Single-channel activity and expression of atrial L-type Ca(2+) channels in patients with latent hyperthyroidism

Patients with "latent hyperthyroidism" (suppressed thyroid-stimulating hormone and normal circulating thyroid hormones) are at risk to develop atrial fibrillation. In animal models, hyperthyroidism is associated with increased cardiac L-type Ca(2+) current. Therefore, we assessed L-type channel function and expression in right atria from patients undergoing cardiac surgery. Single L-type channels were studied in the cell-attached condition. Voltage dependence of gating was similar in patients with and without latent hyperthyroidism. With use of a pulse protocol leading to maximum channel availability, single-channel activity was further analyzed. Average peak current was significantly enhanced in latent hyperthyroidism, mainly because of an increased channel availability (P < 0.05). Protein expression was analyzed by Western blot. In latent hyperthyroidism, expression of Ca(2+) channel alpha(1)-subunits was increased more than threefold (P < 0.01). In contrast, sarco(endo)plasmic reticulum Ca(2+)-ATPase and phospholamban levels were not significantly changed. We only observed a trend toward increased sarco(endo)plasmic reticulum Ca(2+)-ATPase expression (P = 0.085). Function and expression of human atrial L-type Ca(2+) channels are increased in latent hyperthyroidism. These endocrine effects on the heart may be clinically relevant.     

Atrial fibrillation and hyperthyroidism

Atrial fibrillation occurs in 10 - 15% of patients with hyperthyroidism. Low serum thyrotropin concentration is an independent risk factor for atrial fibrillation. Thyroid hormone contributes to arrythmogenic activity by altering the electrophysiological characteristics of atrial myocytes by shortening the action potential duration, enhancing automaticity and triggered activity in the pulmonary vein cardio myocytes. Hyperthyroidism results in excess mortality from increased incidence of circulatory diseases and dysrhythmias. Incidence of cerebral embolism is more in hyperthyroid patients with atrial fibrillation, especially in the elderly and anti-coagulation is indicated in them. Treatment of hyperthyroidism results in conversion to sinus rhythm in up to two-third of patients. Beta-blockers reduce left ventricular hypertrophy and atrial and ventricular arrhythmias in patients with hyperthyroidism. Treatment of sub clinical hyperthyroidism is controversial. Optimizing dose of thyroxine treatment in those with replacement therapy and beta-blockers is useful in exogenous subclinical hyperthyroidism.     

New-Onset Atrial Fibrillation Is a Predictor of Subsequent Hyperthyroidism: A Nationwide Cohort Study

Aims

To examine the long-term risk of hyperthyroidism in patients admitted to hospital with new-onset AF. Hyperthyroidism is a well-known risk factor for atrial fibrillation (AF), but it is unknown whether new-onset AF predicts later-occurring hyperthyroidism.

Methods and Results

All patients admitted with new-onset AF in Denmark from 1997–2009, and their present and subsequent use of anti-thyroid medication was identified by individual-level linkage of nationwide registries. Patients with previous thyroid diagnosis or thyroid medication use were excluded. Development of hyperthyroidism was assessed as initiation of methimazole or propylthiouracil up to a 13-year period. Risk of hyperthyroidism was analysed by Poisson regression models adjusted for important confounders such as amiodarone treatment. Non-AF individuals from the general population served as reference. A total of 145,623 patients with new-onset AF were included (mean age 66.4 years [SD ±13.2] and 55.3% males) of whom 3% (4,620 events; 62.2% women) developed hyperthyroidism in the post-hospitalization period compared to 1% (48,609 events; 82% women) in the general population (n = 3,866,889). In both women and men we found a significantly increased risk of hyperthyroidism associated with new-onset AF compared to individuals in the general population. The highest risk was found in middle-aged men and was consistently increased throughout the 13-year period of observation. The results were confirmed in a substudy analysis of 527,352 patients who had thyroid screening done.

Conclusion

New-onset AF seems to be a predictor of hyperthyroidism. Increased focus on subsequent risk of hyperthyroidism in patients with new-onset AF is warranted.     

