ARBs

98
Pharmacotherapy

• Examples of ACE inhibitors
• Captopril (Capoten)
• Enalapril (Vasotec)
• Lisinopril (Prinivil/Zestril)
• Fosinopril (Monopril)
• Benazepril ( Lotensin)
• Ramipril (Altace)

• Examples of ARBs
• Losartan (Cozaar)
• Irbesartan (Avapro)
• Telmisartan (Micardis)
• Candesartan (Atacand)
• Olmesartan (Benicar)
• Valsartan (Diovan)
• Eposartan (Teveten)

99
Pharmacotherapy

• Calcium Channel Blockers
• Decrease TPR by reducing Ca concentrations in
  smooth muscle causing vasodilation
• Decreases HR by decreasing AV conduction but SV
  increases so CO maintained
• Generally allow for a normal physiologic response
  to exercise

100
Pharmacotherapy

• Calcium Channel Blockers (continued)
• No decrease in maximal aerobic capacity noted
• Extend cool down period as can get orthostatic
  from fluid pooling in LEs
• Most frequent side effects
• Reflex tachycardia
• Pedal edema
• Constipation
• Headache

101
Pharmacotherapy - Ca Channel Blockers

• Dihydropyridines
• Nifedipine (Procardia)
• Amlodipine (Norvasc)
• Felodipine (Plendil)
• Isradipine (DynaCirc)
• Nicardipine (Cardene)
• Nimodipine (Nimotop)
• Nisoldipine (Sular)

• Phenylalkylamines
• Verapamil (Calan/Isoptin)
• Benzothiazepines
• Diltiazem (Cardizem)

102
Hypertension Recap

• Dynamic exercise has been proven to reduce SBP by
  7-12 mmHg and DBP by 5-10mmHG
• This effect is independent of weight loss, body
  fat percentage, age, sex, dietary changes, or race

103
Hypertension Recap

• A dynamic exercise regimen involving large muscle
  groups 3 times a week for 50-60 minutes at 40-60
  VO2 Max has been shown to be the most effective
  at controlling hypertension
• Use antihypertensive medications appropriately
  when necessary

104
Hypertension Recap

• The benefits of exercise last only as long as
  people continue to exercise with return to
  baseline blood pressure responses over 3-6 months.

105
Hypercholesterolemia
106
Cholesterol

• A direct relationship exists between elevated
  total cholesterol levels and cardiovascular risk
• Cholesterol plays an important role in cell
  membrane structure and cellular communication
• Act to shuttle lipids through the plasma

107
Major Classes of Lipoproteins

• Triglycerides
• VLDL -Very low density lipid
• IDL - Intermediate density lipid
• Chylomicrons
• LDL - Low density lipid
• Bad cholesterol
• Transfers lipids from liver to periphery
• HDL - High density lipid
• Good cholesterol
• Transfers lipids from periphery to liver

108
(No Transcript)
109
Cholesterol

• When we get a lipid profile we look at
• Total Cholesterol
• LDL
• HDL
• Triglycerides

110
Adult Treatment Panel III (ATP III) Guidelines

• National Cholesterol Education Program

111
Focus on Multiple Risk Factors

• Diabetes CHD risk equivalent
• Framingham projections of 10-year CHD risk
• Identify certain patients with multiple risk
  factors for more intensive treatment
• Multiple metabolic risk factors (metabolic
  syndrome)
• Intensified therapeutic lifestyle changes

112
Modification of Lipid and Lipoprotein
Classification

• LDL cholesterol lt100 mg/dLoptimal
• HDL cholesterol gt40 mg/dL
• The higher the better
• Categorical risk factor
• Lower triglyceride classification cut points
• More attention to moderate elevations

113
Recommendation for Screening/Detection

• Complete lipoprotein profile preferred
• Fasting total cholesterol, LDL, HDL,
  triglycerides
• Secondary option
• Non-fasting total cholesterol and HDL
• Proceed to lipoprotein profile if TC ?200 mg/dL
  or HDL lt40 mg/dL

