A. Martin Gerdes

Both Hypothyroidism and Hyperthyroidism Increase Atrial Fibrillation Inducibility in Rats

Background— Evidence indicates that cardiac hypothyroidism may contribute to heart failure progression. It is also known that heart failure is associated with an increased risk of atrial fibrillation (AF). Although it is established that hyperthyroidism increases AF incidence, the effect of hypothyroidism on AF is unclear. This study investigated the effects of different thyroid hormone levels, ranging from hypothyroidism to hyperthyroidism on AF inducibility in thyroidectomized rats. Methods and Results— Thyroidectomized rats with serum-confirmed hypothyroidism 1 month after surgery were randomized into hypothyroid (N=9), euthyroid (N=9), and hyperthyroid (N=9) groups. Rats received placebo, 3.3-mg L-thyroxine (T4), or 20-mg T4 pellets (60-day release form) for 2 months, respectively. At the end of treatment, hypothyroid, euthyroid, and hyperthyroid status was confirmed. Hypothyroid animals showed cardiac atrophy and reduced cardiac systolic and diastolic functions, whereas hyperthyroid rats exhibited cardiac hypertrophy and increased cardiac function. Hypothyroidism and hyperthyroidism produced opposite electrophysiological changes in heart rates and atrial effective refractory period, but both significantly increased AF susceptibility. AF incidence was 78% in hypothyroid, 67% in hyperthyroid, and the duration of induced AF was also longer, compared with 11% in the euthyroid group (all P<0.05). Hypothyroidism increased atrial interstitial fibrosis, but connexin 43 was not affected. Conclusions— Both hypothyroidism and hyperthyroidism lead to increased AF vulnerability in a rat thyroidectomy model. Our results stress that normal thyroid hormone levels are required to maintain normal cardiac electrophysiology and to prevent cardiac arrhythmias and AF.

Thyroid hormone replacement therapy attenuates atrial remodeling and reduces atrial fibrillation inducibility in a rat myocardial infarction-heart failure model.

BACKGROUNDnHeart failure (HF) is associated with increased atrial fibrillation (AF) risk. Accumulating evidence suggests the presence of myocardial tissue hypothyroidism in HF, which may contribute to HF development. In a recent report we demonstrated that hypothyroidism, like hyperthyroidism, leads to increased AF inducibility. The present study was designed to investigate the effect of thyroid hormone (TH) replacement therapy on AF arrhythmogenesis in HF.nnnMETHODS AND RESULTSnMyocardial infarction (MI) was produced in rats by means of coronary artery ligation. Rats with large MIs (>40%) were randomized into L-thyroxine (T4; nxa0= 14) and placebo (nxa0= 15) groups 2 weeks after MI. Rats received 3.3 mg T4 (in 60-day release form) or placebo pellets for 2 months. Compared with the placebo, T4 treatment improved cardiac function and decreased left ventricular internal diameters as well as left atrial diameter. T4 treatment attenuated atrial effective refractory period prolongation (45 ± 1.5 ms in placebo group vs 37 ± 1.6 ms in T4 group; P < .01) and reduced AF inducibility (AF/atrial flutter/tachycardia were inducible in 11/15 rats [73%] in the placebo- vs 4/14 rats [29%] in the T4-treated group; P < .05). Arrhythmia reduction was associated with decreased atrial fibrosis but was not associated with connexin 43 changes.nnnCONCLUSIONSnTo our knowledge this is the first study demonstrating that TH replacement therapy in HF attenuates atrial remodeling and reduces AF inducibility after MI-HF. Clinical studies are needed to confirm such benefits in human patients.

Restoration of Cardiac Tissue Thyroid Hormone Status in Experimental Hypothyroidism: A Dose-Response Study in Female Rats

Thyroid hormones (THs) play a pivotal role in regulating cardiovascular homeostasis. To provide a better understanding of the coordinated processes that govern cardiac TH bioavailability, this study investigated the influence of serum and cardiac TH status on the expression of TH transporters and cytosolic binding proteins in the myocardium. In addition, we sought to determine whether the administration of T(3) (instead of T(4)) improves the relationship between THs in serum and cardiac tissue and cardiac function over a short-term treatment period. Adult female Sprague Dawley rats were made hypothyroid by 7 weeks treatment with the antithyroid drug 6-n-propyl-2-thiouracil (PTU). After establishing hypothyroidism, rats were assigned to 1 of 5 graded T(3) dosages plus PTU for a 2-week dose-response experiment. Untreated, age-matched rats served as euthyroid controls. PTU was associated with depressed serum and cardiac tissue T(3) and T(4) levels, arteriolar atrophy, altered TH transporter and cytosolic TH binding protein expression, fetal gene reexpression, and cardiac dysfunction. Short-term administration of T(3) led to a mismatch between serum and cardiac tissue TH levels. Normalization of serum T(3) levels was not associated with restoration of cardiac tissue T(3) levels or cardiac function. In fact, a 3-fold higher T(3) dosage was necessary to normalize cardiac tissue T(3) levels and cardiac function. Importantly, this study provides the first comprehensive data on the relationship between altered TH status (serum and cardiac tissue), cardiac function, and the coordinated in vivo changes in cardiac TH membrane transporters and cytosolic TH binding proteins in altered TH states.

