1. Shu Wang, MD, PhD
The archiater of Department of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, China. Doctoral supervisor.
Received his master degree in 1994 at Shanghai Second Medical University;
Took his doctor’s degree on Endocrinology at shanghai Jiaotong University school of medicine in 2007;
From the year 2001 to 2003, He took an advanced study in Baylor College of Medicine , America.
Headman, Endocrinology and Metabolism section, Institute of Health Sciences, Shanghai Institutes for Biological Sciences since 2004.
Chief of office, Thyroid disease education project team, Ministry of Health, China since 2009;
Youth member, Endocrinology society of Chinese Medical Association in 2009.
Committee member of Chinese thyroid Association in 2010.

2. The Cardiovascular System in Thyrotoxicosis
Dept. of Endocrinology and Metabolism, Ruijin Hospital,
Shanghai Jiaotong University, School of Medicine
Shanghai, China
Dr. Shu Wang

3. Thyrotoxicosis has important clinical
Thyrotoxicosis is the clinical syndrome of hyperthyroidism resulting from excessive quantities of the thyroid hormones.
Thyrotoxicosis has important clinical
consequences for the cardiovascular systems.
Thyrotoxicosis can increase cardiovascular
morbidity and mortality.
The cause of cardiovascular signs and symptoms by thyrotoxicosis can easily be neglected.
keep
“Thyrotoxicosis”
in mind!
照读。

4. Case 1 Is it an accurate diagnosis ? A 63-year-old female patient
Chest distress ,palpitation behind fatigue,
sweating,weight loss of 1 year
Oral glyceryl trinitrate provided no relief
PE: heart rate:120 beats per minute; arrhythmia
ECG: atrial fibrillation; ST-Tchange
Diagnosis:coronary heart disease;atrial fibrillation
let’s have a short look at the first case: 照读
A 63-year-old female patient，
she has Chest distress ,palpitation behind fatigue,
sweating,weight loss of 1 year.
Taking Oral glyceryl trinitrate [‘glisəril][’trai‘naitreit] has no relief（is not working）
PE shows ：heart rate:120 beats per minute; arrhythmia
And ECG shows atrial fibrillation; ST-Tchange
The diagnosis is coronary heart disease;atrial fibrillation；
Is it an accurate diagnosis？ What is the pathogenesis [.pæθə‘dʒenisis] of atrial fibrillation.
Is it an accurate diagnosis ?

5. The causes of atrial fibrillation
★Thyrotoxicosis
Heart
Alcohol
Drugs
Electric shock
Surgery
......
Atrial Fibrillation
Neurogenic AF
There are many causes of Atrial fibrillation. Basically heart diseases ,but thyrotoxicosis is important one.
Pulmonary disease
Infections

6. thyrotoxicosis induced cardiovascular dysfunction
Atrial fibrillation
Angina pectoris
Sweating
Weight loss
heart rate increased
Thyroid funtion ?
FT3>46.08pmol/L
FT4 67.5pmol/L
TSH＜0.0025μU/L
TRAb>40IU/L
TGAb 14.51IU/L
TPOAb
thyrotoxicosis induced cardiovascular dysfunction
Looking back on the case, the patient’s symptoms and signs should draw attention to its thyroid function.
And the biochemical test confirmed our suspection. It is thyrotoxicosis induced cardiovascular dysfunction.