Subclinical hyperthyroidism

Subclinical hyperthyroidism is a term used to define a clinical condition in which a reduced serum thyroid stimulating hormone (TSH) level is accompanied by thyroxine and tri-iodothyronine levels within the reference ranges. It is a common condition with the prevalence in the general population estimated on 0.6-16%. Subclinical hypethyroidism may progress to overt hyperthyroidism and is associated with the risk of the development of cardiovascular complications (especially atrial fibrillation), osteoporosis and dementia. Indications for the management of subclinical hyperthyroidism still remain controversial. The aim of this paper is to familiarise the reader with the present state of knowledge on the prevalence, etiopathogenesis, clinical manifestation, diagnosis, potential complications, prognosis and treatment of subclinical hyperthyroidism.     

Hyperthyroidism in the elderly: aspecific signs may cause a delay in diagnosis

The clinical manifestations of thyroid diseases in the elderly are often atypical and can easily be attributed to other medical conditions or 'normal aging'. Two nursing home patients with hyperthyroidism are described. Due to the atypical presentation of the thyroid disease their complaints were attributed to other conditions. In both patients there was a significant delay in diagnosis and treatment of hyperthyroidism. In elder patients signs and symptoms of thyreotoxicosis are frequently related to cardiovascular, gastrointestinal and neuropsychiatric disorders. Most often occur atrial fibrillation, worsening of cardiac failure and angina pectoris, weight loss, anorexia, constipation, cognitive impairment and delirium. Delay of diagnosis and treatment of hyperthyroidism may be potentially harmful to the patient. Untreated thyreotoxicosis may lead to serious cardiovasculair complications (particularly cardiac failure and cerebrovascular accidents), mental deterioration and osteoporosis. In elder people with unexplained and vague signs and symptoms thyroid function should always be checked. The TSH assay is a very accurate diagnostic test for screening thyroid function. A normal TSH indicates euthyroidism with an accuracy of almost 100%. The medical treatment for hyperthyreoidism in the elderly are antithyroid drugs. When an euthyroid state is rendered, suppletion with L-thyroxine may be nessecary. Radioactive iodine treatment is preferred in some cases though there may be practical difficulties with the application of this treatment in nursing home patients because temporary isolation is necessary.     

Diagnostic value of thyrotrophin releasing hormone tests in elderly patients with atrial fibrillation.

A prospective study was carried out to compare clinical and biochemical thyroid states with responses of thyroid stimulating hormone (TSH) to thyrotrophin releasing hormone (TRH) in elderly patients with either atrial fibrillation (n = 75; mean age (SD) 79.3 (6.0) years) or sinus rhythm (n = 73; mean age 78.4 (5.6) years) admitted consecutively to the department of geriatric medicine. No patient in either group had symptoms or signs of hyperthyroidism. Overall, the TSH responses to TRH did not differ significantly between the two groups. Ten (13%) of the patients with atrial fibrillation (of whom four had raised thyroid hormone concentrations) and five (7%) of the patients with sinus rhythm showed no TSH response to TRH while 26% of each group (20 and 19 patients, respectively) showed a much reduced response. Only one of 13 patients with apparently isolated atrial fibrillation showed no TSH response to TRH, and none of these 13 patients was hyperthyroid. In particular, three patients (two with atrial fibrillation and one with sinus rhythm) who showed no TSH response to TRH at presentation exhibited a return of TSH response to TRH at follow up six weeks later. In conclusion, reduced or absent TSH responses to TRH are common in sick elderly patients whether they have atrial fibrillation or sinus rhythm and whether they are euthyroid or hyperthyroid biochemically. An absence of response is therefore an uncertain marker of hyperthyroidism in these groups of patients, and diagnosis and ablative treatment should be based at least on the presence of raised circulating free triiodothyronine or free thyroxine concentrations, or both.     

Thyroid hormone regulates mRNA expression and currents of ion channels in rat atrium

Atrial fibrillation is one of the common arrhythmias associated with hyperthyroidism. This study examined the effects of thyroid hormone (T3) on mRNA expression and currents of major ionic channels determining the action potential duration (APD) in the rat atrium using the RNase protection assay and the whole-cell patch-clamp technique, respectively. T3 increased the Kv1.5 mRNA expression and decreased the L-type calcium channel mRNA expression, while the Kv4.2 mRNA expression did not change. APD was shorter in hyperthyroid than in euthyroid myocytes. The ultrarapid delayed rectifier potassium currents were remarkably increased in hyperthyroid than in euthyroid myocytes, whereas the transient outward potassium currents were unchanged. L-type calcium currents were decreased in hyperthyroid than in euthyroid myocytes. T3 shifted the current-voltage relationship for calcium currents negatively. In conclusion, T3 increased the outward currents and decreased the inward currents. The resultant changes of ionic currents shortened APD, providing a substrate for atrial fibrillation.     

