Thyroid Status and Cardiovascular Disease

Also see:
High Cholesterol and Metabolism
Heart Arrhythmia
High Blood Pressure and Hypothyroidism
The Cholesterol and Thyroid Connection
The Truth about Low Cholesterol
Inflammatory TSH
“Normal” TSH: Marker for Increased Risk of Fatal Coronary Heart Disease
The Cholesterol and Thyroid Connection
High Blood Pressure and Hypothyroidism
A Cure for Heart Disease
Hypothyroidism and A Shift in Death Patterns
Low Blood Cholesterol Compromises Immune Function
Thyroid Hormones: The Ultimate Weapon Against Heart Disease?

“Broda Barnes was right when he said that the “riddle of heart attacks” was solved when he demonstrated that hypothyroidism caused heart attacks, and that they were prevented by correcting hypothyroidism. He also observed that correcting hypothyroidism prevented the degenerative conditions (including heart disease) that so often occur in diabetics.” -Ray Peat, PhD

“One of my recurring objects of thought has been the slowness with which raw knowledge is assimilated. For example, I have been thinking about Broda Barnes’s work on the prevention of heart disease with thyroid extract. He did solve much of ‘the riddle of heart attacks,’ but recent statements by the Heart Association show that the dominant forces in the health business haven’t learned anything at all from his work, which he began 50 years ago. His work is clearly presented, not hard to understand, and it is scientifically so sound that no one challenges it, at least not on the scientific level. It is ignored, rejected by people who choose not to be bothered to read it. How many people have died from heart disease, since his work first became available? (And how many more from cancer, tuberculosis, and other diseases he showed occur mainly among hypothyroid people?)” -Ray Peat, PhD

“[Broda] Barnes experimented on rabbits, and found that when their thyroid glands were removed, they developed atherosclerosis, just as hypothyroid people did. By the mid-1930s, it was generally known that hypothyroidism causes the cholesterol level in the blood to increase; hypercholesterolemia was a diagnostic sign of hypothyroidism. Administering a thyroid supplement, blood cholesterol came down to normal exactly as the basal metabolic rate came up to the normal rate. The biology of atherosclerotic heart disease was basically solved before the second world war.” -Ray Peat, PhD

J Clin Endocrinol Metab. 2006 Jun;91(6):2126-32. Epub 2006 Mar 14.
Subclinical hypothyroidism, arterial stiffness, and myocardial reserve.
Owen PJ, Rajiv C, Vinereanu D, Mathew T, Fraser AG, Lazarus JH.
CONTEXT:
Subclinical hypothyroidism (SCH) is associated with increased risk of cardiac disease; its impact on arterial function is less clear.
OBJECTIVE:
The objective of the study was the assessment of arterial and cardiac function.
DESIGN:
The study was a 6-month controlled observational study using pulse wave analysis and tissue Doppler dobutamine stress echocardiography.
SETTING:
The study was conducted at a thyroid clinic.
PATIENTS:
Nineteen female SCH patients with raised TSH, normal free T(4), and no cardiovascular disease [aged 49.2 +/- 3.8 yr; body mass index (BMI) 29.9 +/- 6.7 kg/m(2)] were recruited from the thyroid clinic, and 10 female controls (aged 50.2 +/- 3.4 yr; BMI 29.7 +/- 7.2 kg/m(2)) also participated in the study.
INTERVENTIONS:
Incremental doses of l-thyroxine were used.
MAIN OUTCOME MEASURES:
Indices of vascular stiffness and left ventricular echocardiographic function were measured.
RESULTS:
Baseline augmentation gradient was elevated in SCH, compared with controls [10.3 +/- 5.1 (sd) mm Hg vs. 8.0 +/- 4.2, P < 0.05]; when euthyroid (mean T(4) dose 114 mug/d), it fell to 8.8 +/- 5.3 mm Hg (P < 0.05). Heart rate-corrected augmentation index was 26.7 +/- 9.9 vs. 18.8 +/- 9.9% (P < 0.02), falling to 19.7 +/- 9.6% (P < 0.001) after treatment. Time of travel of the reflected wave was 139.3 +/- 11.7 msec, compared with 141.5 +/- 8.8 msec in controls (P < 0.05), increasing to 144.9 +/- 11.9 msec (P < 0.05). There were no differences in resting global, regional left ventricular function, or regional myocardial velocities during maximal dobutamine stress between SCH patients and controls, or in treated patients, compared with baseline. CONCLUSIONS: Arterial stiffness was increased in SCH and improved with l-thyroxine, which may be beneficial, whereas myocardial functional reserve was similar to controls and remained unaltered after treatment.

Endocrine. 2004 Jun;24(1):1-13.
Hypothyroidism as a risk factor for cardiovascular disease.
Biondi B, Klein I.
The cardiovascular risk in patients with hypothyroidism is related to an increased risk of functional cardiovascular abnormalities and to an increased risk of atherosclerosis. The pattern of cardiovascular abnormalities is similar in subclinical and overt hypothyroidism, suggesting that a lesser degree of thyroid hormone deficiency may also affect the cardiovascular system. Hypothyroid patients, even those with subclinical hypothyroidism, have impaired endothelial function, normal/depressed systolic function, left ventricular diastolic dysfunction at rest, and systolic and diastolic dysfunction on effort, which may result in poor physical exercise capacity. There is also a tendency to increase diastolic blood pressure as a result of increased systemic vascular resistance. All these abnormalities regress with L-T4 replacement therapy. An increased risk for atherosclerosis is supported by autopsy and epidemiological studies in patients with thyroid hormone deficiency. The “traditional” risk factors are hypertension in conjunction with an atherogenic lipid profile; the latter is more often observed in patients with TSH >10 mU/L. More recently, C-reactive protein, homocysteine, increased arterial stiffness, endothelial dysfunction, and altered coagulation parameters have been recognized as risk factors for atherosclerosis in patients with thyroid hormone deficiency. This constellation of reversible cardiovascular abnormalities in patient with TSH levels <10 mU/L indicate that the benefits of treatment of mild thyroid failure with appropriate doses of L-thyroxine outweigh the risk.

Arch Intern Med. 2000 Feb 28;160(4):526-34.
The Colorado thyroid disease prevalence study.
Canaris GJ, Manowitz NR, Mayor G, Ridgway EC.
CONTEXT:
The prevalence of abnormal thyroid function in the United States and the significance of thyroid dysfunction remain controversial. Systemic effects of abnormal thyroid function have not been fully delineated, particularly in cases of mild thyroid failure. Also, the relationship between traditional hypothyroid symptoms and biochemical thyroid function is unclear.
OBJECTIVE:
To determine the prevalence of abnormal thyroid function and the relationship between (1) abnormal thyroid function and lipid levels and (2) abnormal thyroid function and symptoms using modern and sensitive thyroid tests.
DESIGN:
Cross-sectional study.
PARTICIPANTS:
Participants in a statewide health fair in Colorado, 1995 (N = 25 862).
MAIN OUTCOME MEASURES:
Serum thyrotropin (thyroid-stimulating hormone [TSH]) and total thyroxine (T4) concentrations, serum lipid levels, and responses to a hypothyroid symptoms questionnaire.
RESULTS:
The prevalence of elevated TSH levels (normal range, 0.3-5.1 mIU/L) in this population was 9.5%, and the prevalence of decreased TSH levels was 2.2%. Forty percent of patients taking thyroid medications had abnormal TSH levels. Lipid levels increased in a graded fashion as thyroid function declined. Also, the mean total cholesterol and low-density lipoprotein cholesterol levels of subjects with TSH values between 5.1 and 10 mIU/L were significantly greater than the corresponding mean lipid levels in euthyroid subjects. Symptoms were reported more often in hypothyroid vs euthyroid individuals, but individual symptom sensitivities were low.
CONCLUSIONS:
The prevalence of abnormal biochemical thyroid function reported here is substantial and confirms previous reports in smaller populations. Among patients taking thyroid medication, only 60% were within the normal range of TSH. Modest elevations of TSH corresponded to changes in lipid levels that may affect cardiovascular health. Individual symptoms were not very sensitive, but patients who report multiple thyroid symptoms warrant serum thyroid testing. These results confirm that thyroid dysfunction is common, may often go undetected, and may be associated with adverse health outcomes that can be avoided by serum TSH measurement.