7. Thyrotoxicosis induced cardiovascular dysfunction
The morbidity of thyrotoxicosis induced cardiovascular dysfunction is about 5％～10％.
Graves disease is the most common cause of thyrotoxicosis accounting for 60% to 90% of cases.
Clinical classification:
1) Hyperthyoidism as an initial cause;
2) Hyperthyoidism as a worsen factor when patient has underlying cardiac disease. 照读

8. Clinical manifestation
Thyrotoxicosis induced cardiovascular dysfunction
Clinical manifestation
Hypermetabolism syndrome:
Weight loss with increased appetite
Warm and sweating
Coarse tremor in extremities,etc.
Cardiac symptoms in an early stage：
Palptations, Exercise intolerance,
Dyspnea on exertion, Tachycardia,etc.
Heart complication：
Atrial fibrillation, Cardiomyopathy, Heart failure, Angina pectoris and Myocardial infarction.
The patient
presents
Sweating
Weight loss
Palpitations
chest distress
Atrial fibrillation
Angina pectoris
The Clinical manifestation is gradual
In early stage， patients have ~~~(照读两点)
In long term，heart complications may occur.

9. Chinese scholars’ consensus NYHA
Thyrotoxicosis induced cardiovascular dysfunction
Chinese scholars’ consensus
NYHA
(New York Heart Association)
Along with hyperthyroidism，One having at least one item of heart abnormality can diagnosed hyperthyroidism heart disease：
①enlarged heart；② Arrhythmias；③ congestive heart failure；④ Angina pectoris and myocardial infarction；
Meanwhile，another factors changing heart functions should be excluded
① Atrial Arrhythmias, enlarged heart or ventricular failure
②Clinical manifestations
and biochemical proof of Hyperthyroidism
③After specific treatment，the above-mentioned can disappear
Diagnostic criteria ?
The criteria from NYHA is ~~~
Chinese scholars’consensus is ~~~
Rarely，young patients with thyrotoxicosis may have chest pain similar in almost all respects to angina pectoris.

10. Types: Arrhythmia type
Thyrotoxicosis induced cardiovascular dysfunction
What type of thyrotoxicosis induced cardiovascular diseases is the patient？
Types: Arrhythmia type
Heart failure type
Cardiomyopathy type

11. The incidence is about 10%~20% hyperthyroidism patients.
Thyrotoxicosis induced cardiovascular dysfunction
Arrhythmia Type
Atrial fibrillation is the most common arrhythmia.
The incidence is about 10%~20% hyperthyroidism patients.
Heart failure Type
Present in 6% of cases. It can be divided into high output failure and pump failure.
Risk factors: Age＞60, long term uncontrolled hyperthyroidism,underlying heart disease and AF .
Cardiomyopathy Type: (rare)
Rate-related cardiomyopathy: Tachycardiainduced cardiomyopathy can cause heart failure, although LVEF usually normalizes after heart rate or rhythm control.
Dilated cardiomyopathy: Associated with Graves disease might have an auto-immune origin.
We divided three types in clinics:
Arrhythmia Type : is the most common arrhythmia,the incidence is about 10%~20% in hyperthyroid patients.
Heart failure type :Present in 6% of cases,it is more likely to happen in those whose age over 60, or with long term uncontrolled hyperthyroidism,or with underlying heart disease and AF.
Cardiomyopathy Tye is quite rare.

12. In patients with hyperthyroidism ：Morbidity of AF is 8.3%
Arch Intern Med. 2004;164:
Here is a population-based study from Denmark about Hyperthyroidism and Risk of Atrial Fibrillation or Flutter.
①：Over 40,000 patients diagnosed hyperthyroidism, (8.3%)were diagnosed atrial fibrillation or flutter.
②：Male sex is a risk factor of Atrial Fibrillation in Hyperthyroidism patients.
③：Age is a remarkable factor，OR is 1.7 ，and the incidence of AF increases with age.
④：Medical conditions especially ischemic heart disease, congestive heart failure, and heart valve disease are closely associated with AF.
In patients with hyperthyroidism ：Morbidity of AF is 8.3%
Male sex, increasing age, ischemic heart disease, congestive heart failure, and heart valve disease are associated with an increased risk of AF

13. It is an investigation from China Hangkang, .
The study enrolled 591 hyperthroidism patients. Congestive heart failure(CHF) as the initial clinical presentation occured in 34 patients (5.8%). Atrial fibrillation (AF) occured in 82 patients(14%).