Effects of Thyroid Dysfunction and the Thyroid-Stimulating Hormone Levels on the Risk of Atrial Fibrillation: A Systematic Review and Dose-Response Meta-Analysis from Cohort Studies

ObjectiveTo explore the relationship between thyroid dysfunction, thyroid-stimulating hormone (TSH) levels, and risks of atrial fibrillation (AF) in studies and conduct a dose-response meta-analysis on the correlation between the TSH levels and risk of AF.MethodsThirteen studies from 5 databases with 649 293 subjects (mean age, 65.1 years) were included. The dose-response meta-analysis was conducted by comparing the risk ratios (RRs) and 95% confidence intervals (CIs) for incident AF associated with different levels of TSH (vs TSH level of 0 mU/L) across studies. Data were collected until October 25, 2021.ResultsSubclinical hyperthyroidism, subclinical hypothyroidism, and clinical hyperthyroidism were associated with an increased risk of AF (RR, 1.70; 95% CI, 1.11-2.62; RR, 1.23; 95% CI, 1.05-1.44; and RR, 2.35; 95% CI, 1.07-5.16, respectively), whereas clinical hypothyroidism was not associated with the significantly increased risk of AF (RR, 1.20; 95% CI, 0.72-1.99). A nonlinear relationship was observed in 2 models (crude model, P_nonlinear < .001; adjusted model, P_nonlinear = .0391) between the TSH levels and risks of AF.ConclusionsOur study indicated that subclinical hyperthyroidism, subclinical hypothyroidism, clinical hyperthyroidism were associated with the risk of AF, and the results for the TSH levels and risk of AF were mixed, which showed a U-shaped relationship.     

Mortality Risk After Radioiodine Therapy for Hyperthyroidism: A Systematic Review and Meta-Analysis

ObjectiveRadioiodine has been increasingly used to treat hyperthyroidism for many years. Although widely regarded as an effective therapy, radioiodine treatment for hyperthyroidism has been suspected to be associated with the risk of mortality. This study aimed to quantify the mortality outcomes in patients who were treated for hyperthyroidism with radioiodine.MethodsSystematic search and meta-analysis were performed to determine the risk of mortality in patients treated with radioiodine for hyperthyroidism. Relevant studies were searched through August 2020 and selected in accordance with the inclusion criteria.ResultsA total of 13 studies were identified. The summary odds ratios (ORs) showed an increased risk of all-cause mortality in patients who were treated with radioiodine for hyperthyroidism (OR = 1.20; 95% CI = 1.07-1.35). The risk of death attributed to all forms of circulatory, respiratory, and endocrine and metabolic diseases was significantly increased, with summary ORs of 1.23 (95% CI, 1.12-1.35), 1.43 (95% CI, 1.17-1.75), and 2.38 (95% CI, 1.85-3.06), respectively. The summary ORs revealed no significant association between radioiodine treatment for hyperthyroidism and the risk of cancer mortality (OR = 1.03; 95% CI, 0.98-1.09). Radioiodine treatment for hyperthyroidism was not associated with the risk of mortality from breast, respiratory system, gastrointestinal, and genitourinary cancers.ConclusionRadioiodine treatment for hyperthyroidism is associated with the risk of all-cause mortality but not cancer mortality. Future research needs to address the causes of hyperthyroidism, effects of radioiodine therapy, and potential effects of confounding to identify causality.     

Prolonged ventricular repolarization measured by corrected QT interval (QTc) in subclinical hyperthyroidism.