Endocr Pract. 2008 Jul-Aug;14(5):570-5.
Increased atherogenic low-density lipoprotein cholesterol in untreated subclinical hypothyroidism.
Mikhail GS, Alshammari SM, Alenezi MY, Mansour M, Khalil NA.
OBJECTIVE:
To evaluate the effects of physiologic doses of levothyroxine replacement on the lipoprotein profile in patients with subclinical hypothyroidism (SCH).
METHODS:
In a prospective, double-blind, placebo-controlled study, we enrolled 120 patients–mostly, but not exclusively, premenopausal women–with SCH. Patients were randomly assigned to either a levothyroxine-treated group (n = 60) or a placebo (control) group (n = 60). Total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG) were measured before and 52 weeks after assignment to either group.
RESULTS:
In the levothyroxine-treated group, the lipoprotein mean values before and after the 52-week study were as follows: TC, 5.05 +/- 0.98 mmol/L versus 4.74 +/- 0.87 mmol/L (P<.0001); LDL-C, 3.30 +/- 0.90 mmol/L versus 2.89 +/- 0.59 mmol/L (P<.01); TG, 1.18 +/- 0.71 mmol/L versus 0.95 +/- 0.53 mmol/L (P<.002); and HDL-C, 1.20 +/- 0.33 mmol/L versus 1.19 +/- 0.32 mmol/L (P = .29). In the control group, TC, HDL-C, and TG values remained unchanged after 52 weeks in comparison with baseline, but LDL-C mean values increased from 2.79 +/- 0.60 mmol/L to 3.11 +/- 0.77 mmol/L, a change that was statistically significant (P<.001). At the end of the study, the lipid profile changes between levothyroxine-treated and control groups were compared. Total cholesterol and LDL-C were significantly lower in the levothyroxine-receiving group (P<.029 and P<.0001, respectively) in comparison with the control group. The difference did not reach statistical significance for TG and HDL-C values.
CONCLUSION:
In premenopausal women, SCH has a negative effect on the lipoprotein profile and may translate into a sizable cardiovascular risk if left untreated.

Ann Intern Med. 1999 Sep 7;131(5):348-51.
Normalization of hyperhomocysteinemia with L-thyroxine in hypothyroidism.
Hussein WI, Green R, Jacobsen DW, Faiman C.
BACKGROUND:
Hyperhomocysteinemia is an independent risk factor for coronary, peripheral, and cerebrovascular disease. Elevated plasma homocysteine levels were described in a preliminary report on primary hypothyroidism.
OBJECTIVE:
To determine whether restoration of euthyroidism by L-thyroxine replacement therapy would reduce or normalize plasma homocysteine levels.
DESIGN:
Prospective cohort study.
SETTING:
Outpatient endocrinology department of a tertiary center.
PATIENTS:
14 patients (10 women and 4 men; 25 to 77 years of age): 4 with newly diagnosed chronic (Hashimoto) hypothyroidism and 10 who had been rendered acutely hypothyroid (thyroid-stimulating hormone level > 25 mU/L) by total thyroidectomy for thyroid carcinoma.
MEASUREMENTS:
Total plasma homocysteine levels were measured at baseline and 3 to 9 months later, after euthyroidism had been attained by L-thyroxine replacement therapy.
RESULTS:
Median baseline plasma homocysteine levels in both sexes (women, 11.65 micromol/L [range, 7.2 to 26.5 micromol/L]; men, 15.1 micromol/L [range, 14.1 to 16.3 micromol/L]) were higher (P = 0.002) than those in healthy female (n = 35) and male (n = 36) volunteers (women, 7.52 micromol/L [range, 4.3 to 14.0 micromol/L]; men, 8.72 micromol/L [range, 5.94 to 14.98 micromol/L]). Eight patients (57%) had baseline plasma homocysteine levels that exceeded the upper limit of sex-specific reference ranges. Upon attainment of euthyroidism, all patients had a diminution in plasma homocysteine levels. The median overall change of -5.5 micromol/L (range, -15.4 to -1.8 micromol/L) corresponds to a difference of -44% (range, -58% to -13%) (P < 0.001). Homocysteine levels returned to normal in 7 of the 8 patients with elevated pretreatment values.
CONCLUSIONS:
Hypothyroidism may be a treatable cause of hyperhomocysteinemia, and elevated plasma homocysteine levels may be an independent risk factor for the accelerated atherosclerosis seen in primary hypothyroidism.

Thyroid. 2002 May;12(5):421-5.
Risk factors for cardiovascular disease in women with subclinical hypothyroidism.
Luboshitzky R, Aviv A, Herer P, Lavie L.
Overt hypothyroidism may result in accelerated atherosclerosis and coronary heart disease (CHD) presumably because of the associated hypertension, hypercholesterolemia, and hyperhomocysteinemia. As many as 10%-15% of older women have subclinical hypothyroidism (SH) and thyroid autoimmunity. Whether SH is associated with risk for CHD is controversial. We examined 57 women with SH and 34 healthy controls. SH was defined as an elevated thyrotropin (TSH) (>4.5 mU/L) and normal free thyroxine (FT(4)) level (8.7-22.6 nmol/L). None of the patients had been previously treated with thyroxine. In all participants we determined blood pressure, body mass index (BMI), and fasting TSH, FT(4), antibodies to thyroid peroxidase and thyroglobulin, total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglycerides, folic acid, vitamin B(12), creatinine, and total plasma homocysteine levels. The SH and control groups did not differ in their total homocysteine values. Mean diastolic blood pressure was increased in SH patients versus controls (82 vs. 75 mm Hg; p < 0.01). Mean values of TC, HDL-C, LDL-C, triglycerides, TC/HDL-C, and LDL-C/HDL-C were not different in patients with SH compared with controls. Individual analysis revealed that the percentage of patients with SH having hypertension (20%), hypertriglyceridemia (26.9%), elevated TC/HDL-C (11.5%), and LDL-C/HDL-C (4%) ratios were higher than the percentages in controls. Hyperhomocysteinemia (> or = 10.98 micromol/L) was observed in 29.4% of SH and was not significantly different from the percentage in controls (21.4%). No significant correlation between TSH and biochemical parameters was detected. We conclude that subclinical hypothyroidism in middle-aged women is associated with hypertension, hypertriglyceridemia, and elevated TC/HDL-C ratio. This may increase the risk of accelerated atherosclerosis and premature coronary artery disease in some patients.

