Cardiovascular effects of hypothyroidism

INTRODUCTION — Hypothyroidism is characterized by a decrease in oxygen and substrate utilization by all the major organ systems of the body. As a result, the demands for cardiac output decrease; in addition, hypothyroidism directly alters cardiac function through changes in myocyte-specific gene expression [1]. This topic will review the cardiovascular manifestations of overt hypothyroidism. Other symptoms of hypothyroidism and cardiovascular manifestations of subclinical hypothyroidism are discussed separately. (See "Clinical manifestations of hypothyroidism" and "Subclinical hypothyroidism in nonpregnant adults".)

PATHOPHYSIOLOGY — The major cardiovascular changes that occur in hypothyroidism include a decrease in cardiac output and cardiac contractility, a reduction in heart rate, and an increase in peripheral vascular resistance (figure 1) [2,3]. There are also significant changes in modifiable atherosclerotic risk factors, including hypercholesterolemia, diastolic hypertension, carotid intimal media thickness, and endothelial derived relaxation factor (nitric oxide), which accompany overt hypothyroidism [1-5].

Cardiac contractility — All measures of left ventricular performance are impaired in both short- and long-term hypothyroidism, leading to a reduction in cardiac output [4,5]. There is also a decrease in the rate of ventricular diastolic relaxation; as a result, compliance and diastolic filling are impaired [6].

The reduced ventricular performance is probably multifactorial. Possible mechanisms include increases in afterload and changes in expression of the genes for myocardial calcium regulatory proteins [1,6]. Several enzymes involved in regulating calcium fluxes in the heart are controlled by thyroid hormone, including the calcium-dependent adenosine triphosphatase and phospholamban [3,7]. Hypothyroidism-dependent decreases in the expression and activity of these enzymes could potentially impair systolic performance and diastolic relaxation [6]. Beta-adrenergic receptor expression is also decreased, resulting in a blunted response to catecholamine mediated increases in inotropy.

Vascular resistance — Thyroid hormone relaxes vascular smooth muscle cells, thereby reducing peripheral vascular resistance [3]. Conversely, hypothyroidism causes a decrease in the release of endothelial-derived relaxing factor (EDRF), which in turn promotes contraction of these cells, thereby increasing peripheral vascular resistance [2]. This change results in reductions in cardiac output (in part because the heart cannot increase contractility to compensate) and tissue perfusion. Tissue oxygen utilization is also decreased; thus, arteriovenous (A-V) oxygen extraction is not different from that in normal subjects [4].

CLINICAL MANIFESTATIONS — Symptoms and signs of cardiovascular dysfunction are not common or prominent in patients with hypothyroidism. Those that do occur include (table 1) [1,3,6]:

●Exertional dyspnea and exercise intolerance, although these symptoms are probably due to skeletal muscle dysfunction

●Bradycardia

●Hypertension resulting from the increase in vascular resistance and the fall in endothelial-derived relaxing factor (EDRF) [3]

●Cardiac dysfunction with poor contractility, dilatation, or pericardial effusion

●Edema, often nonpitting

●Pericardial effusions, which occur in approximately 25 percent of patients and may be quite large

Rhythm disturbances — In addition to a slow pulse rate, hypothyroid patients may have ventricular premature beats and rarely ventricular tachycardia with a long QT interval (torsade de pointes) [8] (see "Acquired long QT syndrome: Definitions, pathophysiology, and causes"). This can be especially problematic in patients with underlying ischemic heart disease or known ventricular arrhythmias. Treatment with amiodarone can produce hypothyroidism and, in turn, further predispose the ischemic heart to ventricular arrhythmias. (See "Amiodarone and thyroid dysfunction", section on 'Hypothyroidism'.)

Blood pressure — Thyroid hormone plays a role in blood pressure homeostasis. In patients who had undergone total thyroidectomy for thyroid cancer, withdrawal of thyroxine (T4) for six weeks results in an increase in serum norepinephrine and aldosterone concentrations and an increase in blood pressure with a greater rise in diastolic pressure (126/85 compared with 120/76 mmHg at baseline) [9]. Diastolic blood pressure may vary directly with serum thyroid-stimulating hormone (TSH) levels over the entire spectrum of thyroid disease [1,9].

Approximately 20 to 40 percent of hypothyroid patients have hypertension, even though cardiac output is reduced [6,10]. The hypertension is primarily diastolic, and the pulse pressure is diminished. In hypertensive hypothyroid patients, the serum levels of renin are low and there is an increased prevalence of salt sensitivity, confirming the importance of the increase in systemic vascular resistance [1,8]. Among large groups of patients with hypertension, however, hypothyroidism is a contributory factor in only a small percentage [10].

Cardiac dysfunction — The upstroke of the pulse may be slow and the left ventricular apical impulse weak [5]. The heart may be enlarged and the heart sounds distant. These findings, plus dyspnea, exercise intolerance, and edema, may make it seem as if the patient has heart failure. While heart failure due solely to hypothyroidism is rare [3], in patients with underlying or preexistent cardiac disease, the presence or development of hypothyroidism leads to more severe heart failure, higher levels of brain natriuretic peptide (BNP) [7], and worse short-term hospital outcomes [11].

Electrocardiograms may show low voltage and nonspecific ST segment and Q wave changes. Occasionally, large pericardial effusion can occur, characterized by a high protein and cholesterol content (image 1). These are rarely hemodynamically important and should be managed with thyroid hormone replacement, not by needle or surgical drainage. The latter can lead to hemodynamic worsening [12].