Overt hyperthyroidism and hypothyroidism exert a major effect on cardiac function and on ECG. The influence of subclinical hyperthyroidism on the circulatory system is still under debate. Few studies examined the effect of thyroid hormones on ventricular repolarization measured by corrected QT interval (QTc). Longer QTc is associated with increased risk of arrhythmia and cardiac mortality. The aim of this study was to examine the influence of subclinical hyperthyroidism on ventricular repolarization measured by corrected QTc in a standard 12-lead electrocardiogram. The examined group consisted of thirty-two patients with subclinical hyperthyroidism; the controls were thirty-nine healthy individuals. In the group with subclinical hyperthyroidism, we observed a significant increase in heart rate (80.3 +/- 10.59 vs. 73.7 +/- 11.37 bpm, p < 0.05). The mean corrected QTc was 0.434 +/- 0.0207 seconds and 0.414 +/- 0.0208 in the examined groups and in controls, respectively (p < 0.001). QTc did not correlate with free thyroxin concentrations (p = 0.5084). Conclusion: Corrected QT intervals were significantly longer in patients with subclinical hyperthyroidism.     

Atrial fibrillation and preexcitation - A licence to kill

Atrial fibrillation becomes a potentially lethal arrhythmia in the presence of preexcitation because the rapid ventricular activation can result in ventricular fibrillation. Fortunately, radiofrequency ablation is an effective treatment for these patients. Specific points of interest regarding this association are the mechanism of increased incidence of atrial fibrillation and the current management of patients presenting in atrial fibrillation. These are discussed in this editorial.     

Thyrometabolic disorders and heart failure

Thyroid hormones are essential to maintain normal function of many systems including the cardiovascular system. Their excess or deficiency may upset human body homeostasis. Hyperthyroidism leads to cardiovascular system's hyperdynamic status which is characterized by tachycardia, increased difference between systolic and diastolic arterial pressure, significant increase of the stroke volume and improvement of the left ventricular diastolic function. Long-lasting thyrotoxicosis in patient with heart disease may result in atrial fibrillation, deterioration of angina pectoris or congestive heart failure. Hypothyroidism leads to hemodynamic disturbances which are quite different than those observed in hyperthyroidism, but cardiac symptoms are scant in clinical practice. Hypothyroidism's clinical significance is limited to atherosclerosis progression and intensification of ischaemic heart disease symptoms. Both leads to symptomatic cardiovascular system failure or its deterioration. We should emphasize that cardiovascular system dysfunction associated with thyrometabolic disturbances subsides when euthyreosis is restored. It sounds promising that there are reports suggesting a potential advantage of thyroxin treatment in patients with acute or chronic cardiovascular system diseases. These hypotheses result from the observations that heart dysfunction in hypothyroidism is similar to that observed in heart failure.     

Lycopus europaeus (Gypsywort): effects on the thyroidal parameters and symptoms associated with thyroid function.

The aim of the prospective two-armed open study was to examine the effect of Lycopi europaei herba on thyroid function and on associated symptoms during a 3-month follow-up phase. The study population consisted of patients with a basal TSH<1.0 mU/l and hyperthyroidism-associated symptoms. For the first time, the T3/T4 excretion in 24h urine was measured as a primary objective parameter. As secondary parameters, further hormones, the general condition and the symptoms associated with hyperthyroidism were registered. The urinary T4 excretion was significantly increased in Lycopus europaeus-treated patients (p=0.032). It is supposed that renal mechanisms cause the increased T4 excretion either by a modification within the glomeruli or by impaired reabsorption. Symptoms being specific to the thyroid gland were diminished, as e.g. the increased heart rate in the morning. The Lycopus europaeus preparation showed a good tolerance. These findings confirm positive effects of Lycopus europaeus in slight forms of hyperthyroidism.     

Hyperthyroidism with Periodic Paralysis

Hyperthyroidism may be associated with hypokalemic periodic paralysis. Two cases are presented demonstrating intermittent attacks of flaccid paralysis associated with clinical symptoms, signs and laboratory findings of hyperthyroidism. During an attack, one patient had a serum potassium of 2.1 mEq. per litre.Various factors such as trauma, exposure to cold, excessive carbohydrate ingestion and certain medications have been stated to precipitate an episode of paralysis. Attacks may range from mild weakness to generalized flaccid paralysis with loss of deep tendon reflexes. Several reported patients have died owing to cardiac arrest or respiratory paralysis.During attacks, the serum potassium is usually in the range of 2.2 to 3.2 mEq. per litre. It is postulated that a metabolic abnormality affecting the muscle-cell membrane can occur in the hyperthyroid state resulting in a shift of potassium to the intracellular position, thus producing a situation of hyperpolarization of the muscle-cell membrane which in turn alters the muscle contractibility.The importance of recognizing the unusual association of hypokalemic periodic paralysis with hyperthyroidism is stressed because, with successful treatment of the hyperthyroidism, the episodes of paralysis disappear.     

