1) The document discusses the effects of thyroid hormones on cardiovascular function and how thyroid diseases can impact the cardiovascular system. 2) It describes the cellular mechanisms of thyroid hormone action on the heart and blood vessels as well as changes in thyroid hormone levels that can occur due to conditions like heart attack or heart failure. 3) Both hyperthyroidism and hypothyroidism are associated with changes in cardiovascular hemodynamics and can manifest as various heart conditions or symptoms. Successful treatment of the underlying thyroid abnormality can help reverse many of these cardiovascular impacts.

1. Presenter :
DR. A.B.M. KAMRUL HASAN
MD Final Part (EM)
Bangabandhu Sheikh Mujib Medical University

2. Irwin Klein, MD; Sara Danzi, PhD
Circulation. 2007;116:1725-1735
doi: 0.1161/CIRCULATIONAHA.106.678326

3. Cellular mechanisms of thyroid hormone action
Effects of thyroid hormone on cardiovascular
hemodynamics
Clinical manifestations of thyroid diseases from a
cardiovascular perspective
Changes in thyroid hormone metabolism that arise
from acute MI and chronic congestive heart failure

4.  Classic “feedback” loop mechanism: T4 & T3 regulate
pituitary synthesis and release of TSH
 A highly sensitive TSH assay- initial test
 Suggestion about narrowing TSH reference range
especially upper limit at which hypothyroidism may be
present
 TSH>20 mIU/L: overt hypothyroidism
 TSH 3-20 mIU/L: milder or subclinical hypothyroidism
 Suppressed TSH <0.1 mIU/L: hyperthyroidism

5. Diagnosis ICD-9 Code
Anemia 285.9
Atrial fibrillation 427.31
Hypertension 401.0
Hypercholesterolemia 272.0
Mixed hyperlipidemia 272.4
Diabetes mellitus 250.00
Obesity 278.00
Weight gain 783.1
Weight loss 783.21
Myopathy 359.9

6.  Thyroid gland secrets mainly (≈85%) T4 which is converted to T3 by
5´-monodeiodinase in various tissues
 No significant myocyte intracellular deiodinase activity- the heart
relies mainly on serum T3
 T3 binds to thyroid hormone nuclear receptors (TRs), belongs to
superfamily of steroid hormone receptors
 TRs bind to thyroid hormone response elements (TREs) in the
promoter region of positively regulated genes → mediate induction
of transcription
 TRs bind to TREs in the absence as well as in the presence of
ligand
 While bound to T3, TRs induce transcription, and in the
absence of T3 they repress the transcription

7.  Occur rapidly, do not involve TRE-mediated transcriptional
events
 Changes in various membrane ion channels for Na, K & Ca
 Effects on:
 Actin polymerization
 Adenine nucleotide translocator 1 in mitochondrial
membrane
 Variety of intracellular signaling pathways in heart &
vascular smooth muscle

8. Positively Regulated Negatively Regulated
α-Myosin heavy chain β-Myosin heavy chain
Sarcoplasmic reticulum Ca2+-ATPase Phospholamban
Na+ / K+ -ATPase Adenylyl cyclase catalytic
subunit
β1- Adrenergic receptor Thyroid hormone receptor α1
Atrial natriuretic hormone Na+ / Ca2+ exchanger
Voltage-gated potassium channels
(Kv1.5, Kv4.2, Kv4.3)

11.  Expression of both structural & regulatory genes in cardiac
myocyte
 ↑ T3 → cardiac hypertrophy, mainly due to ↑ hemodynamic load
 Hyperthyroidism resembles hyperadrenergic state: no evidence to
suggest ↑TH enhance cardiac sensitivity to adrenergic stimulation
 Serum catecholamines low or normal
 Several components of cardiac myocyte β adrenergic system are
regulated by thyroid hormones:
 β1 adrenergic receptors are positively regulated
 Guanine nucleotide regulatory proteins
 Adenylate cyclase

12.  TRα1 receptors are negatively regulated
 Pacemaker-related genes, hyperpolarization-activated cyclic
nucleotide-gated channels 2 & 4 are transcriptionally regulated by
thyroid hormones
 β-adrenergic receptor stimulation → ↑cAMP → accelerates
diastolic depolarization → ↑ HR
 Hyperthyroidism → AF; may be due to combination of genomic &
nongenomic actions on atrial ion channels plus atrial enlargement
 β-adrenergic blockade: ↓HR, enhanced diastolic performance is
not altered (indicating that T3 acts directly on the heart to increase
calcium cycling)

13.  BP is altered across the entire spectrum of thyroid function
 Changes are similar to physiological response to exercise
 Hyperthyroidism:
 Widened pulse pressure
 Increased arterial stiffness
 Low SVR →Isolated Systolic HTN
 Hypothyroidism:
 Endothelial dysfunction
 Impaired VSM relaxation → ↑SVR → Diastolic HTN