Vojnosanit Pregl. 2007 Nov;64(11):749-52.
[Cardiovascular risk factors in patients with subclinical hypothyroidism].
[Article in Serbian]
Pesić M, Antić S, Kocić R, Radojković D, Radenković S.
BACKGROUND/AIMS:
Overt hypothyroidism is disease associated with accelerated arteriosclerosis and coronary heart disease. Whether subclinical hypothyroidism (SH) is associated with increased cardiovascular risk is contraversial. As SH is a high prevalence thyroid dysfunction, specially in older women, it is important to evaluate cardiovascular risk factors in these patients and that was the aim of this study.
METHODS:
We examined 30 patients with SH and 20 healthy controls. Subclinical hypothireoidism was defined as an elevated thyrotropin (TSH) (> 4.5 mU/L) and normal free thyroxine (FT4) level. In all the participants we determined body mass index (BMI), blood pressure, TSH, FT4, antibodies to thyroid peroxidase, antibodies to thyroglobulin, total cholesterol, high density lipoprotein (HDL) cholesterol, low density lipoprotein (LDL) cholesterol, triglicerides, total cholesterol/HDL cholesterol ratio and LDL/HDL cholesterol ratio.
RESULTS:
Mean BMI in patients with SH was significantly higher (p < 0.05), as well as diastolic blood pressure (p < 0.01) compared with the controls. Average levels of total cholesterol (5.40 +/- 0.62 vs 5.06 +/- 0.19 mmol/l, p < 0.01) and triglycerides (2.16 +/- 0.56 vs 1.89 +/- 0.24 mmol/l, p < 0.05) were also significantly higher in the group with SH. Individual analysis revealed that the percentage of patients with SH having borderline elevated total cholesterol (63.33%), hypertrigliceridemia (43.33%) and elevated total cholesterol/HDL cholesterol ratio (26.67%) were significantly higher than the percentage in the controls. No significant correlation between TSH and lipid parameters was detected.
CONCLUSION:
Subclinical hypothyroidism was associated with higher BMI, diastolic hypertension, higher total cholesterol and triglicerides levels and higher total cholesterol/HDL cholesterols ratio. This might increase the risk of accelerated arteriosclerosis in patients with SH.

J Endocrinol Invest. 2004 Nov;27(10):897-903.
The effect of L-thyroxine replacement therapy on lipid based cardiovascular risk in subclinical hypothyroidism.
Serter R, Demirbas B, Korukluoglu B, Culha C, Cakal E, Aral Y.
The aim of our study was to assess the changes in serum lipid profiles after replacement therapy with L-T4 in patients with subclinical hypothyroidism (SCH), and to see whether there is an improvement in dyslipidemia based cardiovascular risk. Thirty non-smoker pre-menopausal women with newly diagnosed SCH (TSH between 4 and 10 microIU/ml) were involved in our study; twenty-six euthyroid healthy subjects were used as control group. TSH, free T3 (FT3), free T4 (FT4), total cholesterol (TC), triglyceride (TG), HDL cholesterol (HDL-C) and LDL cholesterol (LDL-C) levels were measured before and after 6 months of L-T4 (50-100 microg/ day) therapy. TSH levels were targeted as < 2.0 microIU/ml. LDL-C was calculated using the Friedewald formula, while the cardiovascular risk was assessed with the TC/HDL-C ratio. Pre-treatment serum TC and LDL-C concentrations in SCH patients were significantly higher than those of euthyroid subjects (199.8 +/- 22.2 vs 181.5 +/- 24.6 mg/dl, p < 0.01; 146.3 +/- 26.1 vs 124.8 +/- 12 mg/dl, p < 0.001, respectively). TC, LDL-C levels and the TC/HDL-C ratio were reduced significantly after 6-month replacement therapy (-21.1 +/- 34.4 mg/dl or -10.5%, p < 0.01; -21.5 +/- 30.3 mg/dl or -14.7%, p < 0.001, respectively; and TC/HDL-C from 4.8 +/- 0.6 to 4.1 +/- 0.5 mg/dl, p < 0.01), while body mass index (BMI) values did not change. In conclusion, even mild elevations of TSH are associated with changes in lipid profile significant enough to raise the cardiovascular risk ratio, and these changes are corrected once the patients have been rendered euthyroid.

Thyroid. 2005 May;15(5):455-60.
Thyroid substitution therapy induces high-density lipoprotein-associated platelet-activating factor-acetylhydrolase in patients with subclinical hypothyroidism: a potential antiatherogenic effect.
Milionis HJ, Tambaki AP, Kanioglou CN, Elisaf MS, Tselepis AD, Tsatsoulis A.
BACKGROUND:
Subclinical hypothyroidism (SH) has been associated with an increased risk of ischemic heart disease, which has been partly attributed to lipid abnormalities. Human plasma platelet-activating factor acetylhydrolase (PAF-AH) is an enzyme associated with lipoproteins (both low-density lipoproteins [LDL], and high-density lipoproteins [HDL]). Plasma paraoxonase 1 (PON1) is an esterase exclusively associated with HDL.
OBJECTIVE:
To evaluate qualitative changes in lipoprotein metabolism with respect to PAF-AH and PON1 activities in patients with SH before and after the restoration of euthyroidism.
DESIGN AND METHODS:
We determined the PAF-AH activity in plasma and on HDL and PON1 activities as well as the lipid profile patients with SH at baseline and after 6 months of levothyroxine substitution therapy. Thirty normolipidemic healthy individuals comprised the control group.
RESULTS:
Compared to controls, patients with SH showed higher levels of total cholesterol, LDL cholesterol, triglycerides, and apolipoprotein B. Triglycerides were significantly reduced after levothyroxine treatment. Patients with SH exhibited higher plasma baseline PAF-AH activity (63.0 +/- 16.5 versus 44.3 +/- 9.5 nmol/mL per minute p < 0.0001) and lower baseline HDL associated PAF-AH (2.9 +/- 1.1 versus 3.6 +/- 0.9 nmol/mL per minute p = 0.02) compared to the control group. PON1 activities were similar in both groups. Levothyroxine treatment had no effect on plasma PAF-AH activity or PON1 activities but resulted in a significant elevation of HDL-associated PAF-AH activity (from 2.9 +/- 1.1 to 3.5 +/- 1.0 nmol/mL per minute, p = 0.003).
CONCLUSIONS:
Patients with SH exhibit increased plasma PAF-AH activity and low HDL-associated PAF-AH activity. Levothyroxine induces a significant increase in HDL-PAF-AH activity. This action may represent a potential antiatherogenic effect of thyroid.

The Journal of Clinical Endocrinology & Metabolism 88(6):2438 –244
Hypothyroidism and Atherosclerosis
ANNE R. CAPPOLA AND PAUL W. LADENSON
For 125 yr, physicians have appreciated that there is a relationship between hypothyroidism and atherosclerosis. Our growing understanding of thyroid hormone’s regulation of lipid and homocysteine metabolism, effects on vascular reactivity and blood pressure, and modulation of other atherosclerotic factors now provide partial explanations for how hypothyroidism predisposes patients to cardiovascular
disease. In addition to this pathogenic relationship, the multiple direct and indirect actions of thyroid hormone on cardiac and peripheral vascular functions can complicate management of hypothyroid patients with atherosclerotic coronary disease. Despite these advances, today’s clinicians managing patients with hypothyroidism and atherosclerosis are still guided more by medical folklore than evidence based medicine.

The Journal of Clinical Endocrinology & Metabolism August 1, 2008 vol. 93 no. 8 2998-3007
The Influence of Age on the Relationship between Subclinical Hypothyroidism and Ischemic Heart Disease: A Metaanalysis
Salman Razvi, Abdul Shakoor, Mark Vanderpump, Jolanta U. Weaver and Simon H. S. Pearce
Context: Subclinical hypothyroidism (SCH) is a common condition that has been associated with ischemic heart disease (IHD) in some, but not all, studies. This may be due to differences in study design and the characteristics of participants.
Objective: Our objective was to investigate whether age and gender influence IHD prevalence, incidence, and mortality in people with SCH.
Data Sources: Computerized (PubMed, EMBASE, and Cochrane Library) and manual searches of the literature to May 2007, published in English, were performed.
Study Selection: Epidemiological studies that quantified thyroid status and IHD events in adults were performed.
Data Extraction: Two authors independently reviewed articles and abstracted data. Results were compared across two groups based on the minimum age of participants studied (younger than 65 yr and 65 yr or older).
Data Synthesis: There were 15 studies included for analysis with 2,531 SCH participants and 26,491 euthyroid individuals. IHD incidence and prevalence were higher in SCH subjects compared with euthyroid participants from studies including those younger than 65 yr, but not studies of subjects aged older than 65 yr [odds ratio (95% confidence interval)]: 1.57 (1.19–2.06) vs. 1.01 (0.87–1.18) and 1.68 (1.27–2.23) vs. 1.02 (0.85–1.22), respectively. Cardiovascular/all-cause mortality was also elevated in participants from the younger than 65-yr studies, but not from the studies of older people: odds ratio 1.37 (1.04–1.79) vs. 0.85 (0.56–1.29). Prevalent IHD was higher in SCH participants of both genders, although this was statistically significant only in women.
Conclusions: SCH is associated with increased IHD (both prevalence and incidence) and cardiovascular mortality only in subjects from younger populations. These data suggest that increased vascular risk may only be present in younger individuals with SCH.