114
More Intensive Lifestyle Intervention
(Therapeutic Lifestyle Changes TLC)

• Therapeutic diet lowers saturated fat and
  cholesterol intakes to levels of previous Step II
• Adds dietary options to enhance LDL lowering
• Plant stanols/sterols (2 g/d)
• Viscous (soluble) fiber (1025 g/d)
• Increased emphasis on weight management and
  physical activity

115
Cost-Effectiveness Issues

• Therapeutic lifestyle changes (TLC)
• Most cost-effective therapy
• Drug therapy
• Dominant factor affecting costs
• Cost effectiveness one factor in the decision
  for drug therapy
• Declining price of drugs increases cost
  effectiveness

116
CHD Risk Equivalents

• Other clinical forms of atherosclerotic disease
  (peripheral arterial disease, abdominal aortic
  aneurysm, and symptomatic carotid artery disease)
• Diabetes
• Multiple risk factors that confer a 10-year risk
  for CHD gt20

117
Three Categories of Risk that Modify
LDL-Cholesterol Goals

• Risk Category
• CHD and CHD riskequivalents
• Multiple (2) risk factors
• Zero to one risk factor

• LDL Goal (mg/dL)
• lt100
• lt130
• lt160

118
ATP III Lipid and Lipoprotein Classification

• LDL Cholesterol (mg/dL)
• lt100 Optimal
• 100129 Near optimal/above optimal
• 130159 Borderline high
• 160189 High
• ?190 Very high

119
ATP III Lipid and Lipoprotein Classification
(continued)

• HDL Cholesterol (mg/dL)
• lt40 Low
• ?60 High

120
ATP III Lipid and Lipoprotein Classification
(continued)

• Total Cholesterol (mg/dL)
• lt200 Desirable
• 200239 Borderline high
• ?240 High

121
Causes of Secondary Dyslipidemia

• Diabetes
• Hypothyroidism
• Obstructive liver disease
• Chronic renal failure
• Drugs that raise LDL cholesterol and lower HDL
  cholesterol (progestins, anabolic steroids, and
  corticosteroids)

122
LDL Cholesterol Goals and Cutpoints for
Therapeutic Lifestyle Changes (TLC)and Drug
Therapy in Different Risk Categories
123
Benefit Beyond LDL Lowering The Metabolic
Syndrome as a Secondary Target of Therapy

• General Features of the Metabolic Syndrome
• Abdominal obesity
• Atherogenic dyslipidemia
• Elevated triglycerides
• Small LDL particles
• Low HDL cholesterol
• Raised blood pressure
• Insulin resistance (? glucose intolerance)
• Prothrombotic state
• Proinflammatory state

124
Goals and TreatmentOverview
125
Therapeutic Lifestyle ChangesNutrient
Composition of TLC Diet

• Nutrient Recommended Intake
• Saturated fat Less than 7 of total calories
• Polyunsaturated fat Up to 10 of total calories
• Monounsaturated fat Up to 20 of total calories
• Total fat 2535 of total calories
• Carbohydrate 5060 of total calories
• Fiber 2030 grams per day
• Protein Approximately 15 of total calories
• Cholesterol Less than 200 mg/day
• Total calories (energy) Balance energy intake and
  expenditure to maintain desirable body
  weight/ prevent weight gain

126
A Model of Steps in Therapeutic Lifestyle
Changes (TLC)
Visit N
6 wks
6 wks
Q 4-6 mo
MonitorAdherenceto TLC

• Emphasizereduction insaturated fat
  cholesterol
• Encouragemoderate physicalactivity
• Consider referral toa dietitian

• Reinforce reductionin saturated fat
  andcholesterol
• Consider addingplant stanols/sterols
• Increase fiber intake
• Consider referral toa dietitian

• Initiate Tx forMetabolicSyndrome
• Intensify weightmanagement physical activity
• Consider referral to a dietitian

127
Drug Therapy

• HMG CoA Reductase Inhibitors (Statins)
• Reduce LDL-C 1855 TG 730
• Raise HDL-C 515
• Major side effects
• Myopathy/ myalgias
• Increased liver enzymes
• Contraindications
• Absolute liver disease
• Relative use with certain drugs