14.  High prevalence of Pulmonary HTN & AV valve regurgitation in
hyperthyroidism
 Effect of TH to ↓SVR may not occur in pulmonary vasculature
 Primary pulmonary HTN (Pulmonary Artery Pressure >25 mmHg at
rest & >30 mmHg during exercise):
• Often unknown origin
• A link to thyroid disease (both hyper- & hypothyroidism) has
been identified
• Thyroid disease should be considered in DD of Primary
pulmonary HTN

15. ↓ Fractional
clearance of LDL
by liver:
• ↓ No. of LDL
receptors
• ↓ LDL receptor
activity
↓ Catabolism of
cholesterol into
bile
• T3 negatively
regulates liver
specific enzyme
cholesterol 7α-
hydroxylase
Overt
Hypothyroidism:
• Hypercholesterolemia
• Marked ↑ LDL &
Apolipoprotein B
• Changes are also
evident in subclinical
hypothyroidism
90% of hypothyroid patients had hypercholesterolemia
Prevalence of overt hypothyroidism in patients with hypercholesterolemia
is 1.3-2.8%

16. Palpitations Anginal chest pain
Exercise intolerance Atrial fibrillation
Exertional dyspnea Cardiac hypertrophy
Systolic hypertension Peripheral edema
Hyperdynamic circulation Congestive heart failure
Cardiac output increased by 50-300% of normal: combined effect of
increased resting HR, contractility, blood volume & EF with a decrease in
SVR
Cerebrovascular ischemic symptoms has been reported in young patients
with Graves’ disease
Routine TSH in cardiac & cerebral ischemic symptoms

17.  Prevalence: 2-20%, ↑ with age (≈15% in patients >70 yrs)
 40,628 patients in the Danish National Registry:
• 8.3% developed AF
• Male gender, ischemic or valvular heart disease or CHF
increased risk
 Subclinical hyperthyroidism carry same relative risk
 In unselected patients who present with AF, <1% were the result
of overt hyperthyroidism
 Ability to restore thyrotoxic patients to a euthyroid state & sinus
rhythm justifies TSH testing in new onset AF

18.  β-adrenergic blockade: by β1-selective or nonselective agent
 Rapid restoration of chemical euthyroid state: ATD or
Radioiodine
 Digitalis:
• ↑rate of digitalis clearance, ↓sensitivity of hyperthyroid heart
• Needs higher dose with less predictable response
 Calcium channel blockers: sp. parenteral, should be avoided
• Through effects on the smooth muscle cells of the resistance
arterioles, may lead to acute hypotension & CV collapse

19.  Risk for systemic embolization is not precisely known
 Advancing AGE rather than presence of AF was major risk factor
 Review of large series of patients failed to demonstrate a
prevalence of thromboembolic events greater than the risk
reported for major bleeding events from warfarin therapy
 In younger patients with hyperthyroidism, in absence of other
independent risk factors for embolization, the benefits of
anticoagulation may be outweighed by the risk
 Aspirin reduces risk for embolic events and safe alternative

20.  Majority revert to sinus rhythm within 2-3 months of successful
treatment with ATD or RI
 Older (>60 yrs) with AF of longer duration less likely to revert
• If AF persists after chemical euthyroidism is achieved,
electrical or pharmacological cardioversion should be
attempted
• Majority can be restored to sinus rhythm & will remain so for a
prolonged period of time
• Addition of Disopyramide (300mg/d) lets such patents to
maintain sinus rhythm

21.  Paradoxical finding- ?high-output failure, does not accurately apply
 Exaggerated sinus tachycardia or AF can produce LV dysfunction
& HF
 Preexistent ischemic or hypertensive heart disease
 Mitral valve prolapse: increased incidence, causing LA
enlargement & AF
 High prevalence of pulmonary artery HTN: some similar signs
 Exercise intolerance & Exertional dyspnea: may be due to
↓pulmonary compliance or ↓respiratory & skeletal muscle function

22.  Common CV signs & symptoms are:
Bradycardia
Mild hypertension (diastolic)
Narrowed pulse pressure
Cold intolerance
Fatigue

23.  ↓Expression of Sarcoplasmic reticulum Ca2+-ATPase
 ↑Expression of Phospholamban (inhibitor of SR Ca2+-ATPase)
 Slowing of the isovolumic relaxation phase of diastolic function

24. Effect
• Impaired cardiac contractility & diastolic function
• Increased systemic vascular resistance
• Decreased endothelial derived relaxation factor
• Increased serum cholesterol
• Increased C-reactive protein
• Increased homocysteine
Diastolic HTN
• Accelerated atherosclerosis
• Increased risk of CAD
• Increased risk of stroke
RESULTS
IN
• Prolongation of QT interval → Ventricular arrhythmias
• Protein rich pericardial and/or pleural effusion