Can J Cardiol. 1997 Mar;13(3):273-6.
The effect of thyroid hormone therapy on angiographic coronary artery disease progression.
Perk M, O’Neill BJ.
OBJECTIVE:
To study the effect of adequacy of thyroid hormone replacement therapy on coronary atherosclerosis.
DESIGN:
Retrospective cohort study of elderly hypothyroid patients with coexisting coronary artery disease. The association between the adequacy of thyroid replacement and the progression of angiographic coronary artery disease was investigated. Fisher’s exact test was used for statistical analysis.
SETTING:
Coronary angiographies were performed at the Cardiac Catheterization Laboratory of the Victoria General Hospital, Halifax, Nova Scotia, the only tertiary referral centre for Nova Scotia and Prince Edward Island. Information about the past and current thyroid status of the subjects was collected from their family physicians.
PATIENTS:
Of 4103 patients admitted for coronary angiography during 1992 and 1993, 25 were on thyroid replacement therapy to treat hypothyroidism. Ten patients who underwent more than one coronary arteriography were selected (seven females and three males, mean age 65 +/- 10 years).
RESULTS:
Of five patients inadequately treated for hypothyroidism, all demonstrated angiographic evidence of coronary atherosclerosis progression. However, five of seven who were treated adequately did not show atherosclerosis progression (P = 0.02, OR = 0.72, 95% CI 1.36 to infinity). Decreasing or maintaining the dose of L-thyroxine at 100 micrograms or less resulted in coronary atherosclerosis progression in six of six patients, whereas five of six patients taking fixed or increasing doses of L-thyroxine 150 micrograms or higher were spared from disease progression (P = 0.015, OR = 0.41, 95% CI 2.4 to infinity).
CONCLUSIONS:
Angiographic coronary artery disease progression may be prevented by adequate thyroid replacement in hypothyroidism. With the help of modern, sensitive thyroid stimulating hormone assays higher doses of L-thyroxine may be safer and more effective in the atherosclerosis management of this patient population. Thyroid hormones can protect against atherosclerosis, presumably due to their metabolic affects on plaque progression.

Eur J Endocrinol. 2011 Jul;165(1):115-21. Epub 2011 Apr 13.
Impact of subclinical hypothyroidism on the coronary artery disease in apparently healthy subjects.
Park YJ, Lee YJ, Choi SI, Chun EJ, Jang HC, Chang HJ.
OBJECTIVE:
Cardiovascular disease (CVD) occurs frequently and may progress more rapidly in overt hypothyroidism (OVH). However, the role of mild thyroid failure as a risk factor for CVD is not clear. This study is aimed at exploring the association between subclinical hypothyroidism (SCH) and coronary artery disease (CAD), as detected by cardiac computed tomography (CT), in apparently healthy subjects.
SUBJECTS AND METHODS:
We retrospectively enrolled 2404 asymptomatic subjects who underwent cardiac CT with an intermediate to high risk (Framingham 10-year risk ≥10%) of developing CAD but with no known CAD or thyroid disease. Coronary artery calcium score (CACS) was assessed by calcium scan, and the presence of the plaques (CAD), with ≥50% stenosis being indicative of obstructive CAD, was assessed by coronary CT angiography.
RESULTS:
Of the 2404 subjects, 2355 subjects were euthyroid (Eu; 53±9 years, 83 females) and 49 had SCH (58±12 years, seven females). CAD and CACS >100 were more prevalent in SCH subjects than in Eu subjects (Eu vs SCH: CAD, 948 (40.6%) vs 31 (63.3%), P=0.002; CACS >100, 239 (10.3%) vs 10 (20.4%), P=0.031). SCH was also an independent risk factor for CAD after a multivariate analysis (odds ratio: 2.125, 95% confidence interval: 1.049-4.307, P=0.036).
CONCLUSIONS:
SCH subjects who were at an intermediate-to-high risk of developing CAD were significantly more likely to exhibit occult CAD than Eu subjects, especially in men with SCH. These findings suggest that mild thyroid failure also independently contributes to the development of CAD.

JAMA. 2010 Sep 22;304(12):1365-74.
Subclinical hypothyroidism and the risk of coronary heart disease and mortality.
Rodondi N, den Elzen WP, Bauer DC, Cappola AR, Razvi S, Walsh JP, Asvold BO, Iervasi G, Imaizumi M, Collet TH, Bremner A, Maisonneuve P, Sgarbi JA, Khaw KT, Vanderpump MP, Newman AB, Cornuz J, Franklyn JA, Westendorp RG, Vittinghoff E, Gussekloo J; Thyroid Studies Collaboration.
CONTEXT:
Data regarding the association between subclinical hypothyroidism and cardiovascular disease outcomes are conflicting among large prospective cohort studies. This might reflect differences in participants’ age, sex, thyroid-stimulating hormone (TSH) levels, or preexisting cardiovascular disease.
OBJECTIVE:
To assess the risks of coronary heart disease (CHD) and total mortality for adults with subclinical hypothyroidism.
DATA SOURCES AND STUDY SELECTION:
The databases of MEDLINE and EMBASE (1950 to May 31, 2010) were searched without language restrictions for prospective cohort studies with baseline thyroid function and subsequent CHD events, CHD mortality, and total mortality. The reference lists of retrieved articles also were searched.
DATA EXTRACTION:
Individual data on 55,287 participants with 542,494 person-years of follow-up between 1972 and 2007 were supplied from 11 prospective cohorts in the United States, Europe, Australia, Brazil, and Japan. The risk of CHD events was examined in 25,977 participants from 7 cohorts with available data. Euthyroidism was defined as a TSH level of 0.50 to 4.49 mIU/L. Subclinical hypothyroidism was defined as a TSH level of 4.5 to 19.9 mIU/L with normal thyroxine concentrations.
RESULTS:
Among 55,287 adults, 3450 had subclinical hypothyroidism (6.2%) and 51,837 had euthyroidism. During follow-up, 9664 participants died (2168 of CHD), and 4470 participants had CHD events (among 7 studies). The risk of CHD events and CHD mortality increased with higher TSH concentrations. In age- and sex-adjusted analyses, the hazard ratio (HR) for CHD events was 1.00 (95% confidence interval [CI], 0.86-1.18) for a TSH level of 4.5 to 6.9 mIU/L (20.3 vs 20.3/1000 person-years for participants with euthyroidism), 1.17 (95% CI, 0.96-1.43) for a TSH level of 7.0 to 9.9 mIU/L (23.8/1000 person-years), and 1.89 (95% CI, 1.28-2.80) for a TSH level of 10 to 19.9 mIU/L (n = 70 events/235; 38.4/1000 person-years; P <.001 for trend). The corresponding HRs for CHD mortality were 1.09 (95% CI, 0.91-1.30; 5.3 vs 4.9/1000 person-years for participants with euthyroidism), 1.42 (95% CI, 1.03-1.95; 6.9/1000 person-years), and 1.58 (95% CI, 1.10-2.27, n = 28 deaths/333; 7.7/1000 person-years; P = .005 for trend). Total mortality was not increased among participants with subclinical hypothyroidism. Results were similar after further adjustment for traditional cardiovascular risk factors. Risks did not significantly differ by age, sex, or preexisting cardiovascular disease.
CONCLUSIONS:
Subclinical hypothyroidism is associated with an increased risk of CHD events and CHD mortality in those with higher TSH levels, particularly in those with a TSH concentration of 10 mIU/L or greater.