14. Mechanisms ★ The heart is main target organ of Thyroid Hormone.
Thyrotoxicosis induced cardiovascular dysfunction
Mechanisms
★ The heart is main target organ of Thyroid Hormone.
T3 influence cardiac action by three different routes:
T3 exerts a direct effect on cardiac myocytes;
2) T3 may influence the sensitivity of the sympathetic system;
3) T3 leads to periphery hemodynamic changes. 照读

15. T3 effects on the cardiac myocyte
Genomic nuclear effects:
T3 binds to nuclear thyroid hormone receptors (TRs), combined with recruited cofactors.The complex then bind or release specific sequences of DNA , modifying the rate of transcription of specific cardiac genes.
Non-genomic effects:
T3 direct modulate the transport of ions (calcium, sodium and potassium) across the plasma membrane, glucose and amino acid transport,mitochondrial function and various intracellular signalling pathways.
Slide :
T3 has two direct effects on cardiac myocyte :
Its genomic nuclear effects is that T3 can bind to nuclear thyroid hormone receptors and regulate the rate of transcrition of specific cardiac genes.
For example, The gene for the cardiac-specific calcium ATPase that regulate the sequestration [sikwe‘streiʃən] 螯合作用 of calcium in the sarcoplasmic [’sɑ:kəu.plæzəm] re’ticulum during diastole [dai'æstəli] is regulated by thyroid hormone.
Taken together, these modified genes expression account for the increase in Calcium uptake in the sarcoplasmic reticulum.
Its non-genomic effects is quick and is induced by changes in ion flux.T3 stimulates the Ca+ATPase activity as well as the calcium movement across the membrane, which are due to changes in calcium channels;Also it increase the activity of the cardiac Na/KATPase. 15

16. Regulated cardiac gene as reported
The cardiac myocyte genes regulated by TH is as listed. 16

17. Interactions between THs and the sympathetic system
Some T3 effects are mediated by an increased activity of the sympathetic system or an increased responsiveness and sensitivity of cardiac tissue to normal sympathomimetic stimuli.
The enhanced sympathetic sensitivity of the hyperthyroid heart may be mediated by an increased number of β-adrenergic receptors.
The interactions between Thyroid hormone and sympathoadrenal system is an increased activity,an increased responsiveness and sensitivity.

18. Haemodynamic changes
T3 decreases resistance in peripheral arterioles through a direct effect on VSMC.
①：The decreased mean arterial pressure activates the renin-angiotensinealdosterone(RAS) system, increases renal sodium absorption and preload;
②：The decreased peripheral resisitance leads to an reflexible elevated heart rate, and a declined afterload.
③：T3 has a direct effect on systolic function and contractility by increasing a-major histocompatibility complex (MHC) expression associated with a high contractility state and fast myosin production, and decreasing b-MHC expression, associated with energetic efficiency, economy of force maintenance, and slow myosin production.
All contributes an tremendous elevated cardiac output.

19. T3 SVR decreases membrane ion channels vascular relaxation
vascular smooth muscle cells
nongenomic NO T3
paracrine manner
endothelial
cell NO
genomic
The ability of thyroid hormone to alter vascular smooth muscle cells (VSM) and endothelial cell function are important. Thyroid hormone mediated effects are the result of both genomic and nongenomic actions. In the VSM cell,Nongenomic actions target membrane ion channels and endothelial nitric oxide synthase, which serves to decrease SVR. Relaxation of VSM leads to decreased arterial resistance and pressure, which thereby increases cardiac output. Increased endothelial nitric oxide
production may result, in part, from the T3-mediated effects of TR on the protein kinase akt pathway .Nitric oxide synthesized in endothelial cells then acts in a paracrine manner on adjacent VSM cells to facilitate vascular relaxation.
T3 relaxs vascular smooth muscle cells though regulation of nitric oxide ( NO), and decreases peripheral resistance.