Thyroid Status, Cardiac Function, and Mortality in Patients With Idiopathic Dilated Cardiomyopathy

CONTEXTnPrevious studies claiming a relationship between thyroid dysfunction and poor prognosis of heart failure (HF) had a major limitation in that they included patients with different etiologies.nnnOBJECTIVEnWith complete information of thyroid function profile from 458 consecutive patients with idiopathic dilated cardiomyopathy, we tested the hypothesis that thyroid status can independently influence mortality in patients with HF. Design, Patients, and Outcome Measure: The original cohort consisted of 572 consecutive patients with idiopathic dilated cardiomyopathy, and 458 patients remained at the end of follow-up. All patients took thyroid function tests and other regular examinations in hospital. The risk of mortality was evaluated based on free T3, TSH, and the whole thyroid function profile, respectively.nnnRESULTSnThe most frequent thyroid dysfunction was subclinical hypothyroidism (n = 41), followed by subclinical hyperthyroidism (n = 35), low-T3 syndrome (n = 17), and hypothyroidism (n = 12). Logistic analysis showed log-TSH and free T3 as independent predictors of exacerbated cardiac function (New York Heart Association stages III-IV vs New York Heart Association stages I-II). During the follow-up (17 ± 8 mo), 111 cumulative deaths occurred. Hypothyroidism was the strongest predictor of mortality [hazard ratio (HR) 4.189; 95% confidence interval (CI) 2.118-8.283)], followed by low-T3 syndrome (HR 3.147; 95% CI 1.558-6.355) and subclinical hypothyroidism (HR 2.869; 95% CI 1.817-4.532). Subclinical hyperthyroidism showed no significant impact.nnnCONCLUSIONSnWe found a clear association between thyroid dysfunction and increased risk of mortality in idiopathic dilated cardiomyopathy with HF. These results suggest that monitoring thyroid function in HF patients is necessary, and further studies on the treatment of HF with thyroid dysfunction are needed.

Myocyte Changes in Heart Failure

Structural remodeling is a major feature of heart failure and typically precedes the development of symptomatic disease. Structural remodeling of the heart reflects changes in myocyte morphology. Disproportional myocyte growth is observed in pathologic concentric hypertrophy (myocyte thickening) and in eccentric dilated hypertrophy (myocyte lengthening). Alterations in myocyte shape lead to changes in chamber geometry and wall stress. Human and animal studies indicate that changes in myocyte morphology are reversible. Normalization or reversal of maladaptive cardiomyocyte remodeling should be a therapeutic aim that can prevent deterioration or improve cardiac function in heart failure.

Safe Oral Triiodo-L-Thyronine Therapy Protects from Post-Infarct Cardiac Dysfunction and Arrhythmias without Cardiovascular Adverse Effects

Background A large body of evidence suggests that thyroid hormones (THs) are beneficial for the treatment of cardiovascular disorders. We have shown that 3 days of triiodo-L-thyronine (T3) treatment in myocardial infarction (MI) rats increased left ventricular (LV) contractility and decreased myocyte apoptosis. However, no clinically translatable protocol is established for T3 treatment of ischemic heart disease. We hypothesized that low-dose oral T3 will offer safe therapeutic benefits in MI. Methods and Results Adult female rats underwent left coronary artery ligation or sham surgeries. T3 (~6 μg/kg/day) was available in drinking water ad libitum immediately following MI and continuing for 2 month(s) (mo). Compared to vehicle-treated MI, the oral T3-treated MI group at 2 mo had markedly improved anesthetized Magnetic Resonance Imaging-based LV ejection fraction and volumes without significant negative changes in heart rate, serum TH levels or heart weight, indicating safe therapy. Remarkably, T3 decreased the incidence of inducible atrial tachyarrhythmias by 88% and improved remodeling. These were accompanied by restoration of gene expression involving several key pathways including thyroid, ion channels, fibrosis, sympathetic, mitochondria and autophagy. Conclusions Low-dose oral T3 dramatically improved post-MI cardiac performance, decreased atrial arrhythmias and cardiac remodeling, and reversed many adverse changes in gene expression with no observable negative effects. This study also provides a safe and effective treatment/monitoring protocol that should readily translate to humans.

Role of Thyroid Hormones in Ventricular Remodeling

Cardiac remodeling includes alterations in molecular, cellular, and interstitial systems contributing to changes in size, shape, and function of the heart. This may be the result of injury, alterations in hemodynamic load, neurohormonal effects, electrical abnormalities, metabolic changes, etc. Thyroid hormones (THs) serve as master regulators for diverse remodeling processes of the cardiovascular system—from the prenatal period to death. THs promote a beneficial cardiomyocyte shape and improve contractility, relaxation, and survival via reversal of molecular remodeling. THs reduce fibrosis by decreasing interstitial collagen and reduce the incidence and duration of arrhythmias via remodeling ion channel expression and function. THs restore metabolic function and also improve blood flow both by direct effects on the vessel architecture and decreasing atherosclerosis. Optimal levels of THs both in the circulation and in cardiac tissues are critical for normal homeostasis. This review highlights TH-based remodeling and clinically translatable strategies for diverse cardiovascular disorders.