128
Pharmacology

• HMG-CoA reductase (Contd)
• HMG-CoA reductase is the rate limiting enzyme in
  cholesterol synthesis. Inhibition of this enzyme
  stimulates LDL receptor synthesis and increased
  uptake of LDL and VLDL
• All work through Cytochrome P450 so need to
  monitor liver function tests and other drug
  levels
• Potential for rhabdomyolysis
• Used for elevated LDL and /- triglycerides

129
HMG CoA Reductase Inhibitors (Statins)

• Statin Dose Range
• Lovastatin (Mevacor, altoprev) 2080 mg
• Pravastatin (Pravachol) 2040 mg
• Simvastatin (zocor) 2080 mg
• Fluvastatin (Lescol) 2080 mg
• Atorvastatin (Lipitor) 1080 mg
• Resuvastatin (Crestor) 5-40 mg
• Baycol recently taken off market 2o to high rate
  of liver failure and death

130
HMG CoA Reductase Inhibitors (Statins)
(continued)

• Demonstrated Therapeutic Benefits
• Reduce major coronary events
• Reduce CHD mortality
• Reduce coronary procedures (PTCA/CABG)
• Reduce stroke
• Reduce total mortality

131
Drug Therapy

• Bile Acid Sequestrants
• Major actions
• Reduce LDL-C 1530
• Raise HDL-C 35
• May increase TG
• Side effects
• GI distress/constipation
• Decreased absorption of other drugs
• Contraindications
• Dysbetalipoproteinemia
• Raised TG (especially gt400 mg/dL)

132
Bile Acid Sequestrants

• Drug Dose Range
• Cholestyramine 416 g
• Colestipol 520 g
• Colesevelam 2.63.8 g

133
Bile Acid Sequestrants (continued)

• Demonstrated Therapeutic Benefits
• Reduce major coronary events
• Reduce CHD mortality

134
Drug Therapy

• Nicotinic Acid
• Major actions
• Lowers LDL-C 525
• Lowers TG 2050
• Raises HDL-C 1535
• Side effects flushing, hyperglycemia,
  hyperuricemia, upper GI distress, hepatotoxicity
• Contraindications liver disease, severe gout,
  peptic ulcer

135
Nicotinic Acid

• Drug Form Dose Range
• Immediate release 1.53 g(crystalline)
• Extended release 12 g
• Sustained release 12 g

136
Nicotinic Acid (continued)

• Demonstrated Therapeutic Benefits
• Reduces major coronary events
• Possible reduction in total mortality

137
Drug Therapy

• Fibric Acids
• Major actions
• Lower LDL-C 520 (with normal TG)
• May raise LDL-C (with high TG)
• Lower TG 2050
• Raise HDL-C 1020
• Side effects dyspepsia, gallstones, myopathy
• Contraindications Severe renal or hepatic disease

138
Fibric Acids

• Drug Dose
• Gemfibrozil (Lopid/Gemcor) 600 mg BID
• Fenofibrate (Tricor) 200 mg QD

139
Fibric Acids (continued)

• Demonstrated Therapeutic Benefits
• Reduce progression of coronary lesions
• Reduce major coronary events

140
Inhibitors of Absorption

• Ezetimibe (Zetia)
• New class of agent
• Inhibits small intestine brush border absorption
• Works in conjunction with other medications to
  lower cholesterol by additional 10
• Allows lower doses of statins thereby reducing
  side-effect profile
• Vytorin ezetimibe simvastatin

141
Patterns of Lipoprotein Elevation
Major elevations in Plasma levels
142
Familial Hyperlipoproteinemia

• Many of these patterns are familial in nature
• Familial lipoprotein lipase deficiency Type I
• Familial apoprotein CII deficiency Type I or 5
• Familial type 3 hyperlipoproteinemia 3,2a,2b,
  or 4
• Familial hypercholesterolemia 2a (rarely 2b)
• Familial hypertriglyceridemia 4 (rarely 5)