20. LV diastolic dysfunction may involve in the remaining half.
only 50% of hyperthyroidism patients with congestive heart failure have impaired left ventricular (LV) systolic function .
LV diastolic dysfunction may involve in the remaining half.
This slide shows us that only 50% of hyperthyroid patients with congestive heart failure have impaired left ventricular (LV) systolic function.
② The proportion of hyperthyroid patients with diastolic dysfunction increased with age,17.9% in patients <40 years to 100% in those >60 years. ③
In addition，the proportion of those who normalized LV diastolic function decreased in line with increasing age: from 100% in aged <40 years, but only one-third in those aged>60 years.

21. The patient has been confirmed，and how to treat it ？
Thyrotoxicosis induced cardiovascular dysfunction
The patient has been confirmed，and how to treat it ？

22. Management and Treatment
Thyrotoxicosis induced cardiovascular dysfunction
Management and Treatment
Principle:
①Recover the thyroid function as soon as possible.To rapidly reduce the actions of thyroid hormone, ATDs and Radioiodine is recommended;
②Acute treatment of cardiac complications；
Most patients who get immediate control of hyperthyroidism，can self-recover cardiac disorders gradually.
读大字

23. Therapy of atrial fibrillation
Control the thyroid function
About 50% AF in young and new onsets can convert to sinus rhythm after keeping euthyroid for 6~12 months.
Those AF consisting for more than 4 months after euthyroid，Drugs and Electroversion can be considered.
Anticoagulative therapy is recommended in the absence of a specific contraindication, at least until a euthyroid state has been restored and heart failure has been cured.(ACC/AHA)
大体点点红体字

24. Therapy of heart failure
Thyrotoxicosis induced cardiovascular dysfunction
Therapy of heart failure
Control the thyroid function;
(The treatment of HF follows its conventional therapy.）
Expectant treatment: Sedation, oxygen uptaking, sodium limiting，etc.
β-blokers is used to stable the heart rate
Digitalis and Diuretic can effectively relieve heart burden and pulmonary congestion symptoms. However it is hard to restore totally.
Dosage of Digitalis is greater than usual loading and maintenance dosage maybe needed.
The treatment of heart failure follows its conventional therapy.But recover the thyroid function is an important step.

25. Case 2 A 60-year-old male patient Palpitations, fatigue, weakness,
weight loss of 1 month's duration
The patient had been taking amiodarone for 2.5 years for non-sustained ventricular tachycardia episodes.
amiodarone had been discontinued for six months
PE: heart rate:98 beats per minute
what about thyroid function?
Case 2 is a~~~照读。
We tested his thyroid function.It is hyperthroidism. What was the cause then.
laboratory analysis:FT3：20.08pmol/L FT4：44.5pmol/L TSH：0.083U/L
Is it Amiodarone-Induced Thyrotoxicosis?

26. Amiodarone-Induced Thyrotoxicosis(AIT)
The incidence of AIT reported in different studies varies but remains within the range of 5–10% in most studies.
AIT may develop suddenly and early or after many years of treatment, the usual time period is 2–47 months;
AIT may also develop many months after drug withdrawal.
Iodine deficient individuals render more sensitive to exogenous iodine
Risk factors：female sex, complex cyanotic heart disease, previous Fontan type surgery, and a total daily dose above 200 mg
读大体的字

27. Why does Amiodarone can Induce Thyrotoxicosis?
Its intrinsic effects on throid gland are
Blockage of thyroid hormone entry into peripheral tissues.
Inhibition of deiodinase activity and stop T4 to T3 transformation.
Decreased T3 binding to receptors(照读)
failure to escape from Wolff-Chaikoff effect.Iodine induced specific autoimmunity, and unregulated hormone synthesis.（照读）
Iodine-induced effects are
The direct effect on thyroidal cells is due to failure to escape from Wolff-Chaikoff effect.Some of its other effects include precipitation or exacerbation of a pre-existing organ, specific autoimmunity, and unregulated hormone synthesis.