Estrogen metabolism in hyperthyroidism and in cirrhosis of the liver.

Estrogen metabolism was studied in spontaneous hyperthyroidism (Graves disease) and in alcoholic cirrhosis of the liver. The plasma concentration of estradiol-17beta (PCE2) was increased in men with hyperthyroidism. Although the metabolic clearance rate of estradiol-17beta (MCRE2) was reduced, the production rate (PR) of the steroid was increased above normal. The MCRE2 was also decreased in women with hyperthyroidism but the PCE2 and PRE2 was unchanged from normal. The conversion ratio of estradiol-17beta (CRE2E1) was increased in both hyperthyroid men and women. The PCE2 was significantly increased in men with cirrhosis of the liver. The MCRE2 was normal and this resulted in an increase in the PRE2 in this disorder. The CRE2E1 was significantly higher than normal. The plasma concentration of estrone (E1) was elevated in men with both disorders.     

The relationship between fat synthesis and oxidation in the liver after re-feeding and its regulation by thyroid hormone.

The administration of glucose to 48 h-starved euthyroid or hyperthyroid rats led to decreased blood concentrations of fatty acids and ketone bodies in both groups, but fatty acid concentrations were higher and ketone-body concentrations lower in the latter group. Decreased ketonaemia was not due to increased ketone-body clearance. Flux through carnitine palmitoyltransferase 1 was increased, consistent with the effects of hyperthyroidism on enzyme activity demonstrated in vitro. Correlations between the concentrations of ketone bodies and long-chain acylcarnitine measured in freeze-clamped liver samples indicated that a lower proportion of the product of beta-oxidation was used for ketone-body synthesis. Citrate concentrations were unaffected by hyperthyroidism, but lipogenesis was increased. The results are discussed in relation to the factors controlling hepatic carbon flux and energy requirements after re-feeding.     

New-onset atrial fibrillation in sepsis is associated with increased morbidity and mortality

BackgroundThe development of new-onset atrial fibrillation in sepsis has been associated with adverse outcomes.MethodsA systematic literature search was conducted to retrieve articles that investigated the association of new-onset atrial fibrillation in patients diagnosed with sepsis. The primary outcome of interest was the pooled risk ratio (RR) of in-hospital mortality in patients with new-onset atrial fibrillation and sepsis.ResultsSix studies included 3100 patients with new-onset atrial fibrillation in sepsis and 36,900 patients without new-onset atrial fibrillation in sepsis. The pooled RR for in-hospital mortality was 1.45 (95 % CI 1.32–1.60, p < 0.00001, I^2 =24 %). New-onset atrial fibrillation was also associated with increased ICU mortality, ICU and in-hospital length of stay and stroke. New-onset atrial fibrillation occurred more in the elderly, those with a prior history of cardiovascular and respiratory disease, and those with increased severity of illness.ConclusionProspective randomised trials are needed to clarify the significance of new-onset atrial fibrillation in sepsis, optimal treatment strategies for these patients, and the benefit of systemic anticoagulation. Physicians should be aware that new-onset atrial fibrillation in sepsis is not merely an observed temporary arrhythmia but a marker of poor prognosis and should be managed accordingly.     

