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CONTINUING EDUCATION IN TOXICOLOGIC PATHOLOGY
RESPIRATORY AND CARDIOVASCULAR SYSTEM
ORGANIZED BY
SOCIETY OF TOXICOLOGIC PATHOLOGY - INDIA (STP-I)
NOVEMBER 1-3, 2012
The Atria Hotel, # 1, Palace Road, Bangalore - 560 001
Cardiac dilatation, myocardial
hypertrophy and atrophy
Peter Greaves & C Gopinath
STPI- Nov 2012
Venticular hypertrophy
RV hypertrophy and ventricular
dilation
Cardiac plasticity
Remodels in response to demand Physiological growth
exercise, pregnancy, postnatal growth
Hypertrophic growth Neuro-humoral activation, hypertension, myocardial injury
increases risk of heart failure and malignant arrhythmia
Atrophy protracted bed rest, prolonged weightlessness or
mechanical unloading
Pathological versus physiological or adaptive?
Adverse versus non-adverse?
Do all forms of cardiac hypertrophy have
adverse implications?
Cardiac plasticity
Ideas about cardiac size:
Athlete’s heart, soldier’s heart, effort syndrome, cardiac fatigue
Trained athletes heart weights can increase by 60%
Bed rest for 12 weeks can reduce heart weight by 15% in normal subjects
Applies to race horses and dogs
Remodelling of the Heart
Hill J, Olson E. N Engl J Med 2008;358:1370-1380
?
?
Limits of Cardiac Atrophy and Hypertrophy
Hill J, Olson E. N Engl J Med 2008;358:1370-1380
Normal human heart
Right atrium
Left atrium
Right
ventricle
Left ventricle
Apex
Anterior sulcus
& anterior descending
artery
Brown atrophy
Normal heart 300 g
Brown atrophy:125 g
Brown atrophy
PAS stain – lipofuscin granules
Simple hypertrophy
Left ventricular hypertrophy
Normal & right ventricular hypertrophy
Left & right ventricular hypertrophy
Hypertension Chronic obstructive airways
disease
Rheumatic valve disease
Rheumatic valve disease
Rheumatic valve disease
Myocardial infarction – old
Farrer-Brown 1977
Myocardial infarction - old
Acromegaly
Normal heart 300 g
Heart weight:1240 g.
Primary cardiomyopathy
1/500 of population
50% with family history
Many mutations
e.g. β-myosin heavy chain
cardiac troponin C
Myosin binding protein C
Primary cardiomyopathy
Primary cardiomyopathy
Cardiac plasticity
Highly trained marathon runner aged 57
Died during marathon race
Heart weight high (480g – average 300g)
Thickness of left ventricular wall 19-20 mm
Hypertrophy of papillary muscle and trabeculae
Reduced size of left ventricular cavity
Whyte et al. BJSM, 2008;42, 304-5
Long term consequences of
‘physiological’ cardiac hypertrophy
(Pelliccia et al. J Am Coll Cardiol 55, 1619, 2010)
• 114 Olympic athletes followed up
• Long term endurance training
– Increased ventricular dimensions
(echocardiography)
• No deterioration of cardiac function over
periods of up to 17 years (mean 8.6±3
years
Cyclist
LV thickness =
13 mm in both
Mild hypertrophic
cardiomyopathy
Rawlins et al
Eur J Echocard
(2009) 10,
350–356
Cellular Events Triggered by Altered Workload
Hill J, Olson E. N Engl J Med 2008;358:1370-1380
Physiological Pathological
Limited LV wall thickness
(up to 1.3 cm in humans)
No collagen, rapidly
reversible
LV wall thickness may be
greater than 1.3 cm
Interstitial collagen present
Different isoforms of α and β myosin heavy chains
Down regulation of
hypertrophy genes
-
Different patterns of gene expression α-skeletal actin, β-
myosin & endoplasmic reticulum Ca2+-ATPase
Hill J, Olson E. N Engl J Med 2008;358:1370-1380
Drugs associated with heart weight
changes – pharmacodynamic causes
• Increases
– Cardiovascular agents
• Catecholamines, vasodilators, vasoconstrictors (e.g. egotamine),
inotropes, calcium channel blockers, modifiers of cardiac
metabolism (e.g. troglitazone, oxfenicine)
– Hormones
• Thyroxine, growth hormone, anabolic steroids, recombinant
epidermal growth factor
Environmental- Arsenic in water Heart disease and hypertrophy in
areas and experimentally in mice
• Decreases
– ACE inhibitors, atriopeptin III
– Food restriction • Absolute heart weight and increase in fibre size (Burkhardt et al Tox Pathol 24, 636,
1996
Mycardial hypertrophy
Isomazol 1 year dog study (males)
Positive inotrope + vasodilator
Dose
mg/kg
Body
weight g
Rel. heart
weight
Cardiac
fibrosis
0 9.3 ± 0.82 0.82 ± 0.05 0/4
2 8.9 ± 0.39 0.92 ± 0.05 0/4
6 9.3 ± 0.61 0.83 ± 0.02 0/4
16 9.3 ± 0.79 1.29 ± 0.21 * 2/4
Means et al 13, 418-428, 1989
Prizidilol 2 year rat study heart weights (males)
β adrenoceptor blocker + vasodilator
Dose mg/kg Mean body
weight (g)
Mean heart
weight (g)
Relative
heart
weight (%)
0 509 1.31 0.257
100 520 1.37 0.263
400 519 1.52 0.293
1600* 405 1.86 0.459
* Increased mortality at this dose
Sutton et al Hum Toxicol 5, 183-187, 1986
Inhibitors of long chain fatty acid metabolism
• Oxfenidine
– Indicated for ischaemic heart disease
– Cardiac enlargement in dogs and rats
• McNeil 3716
– Indicated for diabetes mellitus
– Produced enlarged hearts in rats
Oxfenicine (S-4-hydroxyphenylglycine)
• Cardioselective inhibitor of long-chain
fatty acid oxidation + stimulator of
glucose oxidation
› decreases oxygen cost of cardiac work
› increases myocardial blood flow
› reduces enzyme release from ischaemic dog
heart
› myocardial hypertrophy in dogs and rats
› no arteritis induced at high dose toxicity
studies
Hypertrophy oxfenicine 12 month dog study Greaves et al. Arch Toxicol suppl 7
488, 1984
Oxfenicine – dog heart
Oxfenicine - rat heart
Oxfenicine - rat heart
McNeil 3716
• Enlarged hearts in rats were flabby,
discoloured with dilated ventricles
• Myocardial lipid increased
• Biochemical evidence of damage to inner
mitochondrial membrane
(Bachmann et al., Biochemical Pharmacology 33, 1947-1950, 1984)
Direct acting cardiac toxicity
BMY-25282 (mitomycin C derivative)
Heart weights increased in 5 week rat study: 1 dose/week
Bregman et al Fund Appl Toxicol 9, 90-109, 1987
Summary
Heart remodels in response to demand Physiological growth - benign
exercise, pregnancy, postnatal growth
no concurrent cardiac pathology
Hypertrophic growth – pathological neuro-humoral activation, hypertension, myocardial injury
increases the risk of heart failure and malignant arrhythmia
Atrophy - benign or pathological protracted bed rest, prolonged weightlessness or mechanical
unloading
Distinction between physiological an pathological changes requires careful evaluation
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