Aubrey Leatham and the introduction of cardiac pacing to the UK.

In the early 1950s, Dr Aubrey Leatham established a cardiac unit at St. George's Hospital, Hyde Park Corner, London. He developed and taught the essential clinical skill of cardiac auscultation. Under his guidance a clinical department for the care of cardiac patients was developed and coupled to physiological academic research. He was a pioneer in cardiac pacing and, in 1961, Harold Siddons, O'Neal Humphries, and Aubrey Leatham implanted the first 'indwelling' pacemaker in the UK in a 65-year-old man with repeated Stokes-Adams attacks due to complete heart block. The nickel-cadmium 'accumulator', which powered the pacemaker, had to be recharged once a week.

Sudden death in patients receiving drugs tending to prolong the QT interval.

AIMS: To examine risks of sudden death in the community associated with drugs grouped by their risk of causing torsades de pointes (TdP) and to explore the risks for individual drugs. METHODS: Case-control study comparing prior drug intakes and morbidities, using the Arizona classification of drugs causing TdP. Participants included 1010 patients dying suddenly where post-mortem examination did not identify a clear cause of death, and 3030 matched living controls from primary care. RESULTS: Noncardiac drug risk was posed by antipsychotics and antidepressants. Significantly raised odds ratios (ORs) were found for takers of typical and atypical antipsychotics, ORs [95% confidence interval] 3.94 (2.05, 7.55) and 4.36 (2.54, 7.51), and of selective serotonin reuptake inhibitors [SSRIs] rather than tricyclic antidepressants, ORs 2.21 (1.61, 3.05) and 1.44 (0.96, 2.13). No significant risk was associated with other, noncardiac or psychiatric drugs, OR 1.09 (0.85, 1.41). Arizona classified drugs considered to raise risk of TdP were associated with raised risk of sudden death, as were those only weakly associated with TdP and not considered to pose a risk in normal use, ORs 2.08 (1.45, 3.00) and 1.74 (1.33, 2.28), respectively. CONCLUSIONS: Atypical and typical antipsychotic drug use were both strongly associated with raised risks, as were SSRIs. Tricyclic antidepressants were not associated with raised risks. The Arizona classification of risk of TdP was a poor predictor of likelihood of noncardiac drug-associated sudden death.

Treatment of amiodarone-associated thyrotoxicosis.

BACKGROUND: A 75-year-old man had a myocardial infarction complicated by poor left ventricular function and non-sustained ventricular tachycardia. He began treatment with amiodarone and 12 months later developed symptoms of thyrotoxicosis. INVESTIGATIONS: Thyroid function tests after commencement of amiodarone revealed a high-normal level of free T4 and low-normal level of free T3 with a normal serum TSH. When symptoms of thyrotoxicosis developed, significant rises in T4 and T3 levels and suppression of TSH were observed. Thyroid autoantibodies were detected and thyroid ultrasonography revealed a small multinodular goiter. DIAGNOSIS: Amiodarone-induced thyrotoxicosis (AIT) with features consistent with both AIT type I (in which thyroid antibodies and nodular goiter are present) and AIT type II (which is not responsive to thionamide therapy and eventually leads to permanent hypothyroidism). MANAGEMENT: The patient continued to be treated with amiodarone. He commenced thionamide (carbimazole) therapy but failed to improve, even after a dose increase. Glucocorticoid (prednisolone) therapy was therefore added. Combination therapy was associated with gradual clinical and biochemical improvement. The patient became persistently hypothyroid after stopping thionamide and glucocorticoid therapy and was stabilized on long-term thyroxine replacement.

Prevalence of subclinical thyroid dysfunction and its relation to socioeconomic deprivation in the elderly: a community-based cross-sectional survey.