Arch Intern Med. 2005 Nov 28;165(21):2460-6.
Subclinical hypothyroidism and the risk of heart failure, other cardiovascular events, and death.
Rodondi N, Newman AB, Vittinghoff E, de Rekeneire N, Satterfield S, Harris TB, Bauer DC.
BACKGROUND:
Subclinical hypothyroidism has been associated with systolic and diastolic cardiac dysfunction and an elevated cholesterol level, but data on cardiovascular outcomes and death are limited.
METHODS:
We studied 2730 men and women, aged 70 to 79 years, with baseline thyrotropin (TSH) measurements and 4-year follow-up data to determine whether subclinical hypothyroidism was associated with congestive heart failure (CHF), coronary heart disease, stroke, peripheral arterial disease, and cardiovascular-related and total mortality. After the exclusion of participants with abnormal thyroxine levels, subclinical hypothyroidism was defined as a TSH level of 4.5 mIU/L or greater, and was further classified according to TSH levels (4.5-6.9, 7.0-9.9, and > or = 10.0 mIU/L).
RESULTS:
Subclinical hypothyroidism was present in 338 (12.4%) of the participants. Compared with euthyroid participants, CHF events occurred more frequently among those with a TSH level of 7.0 mIU/L or greater (35.0 vs 16.5 per 1000 person-years; P = .006), but not among those with TSH levels between 4.5 and 6.9 mIU/L. In multivariate analyses, the risk of CHF was higher among those with high TSH levels (TSH of 7.0-9.9 mIU/L: hazard ratio, 2.58 [95% confidence interval, 1.19-5.60]; and TSH of > or = 10.0 mIU/L: hazard ratio, 3.26 [95% confidence interval, 1.37-7.77]). Among the 2555 participants without CHF at baseline, the hazard ratio for incident CHF events was 2.33 (95% confidence interval, 1.10-4.96; P = .03) in those with a TSH of 7.0 mIU/L or greater. Subclinical hypothyroidism was not associated with increased risk for coronary heart disease, stroke, peripheral arterial disease, or cardiovascular-related or total mortality.
CONCLUSIONS:
Subclinical hypothyroidism is associated with an increased risk of CHF among older adults with a TSH level of 7.0 mIU/L or greater, but not with other cardiovascular events and mortality. Further investigation is warranted to assess whether subclinical hypothyroidism causes or worsens preexisting heart failure.

Arch Intern Med. 2005 Nov 28;165(21):2467-72.
Subclinical thyroid dysfunction as a risk factor for cardiovascular disease.
Walsh JP, Bremner AP, Bulsara MK, O’Leary P, Leedman PJ, Feddema P, Michelangeli V.
BACKGROUND:
There have been few large epidemiological studies examining the association between thyroid dysfunction and cardiovascular disease. In particular, it is uncertain if subclinical hypothyroidism is a risk factor for cardiovascular disease.
METHODS:
Serum thyrotropin and free thyroxine concentrations were measured in 2108 archived serum samples from a 1981 community health survey in Busselton, Western Australia (Busselton Health Study). In a cross-sectional study, we examined the prevalence of coronary heart disease in subjects with and without subclinical thyroid dysfunction. In a longitudinal study, we examined the risk of cardiovascular mortality and coronary heart disease events (fatal and nonfatal combined) to the end of 2001 (excluding subjects who had coronary heart disease at baseline).
RESULTS:
In the cross-sectional analysis, subjects with subclinical hypothyroidism (n = 119) had a significantly higher prevalence of coronary heart disease than euthyroid subjects (n = 1906) (age- and sex-adjusted prevalence odds ratio, 1.8; 95% confidence interval, 1.0-3.1; P = .04). In the longitudinal analysis of subjects with subclinical hypothyroidism (n = 101), there were 21 cardiovascular deaths observed compared with 9.5 expected (age- and sex-adjusted hazard ratio, 1.5; 95% confidence interval, 1.0-2.4; P = .08) and 33 coronary heart disease events observed compared with 14.7 expected (age- and sex-adjusted hazard ratio, 1.7; 95% confidence interval, 1.2-2.4; P < .01). The increased risk of coronary heart disease events remained significant after further adjustment for standard cardiovascular risk factors. Subjects with subclinical hyperthyroidism (n = 39) had no adverse outcomes.
CONCLUSION:
Subclinical hypothyroidism may be an independent risk factor for coronary heart disease.

Heart. 1997 March; 77(3): 189–190.
Hypothyroidism, thyroxine treatment, and the heart.
M. Gammage and J. Franklyn
Hypothyroidism is a common condition; surveys indicate that approximately 1% of the general population and 4% of people 60 years and older are prescribed thyroxine long
term. Hypothyroidism has cardiovascular consequences resulting from both direct influences of thyroid hormone deficiency on the heart, and adverse effects on circulating lipid concentrations. Furthermore, with the advent of improved tests of thyroid function, it has become clear that even when patients with hypothyroidism are treated with thyroxine long term, about half have serum thyrotrophin concentrations above or below the normal range, indicating a degree of under or over treatment with thyroxine. Although little importance has been attached to these minor biochemical abnormalities, recent evidence suggests that they may have considerable clinical significance.

Lancet. 1967 Oct 14;2(7520):800-2.
Coronary-artery disease in hypothyroidism. Observations in clinical myxoedema.
Vanhaelst L, Neve P, Chailly P, Bastenie PA.
The relation of coronary-artery disease to hypothyroidism has been investigated in 87 patients with clinical myxœdema and in 25 necropsies on patients who died with inadequately treated myxœdema. The clinical and the pathological findings were compared with those in matched controls. Independently of sex, age, and associated disorders, spontaneous hypothyroidism strongly favoured the development of coronary-artery atherosclerosis. In untreated myxœdema, however, despite increased atherosclerosis and myocardial ischæmia, the incidence of myocardial infarcts was not increased.

Br Heart J. 1981 August; 46(2): 202–206.
Borderline low thyroid function and thyroid autoimmunity. Risk factors for coronary heart disease?
M Tièche, G A Lupi, F Gutzwiller, P J Grob, H Studer, and H Bürgi
Assessments were made of 945 consecutive hospital patients with regard to a relation between borderline low thyroid function (recognised by a slightly raised thyroid stimulating hormone), thyroid autoimmunity, serum cholesterol, and coronary heart disease. Men and women with a thyroid autoimmunity, serum cholesterol, and coronary heart disease. Men and women with a thyroid stimulating hormone of 4.0 mU/l or over had a higher prevalence of coronary heart disease than did age-matched controls, and this difference was significant in women. The excess of coronary heart disease was not explained by an excess of other risk factors such as a high cholesterol, hypertension, smoking, and diabetes. Women with thyroid antibodies had a slightly higher prevalence of coronary heart disease despite the unexpected finding of a lower serum cholesterol. The data point to an association between borderline thyroid function and autoimmunity and coronary heart disease which is not mediated through a raised serum cholesterol.