Long-term physiological T3 supplementation in hypertensive heart disease in rats.

Animal studies suggest that hypertension leads to cardiac tissue hypothyroidism, a condition that can by itself lead to heart failure. We have previously shown that short-term thyroid hormone treatment in Spontaneously Hypertensive Heart Failure (SHHF) rats near heart failure is beneficial. This study tested the hypothesis that therapeutic, long-term T3 treatment in SHHF rats can prevent or attenuate cardiac dysfunction. Female SHHF rats were treated orally with a physiological T3 dose (0.04 μg/ml) from 12 to 24 mo of age. Age-matched female SHHF and Wistar-Kyoto rats served as hypertensive and normotensive controls, respectively. SHHF rats had reduced serum free thyroid hormone levels and cardiac tissue T3 levels, LV dysfunction, and elevated LV collagen content compared with normotensive controls. Restoration of serum and cardiac tissue thyroid hormone levels in T3-treated rats was associated with no change in heart rate, but strong trends for improvement in LV systolic function and collagen levels. For instance, end-systolic diameter, fractional shortening, systolic wall stress, and LV collagen levels were no longer significantly different from controls. In conclusion, longstanding hypertension in rats led to chronic low serum and cardiac tissue thyroid hormone levels. Long-term treatment with low-dose T3 was safe. While cardiac dysfunction could not be completely prevented in the absence of antihypertensive treatment, T3 may offer additional benefits as an adjunct therapy with possible improvement in diastolic function.

How to improve the overall quality of cardiac morphometric data.

By the mid-1990s, experts realized that drugs leading to improved ventricular remodeling were doing something remarkable in cardiac patients. The age of cardiac remodeling had begun. This created an experimental need for high-quality assessment of changes in cardiac tissue composition, including myocyte shape, myocardial fibrosis/collagen, and vascular remodeling. Many working in the field today have little or no training related to recognition of fixation artifacts or common errors associated with quantitative morphology. Unfortunately, such skills had become somewhat of a lost art during the ages of cardiac physiology in the mid-20th century and molecular biology, gaining prominence by the mid-1970s. Consequently, cardiac remodeling studies today are often seriously flawed to the point where data are not reproducible and subsequent researchers may be chasing the molecular basis of a nonexistent or erroneous phenotype. The current unacceptably high incidence of irreproducible data is a serious waste of time and resources as recently noted in comments by the National Institutes of Health director. The goal of this how to article is to share some lessons I have learned during nearly 40 years of assessing morphological changes in the heart. It is possible for any laboratory to routinely publish highly reproducible morphological data that stand the test of time and contribute to our fundamental knowledge of cardiac remodeling and the molecular mechanisms that drive it.

Modified Low-Dose Triiodo-L-thyronine Therapy Safely Improves Function Following Myocardial Ischemia-Reperfusion Injury

Background: We have shown that thyroid hormones (THs) are cardioprotective and can be potentially used as safe therapeutic agents for diabetic cardiomyopathy and permanent infarction. However, no reliable, clinically translatable protocol exists for TH treatment of myocardial ischemia-reperfusion (IR) injury. We hypothesized that modified low-dose triiodo-L-thyronine (T3) therapy would confer safe therapeutic benefits against IR injury. Methods: Adult female rats underwent left coronary artery ligation for 60 min or sham surgeries. At 2 months following surgery and T3 treatment (described below), the rats were subjected to functional, morphological, and molecular examination. Results: Following surgery, the rats were treated with T3 (8 μg/kg/day) or vehicle in drinking water ad libitum following IR for 2 months. Oral T3 significantly improved left ventricular (LV) contractility, relaxation, and relaxation time constant, and decreased beta-myosin heavy chain gene expression. As it takes rats ~6 h post-surgery to begin drinking water, we then investigated whether modified T3 dosing initiated immediately upon reperfusion confers additional improvement. We injected an intraperitoneal bolus of T3 (12 μg/kg) upon reperfusion, along with low-dose oral T3 (4.5 μg/kg/day) in drinking water for 2 months. Continuous T3 therapy (bolus + low-dose oral) enhanced LV contractility compared with oral T3 alone. Relaxation parameters were also improved compared to vehicle. Importantly, these were accomplished without significant increases in hypertrophy, serum free T3 levels, or blood pressure. Conclusions: This is the first study to provide a safe cardiac therapeutic window and optimized, clinically translatable treatment-monitoring protocol for myocardial IR using commercially available and inexpensive T3. Low-dose oral T3 therapy supplemented with bolus treatment initiated upon reperfusion is safer and more efficacious.