Thyroid Disease and the HeartIrwin Klein, MD
Professor of Medicine and Cell BiologyNYU School of Medicine
Disclosures
Dr Klein has no conflicts to disclose
In 1786, Caleb Hillier Parry described a woman with goiter and palpitations, whose "each systole shook the whole thorax".
He was the first to suggest "the notion of some connexion (sic) between the malady of the heart and the bronchocoele" (Parry CH, 1815, Crutwell, Bath).
Cardiovascular Symptoms of Hyperthyroidism
• Palpitations• Atrial Fibrillation• Exercise Intolerance• Systolic Hypertension• Angina• Peripheral Edema• Congestive Heart Failure
Cardiovascular Symptoms of Hyperthyroidism
• Palpitations• Atrial Fibrillation• Exercise Intolerance• Systolic Hypertension• Angina• Peripheral Edema• Congestive Heart Failure
Thyroid Hormone and the Cardiovascular System
Thyroid hormone mediated changes may occur via
• Direct effects on the heart• Effects on the peripheral
circulation and then indirectly on the heart
Sites of Action of ThyroidHormone on the Heart andCardiovascular System
Klein and Danzi, In: The Thyroid 2012
Klein I et al. NEJM. 2001;344:501.
SVR (dyne•s•cm-5)
Heart rate (bpm)
% EF
IVRT (msec)
Cardiac output(L/min)
Blood volume(% normal)
1500-1700
72-84
60%
60-80
5.8
100
Normal
2100-2700
60-80
<60%
>80
<4.5
84.5
Hypothyroid
700-1200
88-130
>60%
25-40
>7.0
105.5
Hyper-
Cardiovascular ChangesWith Thyroid Disease
Klein I et al. NEJM. 2001;344:501.
Cellular Mechanisms of Thyroid Hormone Action on the Heart
Klein I et al. NEJM. 2001;344:501.
Thyroid Hormone Responsive Cardiac Genes
Myosin heavy chain-
SR Calcium ATPase (SERCA2)
1 Adrenergic receptor
GTP binding protein Gs
Na+ / K+ – ATPase
Voltage-gated K+ channels(Kv 1.5, 4.2, 4.3)
Positive Regulation
MHC-
Phospholamban
Adenylyl cyclases V, VI
T3 Receptor 1
Na+ / Ca2+ exchanger (NCX)
Negative Regulation
Left Ventricular Diastolic Function in Hyperthyroidism
IUntreated Graves
IIIEuthyroid
IIBeta- Blockade
Control HyperthyroidI II III
Heart Rate (bpm) 73 95 81 70
Diastolic Filling (ms) 225 173 201 216
Diastolic Compliance 156 97 122 148
Relaxation Time 58 33 34 52
70
60
50
40
30
20
Control Hyperthyroid Propranolol Euthyroid(N = 10) (N = 9)
Isovolumic Relaxation TimesIS
OVO
LUM
IC R
ELA
XATI
ON
TIM
E (m
sec)
Mechanisms of Heart Failure inPatients with Thyrotoxicosis
1) Exacerbation of underlying heart disease
2) Rate related left ventricular dysfunction
3) Right ventricular overload- Pulmonary Hypertension
Treatment of the Thyrotoxic Cardiac Patient
1) Beta-adrenergic Blockade2) Radioiodine3) Antithyroid Drugs4) Calcium Channel Blockers5) Anticoagulation
Changes in Subclinical Hyperthyroidism
1) Sinus Tachycardia2) Unexplained Weight Loss3) Atrial Fibrillation4) Cardiac Hypertrophy5) Enhanced Cardiac Contractility6) Skeletal Muscle Weakness
Hypothyroidism and the Heart
• Hypertension• Elevated Cholesterol• Long Q-T Syndrome• Serum CK• Coagulopathy• Response to Treatment
Initial Laboratory Data and Response to Thyroid Hormone Replacement Therapy
Patient THR Rx Cholesterol CK LDHmg/dl U/L U/L
1. Before 322 943 512 During 157 52 125
2. Before 265 2650 760 During 124 67 123
Reference Range <200 <90 <220
DIASTOLIC FUNCTION AND THYROID DISEASE
OH SCH C H H+P E
Isov
olum
ic R
elax
atio
n Ti
me
(mse
c)
0
20
40
60
80
100
120
Klein I. In: Braunwald’s Heart Disease. 8th ed., 2007
Cardiovascular Risk Associated with Hypothyroidism
Hypercholesterolemia ++
Diastolic hypertension +
Left ventricular diastolic dysfunction ++
Impaired endothelial mediated vasodilatation ++
Hypercoagulable state +
Elevated serum homocysteine +
Elevated C-reactive protein –
Risk Factor Response to Treatment
Danzi and Klein, Current Hypertension Reports 2003
ASCVD and Hypothyroidism
1,503 patients
400 (at Risk)
90 Clinical ASCVD
55 Patients with angina before Rx
35 Onset of angina after Rx
Keating, et al. Prog CV Disease 1961.
Effect of treatment
ASCVD and Hypothyroidism
Keating, et al. Prog CV Disease 1961.
Patients with angina before Rx
55
21 (clinically improved)
25(no change)
9 (worse)
Effect of treatment
ASCVD and HypothyroidismEffect of treatment
Keating, et al. Prog CV Disease 1961.
Onset of angina after Rx
35
6 (1st month)
6 (1st year)
23 (>1 year)
Subclinical Hypothyroidism• Definition:
– TSH 5–20 – Normal free T4
• Synonyms:– Compensated hypothyroidism– Decreased thyroid reserve– Mild hypothyroidism/mild thyroid
failure
Biondi B, et al. JECM. 1999;84:2064-2067; Taddei et al. JCEM 2003
FS (%)
CO (mL)
SVR (dyn/sec•cm-5)
IVRT (ms)
EDRF (%)
Control
Changes in Cardiovascular Function in Mild Hypothyroidism
Pre Post
36 +/- 4
5223 +/- 960
1460 +/- 340
84 +/- 8
503%
36 +/- 4
5300 +/- 1260
1470 +/- 370
94 +/- 13
358%
39 +/- 7
5806 +/- 1760
1361 +/- 383
77 +/- 15
446%
Hypothyroid
Risk of MI and Atherosclerosis
Hak AE, et al. Ann Int Med. 2000;132:270-278.
0
0.5
1
1.5
2
2.5
3
3.5
Myocardial Infarction Aortic Atherosclerosis
1.0 1.0
2.3
1.7
3.1
1.9
Euthyroid
Subclinical hypothyroid
Subclinical hypothyroid and antibodiesOddsRatio
Carotid intima-media thickness in subclinical hypothyroidism and the
response to treatment
Kim, et al. Endocrine J. 2009; 56:753.
• 2809 females from the General Practitioner Research Data Base in the UK were analyzed with regard to subclinical hypothyroidism and its treatment.
• 50% of the overall population was treated with L-T4.• When compared to non-treated patients, L-T4 treatment
led to a significant decrease in cardiovascular morbidity and mortality.
Conclusion: L-T4 treatment had the beneficial effect to reduce cardiovascular events and all cause mortality in adults with subclinical hypothyroidism.
Crowley et al. NEJM. 1967.
Thank you for your attention
Questions?