J Gerontol A Biol Sci Med Sci. 2002 Oct;57(10):M658-9.
Subclinical hypothyroidism is associated with coronary artery disease in older persons.
Mya MM, Aronow WS.
BACKGROUND:
We report the prevalence of coronary artery disease (CAD) associated with subclinical hypothyroidism in older persons.
METHODS:
We investigated the prevalence of subclinical hypothyroidism and its association with dyslipidemia and with CAD in 170 women and 110 men, mean age 75 +/- 9 years, in an academic nursing home.
RESULTS:
Of 280 persons, 18 (6%) had subclinical hypothyroidism, 18 (6%) had treated clinical hypothyroidism, 13 (5%) had subclinical hyperthyroidism, and 231 (83%) were euthyroid. Dyslipidemia occurred in 15 of 18 persons (83%) with subclinical hypothyroidism, in nine of 18 persons (50%) treated for hypothyroidism, in six of 13 persons (46%) with subclinical hyperthyroidism, and in 128 of 231 euthyroid persons (55%) (p <.025 comparing subclinical hypothyroidism with euthyroidism and p <.005 comparing subclinical hypothyroidism with treated hypothyroidism and with subclinical hyperthyroidism). CAD was present in 10 of 18 persons (56%) with subclinical hypothyroidism, in nine of 18 persons (50%) with treated hypothyroidism, in 5 of 13 persons (38%) with subclinical hyperthyroidism, and in 38 of 231 euthyroid persons (16%) (p <.001 comparing subclinical hypothyroidism with euthyroidism; p <.005 comparing treated hypothyroidism with euthyroidism; and p <.05 comparing subclinical hyperthyroidism with euthyroidism).
CONCLUSIONS:
Subclinical hypothyroidism was associated with a high prevalence of dyslipidemia and a high prevalence of CAD.

February 15, 2000 vol. 132 no. 4 270-278
Subclinical Hypothyroidism Is an Independent Risk Factor for Atherosclerosis and Myocardial Infarction in Elderly Women: The Rotterdam Study
A. Elisabeth Hak, MD, MSc; Huibert A.P. Pols, MD, PhD; Theo J. Visser, MD, PhD; Hemmo A. Drexhage, MD, PhD; Albert Hofman, MD, PhD; and Jacqueline C.M. Witteman, PhD
Background: Overt hypothyroidism has been found to be associated with cardiovascular disease. Whether subclinical hypothyroidism and thyroid autoimmunity are also risk factors for cardiovascular disease is controversial.
Objective: To investigate whether subclinical hypothyroidism and thyroid autoimmunity are associated with aortic atherosclerosis and myocardial infarction in postmenopausal women.
Design: Population-based cross-sectional study.
Setting: A district of Rotterdam, the Netherlands.
Participants: Random sample of 1149 women (mean age ± SD, 69.0 ± 7.5 years) participating in the Rotterdam Study.
Measurements: Data on thyroid status, aortic atherosclerosis, and history of myocardial infarction were obtained at baseline. Subclinical hypothyroidism was defined as an elevated thyroid-stimulating hormone level (>4.0 mU/L) and a normal serum free thyroxine level (11 to 25 pmol/L [0.9 to 1.9 ng/dL]). In tests for antibodies to thyroid peroxidase, a serum level greater than 10 IU/mL was considered a positive result.
Results: Subclinical hypothyroidism was present in 10.8% of participants and was associated with a greater age-adjusted prevalence of aortic atherosclerosis (odds ratio, 1.7 [95% CI, 1.1 to 2.6]) and myocardial infarction (odds ratio, 2.3 [CI, 1.3 to 4.0]). Additional adjustment for body mass index, total and high-density lipoprotein cholesterol level, blood pressure, and smoking status, as well as exclusion of women who took β-blockers, did not affect these estimates. Associations were slightly stronger in women who had subclinical hypothyroidism and antibodies to thyroid peroxidase (odds ratio for aortic atherosclerosis, 1.9 [CI, 1.1 to 3.6]; odds ratio for myocardial infarction, 3.1 [CI, 1.5 to 6.3]). No association was found between thyroid autoimmunity itself and cardiovascular disease. The population attributable risk percentage for subclinical hypothyroidism associated with myocardial infarction was within the range of that for known major risk factors for cardiovascular disease.
Conclusion: Subclinical hypothyroidism is a strong indicator of risk for atherosclerosis and myocardial infarction in elderly women.

Curr Opin Endocrinol Diabetes Obes. 2007 Jun;14(3):197-208.
Subclinical hypothyroidism.
Papi G, Uberti ED, Betterle C, Carani C, Pearce EN, Braverman LE, Roti E.
PURPOSE OF REVIEW:
Mild or subclinical hypothyroidism is characterized by normal serum free thyroxine concentrations with elevated serum thyroid-stimulating hormone concentrations. Subclinical hypothyroidism is relatively prevalent in the general population, especially among women and the elderly. The main cause of subclinical hypothyroidism is autoimmune chronic thyroiditis. The present report reviews the most important and recent studies on subclinical hypothyroidism, and discusses the most controversial aspects of this topic.
RECENT FINDINGS:
Several studies have demonstrated that subclinical hypothyroidism may affect both diastolic and systolic cardiac function. It may also worsen many risk factors for cardiovascular disease, including hypertension, abnormal endothelial function, and elevated low-density lipoprotein cholesterol concentrations. Furthermore, a growing body of evidence suggests that subclinical hypothyroidism may cause symptoms or progress to symptomatic overt hypothyroidism.
SUMMARY:
Prompt treatment of subclinical hypothyroidism in pregnant women is mandatory to decrease risks for pregnancy complications and impaired cognitive development in offspring. Children with subclinical hypothyroidism should be treated to prevent growth retardation. Whether nonpregnant adult patients with subclinical hypothyroidism should be treated, and at what thyroid-stimulating hormone values, is debatable.

J Clin Endocrinol Metab. 2002 Oct;87(10):4662-6.
Increased central arterial stiffness in hypothyroidism.
Obuobie K, Smith J, Evans LM, John R, Davies JS, Lazarus JH.
Hypothyroidism is associated with cardiovascular dysfunction. It is increasingly apparent that stiffening of central arteries may lead to increased afterload and cardiac dysfunction. We noninvasively studied the peripheral and central pressure waveforms in 12 untreated hypothyroid patients as well as in 12 age-, sex-, and body mass index-matched controls using the technique of pulse wave analysis from recordings at the radial artery. Indexes of arterial stiffness, augmentation index (AI) and augmentation of central arterial pressure (AG), were derived as well as time of travel of the reflected wave (TR), a direct estimate of aortic pulse wave velocity. At baseline, there were no significant differences between the 2 groups in brachial and aortic blood pressures. Hypothyroid patients had significantly higher AI than controls (mean +/- SEM[SCAP], 32.0 +/- 3.4% vs. 17.0 +/- 2.4%; P < 0.0005) even when corrected for heart rate (AI(C); 28.0 +/- 3.2% vs. 17.0 +/- 2.4%; P < 0.006) and AG (13.0 +/- 2.2 vs. 7.0 +/- 2.1 mm Hg; P < 0.03) together with a lower TR (132.0 +/- 4.1 vs. 142.0 +/- 1.5 msec; P < 0.03). After 6 months of therapy with T(4), all patients were euthyroid. AI(C) had decreased in the patient group (23.0 +/- 3.2% vs. 28.0 +/- 3.2%; P < 0.01) as had AG (9.0 +/- 1.5 vs. 13.0 +/- 2.2 mm Hg; P < 0.008), but TR was significantly higher (142.0 +/- 3.0 vs. 132.0 +/- 4.1 msec; P < 0.008). AI correlated with age in all groups (hypothyroid group: r = 0.937; P < 0.0005; control group: r = 0.804; P < 0.0005), but correlated with TSH level only among controls (r = 0.591; P < 0.05). This study confirms that hypothyroidism is associated with increased cardiovascular risk, as evidenced by increased augmentation of central aortic pressures and central arterial stiffness. Furthermore, these abnormalities are reversed after adequate T(4) replacement.