25.  Poses some challenge
 In young healthy patients: full replacement dose of L-thyroxine of
1.6 µg/kg/d can be initiated at the outset
 In older patients: start low (25 to 50 µg/d) and go slow (increase
the dose no more rapidly than every 6 to 8 weeks)
 A predictable improvement in thyroid and CV functional measures
 Concerns that restoration of the heart to a euthyroid state might
adversely affect underlying ischemic heart disease are largely
unfounded
 Patients with atherosclerotic cardiovascular disease more often
improve, rather than worsen, with treatment

26.  Low or undetectable serum TSH with normal T4 & T3
 May have no clinical signs or symptoms
 Prevalence increase with age
 Low TSH is associated with increased risk for CV mortality & AF
 Treatment is controversial
 Older patients with MNG or GD: should be treated especially if
they are deemed to be at risk for cardiovascular disease

27.  Affects 7-10% of older women
 Frequently asymptomatic but many have symptoms of hypo
 ↑Cholesterol & CRP
 Risk of atherosclerosis, CAD & MI increased
 The benefits of the restoration of TSH levels to normal can be
considered to outweigh the risks

28.  The low T3 syndrome: a fall in serum T3 accompanied by
normal serum T4 and TSH levels
 Results from impaired hepatic conversion of T4 to the biologically
active hormone, T3, by 5´-monodeiodinase
 The cardiac myocyte has no appreciable deiodinase activity and
therefore relies on the plasma as the source of T3
 In experimental animals the low T3 syndrome leads to the same
changes in cardiac function and gene expression as does
primary hypothyroidism.
 Significant similarities exist between the hypothyroid phenotype
and the HF phenotype (↓cardiac contractility & cardiac output, &
an altered gene expression profile)

29.  ≈30% of patients with CHF have low T3 levels
 Reduction of T3 is proportional to the severity of HF
 Reduced serum T3 is a strong predictor of all-cause and CV
mortality and, in fact, is a stronger predictor than age, LV EF, or
dyslipidemia
 It has been suggested that T3 therapy might improve cardiac
function in this clinical situation

30.  Antiarrhythmic drug with a high iodine content (75mg iodine/200mg)
 Can cause either hypothyroidism (5% to 25% of treated patients) or
hyperthyroidism (2% to 10% of treated patients)
 Inhibits of 5´-deiodinase activity → Inhibits conversion of T4 to T3
 Iodine released from amiodarone metabolism directly inhibit thyroid
gland function, if the effect persists, lead to amiodarone-induced
hypothyroidism
 Preexistent thyroid disease and Hashimoto’s thyroiditis ↑ risk
 If hypothyroidism develop with a persistent rise in TSH: L-thyroxine
therapy started

31.  Type 1 hyperthyroidism:
• iodine-induced excess thyroid hormone synthesis
• underlying thyroid disorder, e.g., nodular goiter or latent GD
• in regions where iodine intake is low
 Type 2 hyperthyroidism:
• thyroiditis due to a direct cytotoxic effect of amiodarone →↑release of
thyroid hormones → transient thyrotoxicosis in a previously normal
thyroid gland
 Can overlap & difficult to distinguish, RIU is low in both types
 Point favors Type 2 hyperthyroidism: Signs of inflammation, elevated ESR
& IL-6, modest increases in thyroid gland size

32.  ATDs effective in type 1, ineffective in type 2 thyrotoxicosis.
 Prednisolone is beneficial in the type 2 form
 Beta blocker should be started
 A pragmatic approach is to commence combination therapy with an
ATD and glucocorticoid in patients with significant thyrotoxicosis
 A rapid response (within 1–2 weeks) usually indicates a type 2 picture
and permits withdrawal of the antithyroid therapy
 A slower response suggests a type 1 picture, when antithyroid drugs
may be continued and prednisolone withdrawn.
 Potassium perchlorate can be used to inhibit iodine trapping in thyroid

33.  If the cardiac state allows, amiodarone should be discontinued
 The course of the disease may last for anywhere between 1 to 3
months
 In rare cases, surgical thyroidectomy under local anesthesia has
proven to be effective
 To minimize the risk of type 1 thyrotoxicosis, thyroid function should
be measured in all patients prior to commencement of amiodarone
therapy, and amiodarone should be avoided if TSH is suppressed
 In general, patients treated with amiodarone should have thyroid
function (specifically TSH) testing periodically throughout therapy

34.  Thyroid dysfunction (both hypo & hyper) virtually affects the
whole spectrum of cardiovascular hemodynamics
 Thyroid functional abnormality can case a range of
cardiovascular signs-symptoms and cardiovascular
diseases are also associated with derangement of thyroid
functions
 Restoration of normal thyroid function most often reverses
the abnormal cardiovascular hemodynamics

35.  Prof. Md. Farid Uddin
Chairman, Department of Endocrinology, BSMMU
 Prof. M.A. Hasanat
Department of Endocrinology, BSMMU
 All the colleagues of my department