Cardiovascular events in thyroid disease: a population based, prospective study

No consensus exists whether subclinical thyroid disease should be treated or just observed. Untreated overt thyroid disease is associated with increased risk of cardiovascular disease, and this study was conducted to assess the risk of cardiovascular events in subclinical thyroid disease. The population-based prospective study was conducted in Denmark. A total of 609 subjects from general practice aged 50 years or above with normal left ventricular function were examined. During a median of 5 years of follow-up, major cardiovascular events were documented. In subjects with abnormal TSH at baseline, information about potential thyroid treatment during follow-up was obtained from case reports and mailings. At baseline, 549 (90.7%) were euthyroid (TSH 0.40-4.00?mU/l), 31 (5.1%) were subclinical hypothyroid (TSH>4.00?mU/l), and 25 (4.1%) were subclinical hyperthyroid (TSH<0.40?mU/l). 1 overt hyperthyroid and 3 overt hypothyroid participants were excluded from the analyses. At baseline, the levels of NT-proBNP were inversely associated with the levels of TSH; the lower the levels of TSH, the higher the NT-proBNP concentration. During follow-up, 88 participants died, 81 had a major cardiovascular event, and 28 had a stroke. The incidence of stroke was increased among subjects with subclinical hyperthyroidism, HR 3.39 (95% CI 1.15-10.00, p=0.027) after adjusting for sex, age, and atrial fibrillation. Subclinical hypothyroidism was not related with any of the outcome measurements. Subclinical hyperthyroidism seems to be a risk factor of developing major cardiovascular events, especially stroke in older adults from the general population with normal left ventricular function.     

McCune-Albright syndrome associated with non-autoimmune type of hyperthyroidism with development of thyrotoxic crisis

We report on a patient having McCune-Albright syndrome (MAS) associated with non-autoimmune hyperthyroidism associated with thyrotoxic crisis. Polyostotic fibrous dysplasia developed at age 8, and café-au-lait pigmentation was noted on the skin. At age 18, he developed hyperthyroidism with multiple adenomatous changes. The hyperthyroidism had been controlled with an antithyroid drug, but the antithyroid medication was discontinued by the patient at age 23. One year later, thyrotoxic crisis developed with fever, convulsions and loss of consciousness. Thyroid function tests showed serum concentrations of free T(4) of 5.1 ng/dl, and serum TSH of <0.1 microU/ml. Serum thyroglobulin concentrations were markedly increased (1,280 ng/ml). Three major thyroid-related autoantibodies (TSH receptor antibody, antithyroglobulin, and antimicrosomal antibodies) were not detected in serum. Serum GH concentrations were increased, and not suppressed by the glucose tolerance test, but increased paradoxically by TRH. The thyrotoxic crisis was ameliorated by treatment with a beta-adrenergic receptor-blocking agent, glucocoroticoid, iodine, antithyroid drug, and antibiotics. The cause of thyroidal defect in our patient is not considered to be autoimmune hyperthyroidism, but hyperthyroidism due to constitutive activation of G(s)alpha by inhibition of its GTPase. This paper describes, as far as we know, the first case of MAS associated with thyrotoxic crisis. Because hyperthyroidism in this patient recurred quickly after discontinuation of the antithyroid drug, the mode of treatment for MAS-associated hyperthyroidism appears to be total surgical ablation or repetitive radioiodine therapy.     

Atrial fibrillation after but not before primary angioplasty for ST-segment elevation myocardial infarction of prognostic importance

Aim

In patients with ST-segment elevation myocardial infarction (STEMI), it is uncertain whether atrial fibrillation has prognostic implications. There may be a difference between atrial fibrillation before and after reperfusion therapy.

Methods and results

In patients with STEMI treated with primary percutaneous coronary intervention (PCI), ECGs were analysed before and after primary PCI. Of the 1623 patients with electrocardiographic data before primary PCI, 53 patients (3.3%) had atrial fibrillation. Patients with atrial fibrillation were older, were more often female, and less often had anterior MI location. Of the 1728 patients with electrocardiographic data after primary PCI, 52 patients (3.0%) had atrial fibrillation. Atrial fibrillation was more common in older patients and in those with Killip class >1. Also patients with occlusion of the right coronary artery or TIMI flow 0 before primary PCI more commonly had AF after the procedure. Not successful reperfusion was also associated with a higher incidence of AF after primary PCI. Although both atrial fibrillation before and after primary PCI were associated with increased mortality, multivariable analyses, adjusting for differences in age, gender and Killip class on admission, revealed that atrial fibrillation after PCI (OR 3.69, 95% CI 1.87–7.29) but not before PCI (OR 1.86, 95% CI 0.89–3.90) was independent and statistically significantly associated with long-term mortality.

Conclusion

In patients with STEMI, atrial fibrillation after but not before primary PCI has independent prognostic implications. Possibly, atrial fibrillation after the PCI is a symptom of failed reperfusion and a sign of heart failure.