Thyroid. 1996 Oct;6(5):505-12.
Acute effects of thyroid hormone on vascular smooth muscle.
Ojamaa K, Klemperer JD, Klein I.
The enhanced cardiovascular hemodynamics associated with triiodo-L-thyronine (T3) treatment is in part mediated by a decrease in systemic vascular resistance. To determine the molecular mechanisms for the vasoactive properties of T3, we studied primary cultures of aortic endothelial and vascular smooth muscle (VSM) cells. Active tension development by the VSM cells was measured by deformation lines within a siloxane matrix on which the cells were grown. Exposure to T3 (10(-10) M) resulted in cellular relaxation within 10 min. Hormone binding studies to purified VSM cell plasma membranes identified two binding sites specific for T3 with Kd of 1 x 10(-11) and 6.1 x 10(-8) M. L-Thyroxine and reverse T3 did not compete for the L-T3 binding sites. To determine an intracellular signaling pathway of T3 action, cAMP and cGMP content were measured in VSM cell cultures treated with T3. No quantitative changes were observed in a time frame known to cause VSM cell relaxation. The level of myosin light chain phosphorylation is a major determinant of smooth muscle contraction. Thus, treatment of VSM cells with isoproterenol, a vasodilator, caused a significant decrease in radiolabeled phosphate incorporation into the myosin light chains, whereas T3 had no effect on phosphorylation of these proteins. Primary cultures of vascular endothelial cells exposed to T3 showed no nitric oxide production as measured by cellular cGMP content and nitrite release, suggesting that T3 acted directly on the VSM cell to cause vascular relaxation.

Am J Med. 1990 Jun;88(6):638-41.
Recognition and management of cardiovascular disease related to thyroid dysfunction.
Ladenson PW.
Hypothyroidism and hyperthyroidism are both associated with clinically significant cardiovascular derangements. In hypothyroidism, these include pericardial effusion, heart failure, and the complex interrelationship between hypothyroidism and ischemic heart disease. Cardiovascular disorders associated with hyperthyroidism include atrial tachyarrhythmias, mitral valve dysfunction, and heart failure. Although these usually occur in individuals with intrinsic heart disease, thyroid dysfunction alone rarely causes serious but reversible cardiovascular dysfunction. Patients with commonly encountered cardiac disorders, e.g., idiopathic cardiomyopathy and atrial fibrillation, should be screened for potentially contributing subclinical thyroid diseases. In patients with heart failure and hypothyroidism, initial management should focus on diagnosis and optimal management of any primary cardiac disease, whereas in hyperthyroidism, aggressive measures to control excess thyroid hormone action should generally have the highest priority.

Recent Prog Horm Res. 2004;59:31-50.
Effects of thyroid hormone on the cardiovascular system.
Fazio S, Palmieri EA, Lombardi G, Biondi B.
Increased or reduced action of thyroid hormone on certain molecular pathways in the heart and vasculature causes relevant cardiovascular derangements. It is well established that overt hyperthyroidism induces a hyperdynamic cardiovascular state (high cardiac output with low systemic vascular resistance), which is associated with a faster heart rate, enhanced left ventricular (LV) systolic and diastolic function, and increased prevalence of supraventricular tachyarrhythmias – namely, atrial fibrillation – whereas overt hypothyroidism is characterized by the opposite changes. However, whether changes in cardiac performance associated with overt thyroid dysfunction are due mainly to alterations of myocardial contractility or to loading conditions remains unclear. Extensive evidence indicates that the cardiovascular system responds to the minimal but persistent changes in circulating thyroid hormone levels, which are typical of individuals with subclinical thyroid dysfunction. Subclinical hyperthyroidism is associated with increased heart rate, atrial arrhythmias, increased LV mass, impaired ventricular relaxation, reduced exercise performance, and increased risk of cardiovascular mortality. Subclinical hypothyroidism is associated with impaired LV diastolic function and subtle systolic dysfunction and an enhanced risk for atherosclerosis and myocardial infarction. Because all cardiovascular abnormalities are reversed by restoration of euthyroidism (“subclinical hypothyroidism”) or blunted by beta-blockade and L-thyroxine (L-T4) dose tailoring (“subclinical hyperthyroidism”), timely treatment is advisable in an attempt to avoid adverse cardiovascular effects. Interestingly, some data indicate that patients with acute and chronic cardiovascular disorders and those undergoing cardiac surgery may have altered peripheral thyroid hormone metabolism that, in turn, may contribute to altered cardiac function. Preliminary clinical investigations suggest that administration of thyroid hormone or its analogue 3,5-diiodothyropropionic acid greatly benefits these patients, highlighting the potential role of thyroid hormone treatment in patients with acute and chronic cardiovascular disease.

Thyroid. 1995 Dec;5(6):443-7.
Silent myocardial ischemia in hypothyroidism.
Bernstein R, Müller C, Midtbø K, Smith G, Haug E, Hertzenberg L.
In some patients with severe hypothyroidism thyroxine replacement therapy precipitates or aggravates angina pectoris, whereas in other patients angina pectoris is ameliorated or even disappears. The reason for this paradox is unknown. It has been attributed either to reversible endocrine cardiomyopathy in the form of asymmetric septal hypertrophy (ASH) or reversible anatomical narrowing of the coronary arteries. The results of a recent investigation, in which myocardial performance was surveyed by radionuclide ventriculography throughout early thyroxine replacement therapy in severe hypothyroidism, were compatible with the presence of reversible coronary dysfunction rather than of ASH. The aim of the present investigation was to confirm these findings. In six severely hypothyroid patients, without echocardiographic evidence of ASH or evidence of concomitant coronary artery disease (CAD), exercise and redistribution tomographic myocardial thallium-201 imaging (SPECT) was performed before thyroxine replacement therapy and repeated after 10 days and again after 2 months during therapy. In four patients substantial regional perfusion defects were demonstrated after exercise that were normalized at rest both before, and in one subject also after 10 days, on thyroxine. With restoration of euthyroidism, exercise and redistribution SPECT were normal in every patient. Determination of exact confidence limits reveals that the proportional incidence of myocardial perfusion defects in hypothyroidism, indicating myocardial ischemia, will at least be 22% with 95% probability. Despite the relatively low specificity of SPECT it seems pertinent to conclude that impaired myocardial perfusion as assessed by SPECT probably is due to reversible coronary dysfunction inherent in the hypothyroid state, and that this is not an infrequent manifestation of severe hypothyroidism.

J Clin Endocrinol Metab. 2000 May;85(5):1822-7.
Effect of thyroid hormones on cardiac function, geometry, and oxidative metabolism assessed noninvasively by positron emission tomography and magnetic resonance imaging.
Bengel FM, Nekolla SG, Ibrahim T, Weniger C, Ziegler SI, Schwaiger M.
Thyroid hormones influence cardiac performance directly and indirectly via changes in peripheral circulation. Little, however, is known about the effect on myocardial oxidative metabolism and its relation to cardiac function and geometry. Patients with a history of thyroidectomy for thyroid cancer present a unique model to investigate the cardiac effects of hypothyroidism. Ten patients without heart disease were investigated in the hypothyroid state and again 4-6 weeks later under euthyroid conditions. Myocardial oxidative metabolism was measured by positron emission tomography with [11C]acetate and the clearance constant k(mono). Cine magnetic resonance imaging was applied to determine left ventricular geometry. A stroke work index (SWI = stroke volume x systolic blood pressure/ventricular mass) was calculated. Then, to estimate myocardial efficiency, a work metabolic index [WMI = SWI x heart rate/k(mono)] was obtained. Compared to hormone replacement, systemic vascular resistance and left ventricular mass were significantly higher in hypothyroidism. Ejection fraction and SWI were significantly lower. Despite an additional reduction of k(mono), the WMI was significantly lower, too. In summary, cardiac oxygen consumption is reduced in hypothyroidism. This reduction is associated with increased peripheral resistance and reduced contractility. Estimates of cardiac work are more severely suppressed than those of oxidative metabolism, suggesting decreased efficiency. These findings may provide an explanation for development or worsening of heart failure in hypothyroid patients with preexisting heart disease.