Coronary artery disease — Patients with angina pectoris probably have symptoms less often if they become hypothyroid because they are less active and peripheral oxygen demands decrease. The occurrence of anginal-like pain in some hypothyroid patients and the frequent occurrence of hypercholesterolemia diastolic hypertension, and elevated homocysteine levels have led to suggestions that hypothyroidism is associated with accelerated coronary artery disease [1,5].

Potential mechanisms in addition to lipid abnormalities and diastolic hypertension include elevated concentrations of C-reactive protein and endothelial dysfunction [2,13,14].

The potential risk of coronary artery disease in subclinical hypothyroidism is discussed elsewhere. (See "Subclinical hypothyroidism in nonpregnant adults".)

Edema — Periorbital edema and nonpitting edema of the hands and feet are characteristic features of hypothyroidism, albeit rare today. Nonpitting edema is due to interstitial accumulation of glycosaminoglycans (hyaluronic acid and chondroitin sulfate), with associated extravascular water retention at the same time that plasma volume is decreased [3,4,15]. Some patients have pitting edema of the feet and legs, probably secondary to an increase in albumin content of the interstitial fluid [16]. Ascites, pleural, and scrotal effusions may also be present.

Laboratory tests

Lipids — Dyslipidemia is common in hypothyroidism. The usual findings are high serum total and low-density lipoprotein (LDL) cholesterol concentrations. Some patients have high serum very low-density lipoprotein (VLDL) cholesterol concentrations, and a few have hypertriglyceridemia. Lipid abnormalities in hypothyroidism are reviewed in more detail separately. (See "Lipid abnormalities in thyroid disease".)

Homocysteine — Some patients with hypothyroidism have high serum homocysteine concentrations, which fall toward, if not to, normal with T4 therapy [17].

Creatine kinase — Many hypothyroid patients have high serum creatine kinase (CK) concentrations. The isoenzyme distribution is almost completely MM, with less than 4 percent constituting MB, indicating skeletal muscle, not myocardial, origin [18]. However, as many as 14 percent of patients with hypothyroidism have a raised serum concentration of CK-MB, which can be confusing in the evaluation of chest pain. This problem is obviated by measurement of serum troponin I, which is normal in hypothyroidism [14]. (See "Troponin testing: Clinical use".)

EFFECT OF TREATMENT — The changes in cardiovascular function in hypothyroidism respond to replacement therapy with T4 (figure 2) [5]. In older patients or those with a history of angina, it is wise to begin therapy with a low dose of T4 because of the possibility of inducing an arrhythmia or an exacerbation of angina. Patients with coronary artery disease without other cardiopulmonary problems who have had recent successful interventions to treat ischemia (eg, coronary artery bypass grafting [CABG] or coronary artery stenting) are candidates for more conventional initial dosing. (See "Treatment of primary hypothyroidism in adults", section on 'Older patients or those with coronary heart disease'.)

A 1961 report remains the largest and best study of the effects of beginning thyroid hormone on chest pain in patients with hypothyroidism [19]. Among 1503 hypothyroid patients, the following findings were noted:

●Fifty-five patients had angina before thyroid hormone replacement therapy. During therapy, 21 improved, 25 had no change, and 9 had more angina.

●Thirty-five patients developed new angina during therapy, 6 during the first month, 6 during the first year, and 23 after 1 year.

Thus, angina may improve, and it does not often appear during T4 replacement therapy.

In patients with overt hypothyroidism, T4 therapy for several months raises the 24-hour heart rate by approximately 10 percent. It usually does not increase the frequency of premature atrial complex (PAC; also referred to as a premature atrial beat, premature supraventricular complex, or premature supraventricular beat; 22 of 25 patients had no increase in one study [20]) or of premature ventricular beats. TSH measurements should guide treatment to assure precise replacement into the optimal euthyroid range.

The clearance of coagulation factors is decreased in hypothyroidism [21]. In patients being treated with warfarin anticoagulation, the dose required to maintain a therapeutic prothrombin time increases during hypothyroidism, and this increase is reversed with restoration of a normal TSH [1].

The long-term cardiovascular outcomes of patients treated for overt hypothyroidism are unclear. A population-based study assessed mortality and vascular outcomes among 15,889 treated individuals and 524,152 subjects in the general population [22]. Excess cardiovascular morbidity from arrhythmias and nonfatal ischemic heart and cerebrovascular disease was observed among those treated for hypothyroidism [22]. However, there was no increase in all-cause mortality. The long-term cardiovascular effects of treatment of patients with subclinical hypothyroidism are reviewed separately. (See "Subclinical hypothyroidism in nonpregnant adults", section on 'Cardiovascular disease'.)

SUMMARY

●Cardiovascular changes – The major cardiovascular changes that occur in hypothyroidism include a decrease in cardiac output and cardiac contractility, a reduction in heart rate, and an increase in peripheral vascular resistance. (See 'Pathophysiology' above.)

●Cardiac clinical manifestations – Symptoms of cardiovascular dysfunction are not common or prominent in patients with hypothyroidism. They may include exertional dyspnea, exercise intolerance, and edema. Findings on physical examination may include bradycardia, hypertension, nonpitting edema, and pleural or pericardial effusion (table 1). (See 'Clinical manifestations' above.)

Dyslipidemia is common in hypothyroidism. The usual findings are high serum total and low-density lipoprotein (LDL) cholesterol concentrations. (See 'Lipids' above.)

●Effect of treatment – The changes in cardiovascular function in hypothyroidism respond to replacement therapy with thyroxine (T4) (figure 2). (See 'Effect of treatment' above.)