28. ★ Some patients exhibit a mixed pattern
Types
AIT has two types
①Type 1 AIT tends to occur in patients with underlying thyroid autonomy in a nodular goiter, but the term is also used when amiodarone use is associated with GD, whereas type 2 AIT is due to a direct destructive effect of amiodarone on thyrocytes.
②RAIU is occasionally measurable in type 1 AIT (particularly in regions of iodine deficiency), but not in type 2 AIT.
③Increased vascular flow on color-flow Doppler ultrasound study may be seen in patients with type 1 AIT, but not type 2 AIT.
④ Measurement of serum interleukin-6 levels does not reliably distinguish between the two types of AIT .
The distinction between type 1 AIT and type 2 AIT is not always clear, and some patients have elements of both types .
Methimazole should be used to treat type 1 amiodarone-induced thyrotoxicosis and corticosteroids should be used to treat type 2 amiodarone-induced thyrotoxicosis.
★ Some patients exhibit a mixed pattern

29. Is it need for amiodarone discontinuation?
The decision to stop amiodarone in the setting of thyrotoxicosis should be determined on an individual basis in consultation with a cardiologist, based on the presence or absence of effective alternative antiarrhythmic therapy.

30. The need for amiodarone discontinuation is controversial, because :
(1) This drug is frequently the only medication able to control cardiac arrhythmia,
(2) The effects of this fat soluble drug may persist for many months.
(3) Amiodarone may have T3-antagonistic properties and inhibit T4 to T3 conversion, withdrawal Amiodarone may aggravate cardiac manifestations of thyrotoxicosis.
(4) AIT typically resolves even if amiodarone therapy is continued.

31. It is a Randomized Clinical Trial up to date in JCEM.
As we can see:
①All three groups with throtoxisis are taking amiodarone; All are treated with methimazole ；Group A is plus prednision，B is plus perchlorate and C applies both.
②Group A and C treated with prednisone，totally recovered. The 29% failures in group B became euthyroid after addition of prednisone. Recurrent thyrotoxicosis occured in group A and C， when Amiodarone continued. But all became enthyroid after 2 years.
③conclusion：照读
The 29% failures in group B became euthyroid after addition of prednisone.
③Recurrent thyrotoxicosis occured in group A and C， when Amiodarone continued. But all became enthyroid after 2 years.
Conclusion: a:Euthyroidism was reached despite continuation of amiodarone in all patients.
b:Prednisone remains the preferred treatment modality of AIT type 2.
Conclusion:
a: Euthyroidism was reached despite continuation of amiodarone in all patients.
b: Prednisone remains the preferred treatment of AIT type 2.

32. Thyrotoxicosis and Pregnancy
Effects On Cardiovascular hemodynamics are additive
Mother: spontaneous abortion, hyperthyroidism crisis, heart failure, preeclampsia, premature delivery, etc;
Fetus: stillbirth, Growth restriction, goiter, heart failure, etc;
It is more urgent to control thyroid function and monitor heart function.
Pregnant woman with thyrotoxicosis should be more carefully monitored. The effects are additive.β –blockers should be cautiously used.

33. Use β-blocker Cautiously in pregnancy
There is no evidence of teratogenesis following maternal exposure to beta-blockers in the first trimester.
The risk of IUGR associated with maternal use of beta-
blockers exists， use the smallest effective dose (avoiding large doses) and use is limited to the third trimester.
There is also a theoretical risk of neonatal bradycardia, hypotension and hypoglycaemia if beta-blockers are used up to the time of delivery.
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34. Take Home Message
In clinics, the patient's history and thyroid function tests are important. (monitor)
The first step for treating heart complications is hyperthyroidism control. (treatment)
It is important to take risk factors into account, such as age, sex, hyperthyroidism type, underlying health problems. (prevention) 照读

35. Thank you!