Acta Med Scand. 1975 Jan-Feb;197(1-2):15-7.
The adhesiveness of human blood platelets and thyroid function.
Hellem AJ, Segaard E, Solem JH.
Hypothyroidism is associated with severe coronary atherosclerosis. In spite of this the reported incidence of angina pectoris and myocardial infarction in untreated hypothyroidism is small. Since many authors consider the formation of a thrombus in coronary arteries to be the final event of the process which leads to myocardial infarction, changes in the platelet function may explain the paradoxical rarity of myocardial infarction in untreated hypothyroidism. To evaluate this hypothesis, platelet adhesiveness has been estimated before and after treatment in 9 hypothyroid and 16 thyrotoxic patients. In thyrotoxicosis the platelet adhesiveness was significantly increased, but decreased to normal after treatment. In hypothyroidism platelet adhesiveness was abnormally low but increased to normal value after thyroid hormone replacement. This may be an important factor in precipitating myocardial infarction in patients with hypothyroidism and coronary artery atherosclerosis.

Metabolism. 1997 Oct;46(10):1128-31.
Alteration of platelet aggregation in patients with thyroid disorders.
Masunaga R, Nagasaka A, Nakai A, Kotake M, Sawai Y, Oda N, Mokuno T, Shimazaki K, Hayakawa N, Kato R, Hirano E, Hagiwara M, Hidaka H.
To determine whether Graves’ disease or primary hypothyroidism influence platelet function, we evaluated platelet aggregation in the platelet-rich plasma (PRP) from such patients. Platelet aggregation induced by adenosine diphosphate (ADP) in blood obtained from patients with untreated Graves’ disease was significantly lower than normal, whereas that in patients with untreated primary hypothyroidism was relatively increased. The magnitude of platelet aggregation induced by collagen in both groups of patients resembled that induced by ADP. However, significant differences were evident between the two diseases (P < .05). In addition, we observed a significant inverse correlation between the extent of platelet aggregation and plasma levels of thyroid hormones (triiodothyronine [T3], thyroxine [T4], and free T3). Platelet aggregation returned to normal when the euthyroid condition was obtained in the patients following administration of antithyroid drugs or thyroid hormone. The findings are consistent with the possibility that thyroid hormones influence platelet aggregation partly via inhibition of myosin light-chain kinase (MLCK).

J Clin Endocrinol Metab. 2010 Jan;95(1):186-93. Epub 2009 Nov 11.
Serum thyroid-stimulating hormone concentration and morbidity from cardiovascular disease and fractures in patients on long-term thyroxine therapy.
Flynn RW, Bonellie SR, Jung RT, MacDonald TM, Morris AD, Leese GP.
CONTEXT:
For patients on T(4) replacement, the dose is guided by serum TSH concentrations, but some patients request higher doses due to adverse symptoms.
OBJECTIVE:
The aim of the study was to determine the safety of patients having a low but not suppressed serum TSH when receiving long-term T(4) replacement.
DESIGN:
We conducted an observational cohort study, using data linkage from regional datasets between 1993 and 2001.
SETTING:
A population-based study of all patients in Tayside, Scotland, was performed.
PATIENTS:
All patients taking T(4) replacement therapy (n = 17,684) were included.
MAIN OUTCOME MEASURES:
Fatal and nonfatal endpoints were considered for cardiovascular disease, dysrhythmias, and fractures. Patients were categorized as having a suppressed TSH (4.0 mU/liter).
RESULTS:
Cardiovascular disease, dysrhythmias, and fractures were increased in patients with a high TSH: adjusted hazards ratio, 1.95 (1.73-2.21), 1.80 (1.33-2.44), and 1.83 (1.41-2.37), respectively; and patients with a suppressed TSH: 1.37 (1.17-1.60), 1.6 (1.10-2.33), and 2.02 (1.55-2.62), respectively, when compared to patients with a TSH in the laboratory reference range. Patients with a low TSH did not have an increased risk of any of these outcomes [hazards ratio: 1.1 (0.99-1.123), 1.13 (0.88-1.47), and 1.13 (0.92-1.39), respectively].
CONCLUSIONS:
Patients with a high or suppressed TSH had an increased risk of cardiovascular disease, dysrhythmias, and fractures, but patients with a low but unsuppressed TSH did not. It may be safe for patients treated with T(4) to have a low but not suppressed serum TSH concentration.

Thyroid. 2002 Apr;12(4):287-93.
Thyroid disease and lipids.
Duntas LH.
The composition and the transport of lipoproteins are seriously disturbed in thyroid diseases. Overt hypothyroidism is characterized by hypercholesterolaemia and a marked increase in low-density lipoproteins (LDL) and apolipoprotein B (apo A) because of a decreased fractional clearance of LDL by a reduced number of LDL receptors in the liver. The high-density lipoprotein (HDL) levels are normal or even elevated in severe hypothyroidism because of decreased activity of cholesteryl-ester transfer protein (CETP) and hepatic lipase (HL), which are enzymes regulated by thyroid hormones. The low activity of CETP, and more specifically of HL, results in reduced transport of cholesteryl esters from HDL(2) to very low-density lipoproteins (VLDL) and intermediate low-density lipoprotein (IDL), and reduced transport of HDL(2) to HDL(3). Moreover, hypothyroidism increases the oxidation of plasma cholesterol mainly because of an altered pattern of binding and to the increased levels of cholesterol, which presents a substrate for the oxidative stress. Cardiac oxygen consumption is reduced in hypothyroidism. This reduction is associated with increased peripheral resistance and reduced contractility. Hypothyroidism is often accompanied by diastolic hypertension that, in conjunction with the dyslipidemia, may promote atherosclerosis. However, thyroxine therapy, in a thyrotropin (TSH)-suppressive dose, usually leads to a considerable improvement of the lipid profile. The changes in lipoproteins are correlated with changes in free thyroxine (FT(4)) levels. Hyperthyroidism exhibits an enhanced excretion of cholesterol and an increased turnover of LDL resulting in a decrease of total and LDL cholesterol, whereas HDL are decreased or not affected. The action of thyroid hormone on Lp(a) lipoprotein is still debated, because both decrease or no changes have been reported. The discrepancies are mostly because of genetic polymorphism of apo(a) and to the differences between the various study groups. Subclinical hypothyroidism (SH) is associated with lipid disorders that are characterized by normal or slightly elevated total cholesterol levels, increased LDL, and lower HDL. Moreover, SH has been associated with endothelium dysfunction, aortic atherosclerosis, and myocardial infarction. Lipid disorders exhibit great individual variability. Nevertheless, they might be a link, although it has not been proved, between SH and atherosclerosis.

J Rheumatol. 2012 May;39(5):954-8. Epub 2012 Feb 15.
Hypothyroidism as a risk factor for development of cardiovascular disease in patients with rheumatoid arthritis.
McCoy SS, Crowson CS, Gabriel SE, Matteson EL.
OBJECTIVE:
To determine the frequency of hypothyroidism in patients with rheumatoid arthritis (RA), and to elucidate the association of hypothyroidism and development of cardiovascular disease (CVD) in these patients.
METHODS:
A retrospective medical record review was performed using all incident cases of adult-onset RA from Olmsted County, MN, USA, that fulfilled criteria for RA in the years 1988-2007. Patients with and without thyroid disease were followed longitudinally for the development of CVD.
RESULTS:
A cohort of 650 patients with RA and an age and sex-matched comparison cohort of 650 patients without RA was assembled (both cohorts mean age 55.8 yrs; 69% were women). There was no significant difference between cohorts in the presence of hypothyroid disease or subclinical hypothyroidism at time of RA diagnosis. No significant difference was found in the cumulative incidence of hypothyroid disease between the 2 cohorts. Hypothyroid disease was found to be significantly associated with CVD in patients with RA (hazard ratio 2.0; 95% CI 1.1, 3.6). This difference remained significant and unchanged after adjustment for traditional CV risk factors (HR 2.0; 95% CI 1.1, 3.6).
CONCLUSION:
No significant difference was found in either incidence or prevalence of hypothyroidism between patients with and those without RA. Hypothyroid disease was significantly associated with CVD in patients with RA, even after adjustment for other traditional CV risk factors.