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