CONTEXT: Population-based screening has been advocated for subclinical thyroid dysfunction in the elderly because the disorder is perceived to be common, and health benefits may be accrued by detection and treatment. OBJECTIVE: The objective of the study was to determine the prevalence of subclinical thyroid dysfunction and unidentified overt thyroid dysfunction in an elderly population. DESIGN, SETTING, AND PARTICIPANTS: A cross-sectional survey of a community sample of participants aged 65 yr and older registered with 20 family practices in the United Kingdom. EXCLUSIONS: Exclusions included current therapy for thyroid disease, thyroid surgery, or treatment within 12 months. OUTCOME MEASURE: Tests of thyroid function (TSH concentration and free T4 concentration in all, with measurement of free T3 in those with low TSH) were conducted. EXPLANATORY VARIABLES: These included all current medical diagnoses and drug therapies, age, gender, and socioeconomic deprivation (Index of Multiple Deprivation, 2004). ANALYSIS: Standardized prevalence rates were analyzed. Logistic regression modeling was used to determine factors associated with the presence of subclinical thyroid dysfunction. RESULTS: A total of 5960 attended for screening. Using biochemical definitions, 94.2% [95% confidence interval (CI) 93.8-94.6%] were euthyroid. Unidentified overt hyper- and hypothyroidism were uncommon (0.3, 0.4%, respectively). Subclinical hyperthyroidism and hypothyroidism were identified with similar frequency (2.1%, 95% CI 1.8-2.3%; 2.9%, 95% CI 2.6-3.1%, respectively). Subclinical thyroid dysfunction was more common in females (P < 0.001) and with increasing age (P < 0.001). After allowing for comorbidities, concurrent drug therapies, age, and gender, an association between subclinical hyperthyroidism and a composite measure of socioeconomic deprivation remained. CONCLUSIONS: Undiagnosed overt thyroid dysfunction is uncommon. The prevalence of subclinical thyroid dysfunction is 5%. We have, for the first time, identified an independent association between the prevalence of subclinical thyroid dysfunction and deprivation that cannot be explained solely by the greater burden of chronic disease and/or consequent drug therapies in the deprived population.

Successful treatment of amiodarone-induced thyrotoxicosis.

BACKGROUND: Amiodarone-induced thyrotoxicosis (AIT) is a difficult management problem about which there are little published data. We examined whether continuing amiodarone or differentiating AIT into 2 subtypes affected outcome. METHODS AND RESULTS: The type and duration of antithyroid treatment and response were recorded in a consecutive series of 28 cases. Comparisons were made between those in whom amiodarone either was continued or stopped and between those with either possible type 1 or type 2 AIT. Of the 28 cases, 5 had spontaneous resolution of AIT; 23 received carbimazole (CBZ) alone as first-line therapy. Eleven achieved long-term euthyroidism off CBZ or on a maintenance dose. Five became hypothyroid and required long-term thyroxine. Five relapsed after stopping CBZ treatment and were rendered euthyroid with either long-term CBZ (n=3) or radioiodine (n=2). Four were intolerant of CBZ and received propylthiouracil (PTU), with good effect in 3. One was resistant to thionamide alone (CBZ then PTU) and responded to adjunctive steroids. No difference in presentation or outcome was noted between those in whom amiodarone was continued or stopped or between possible type 1 or type 2 AIT. CONCLUSIONS: Continuing amiodarone has no adverse influence on response to treatment of AIT. First-line therapy with a thionamide alone is appropriate in iodine-replete areas, thus avoiding potential complications of other drugs. Differentiating between 2 possible types of AIT does not influence management or outcome.

Clinical review 142: cardiac dysrhythmias and thyroid dysfunction: the hidden menace?

Thyrotoxicosis is often perceived as a reversible disorder without long-term consequences, perhaps because of the availability of effective treatments, but recent evidence suggests that there may, in fact, be adverse outcomes. Long-term follow-up studies have revealed increased mortality from cardiovascular and cerebrovascular disease in those with a past history of overt hyperthyroidism treated with radioiodine as well as in those with subclinical hyperthyroidism indicated by a low serum TSH concentration. Thyroid hormones exert direct effects on the myocardium as well as the systemic vasculature predisposing to dysrhythmias, especially supraventricular. Effects of thyroid hormones on the autonomic nervous system may also contribute to arrhythmogenesis. Atrial fibrillation is a recognized complication of hyperthyroidism that predisposes to embolic events. Development of atrial fibrillation, together with other supraventricular dysrhythmias (both clinically obvious and those detected only by Holter monitoring) in those with hyperthyroidism may account for increased vascular mortality. Improved detection of supraventricular dysrhythmias and therapeutic intervention (e.g. anticoagulants, antiarrhythmics) may improve the long-term vascular prognosis, but their role remains to be established in large therapeutic trials.

Heart rate variability and turbulence in hyperthyroidism before, during, and after treatment.

Patients with subclinical and treated overt hyperthyroidism have an excess vascular mortality rate. Several symptoms and signs in overt hyperthyroidism suggest abnormality of cardiac autonomic function that may account in part for this excess mortality rate, but few studies have examined cardiac autonomic function in untreated and treated hyperthyroidism. We assessed heart rate turbulence (HRT) and time-domain parameters of heart rate variability in a large, unselected cohort of patients with overt hyperthyroidism referred to our thyroid clinic (n = 259) and compared findings with a group of normal subjects with euthyroidism (n = 440). These measures were also evaluated during antithyroid therapy (when serum-free thyroxine and triiodothyronine concentrations returned to normal but thyrotropin remained suppressed (i.e., subclinical hyperthyroidism, n = 110) and when subjects were rendered clinically and biochemically euthyroid (normal serum thyrotropin, free thyroxine and triiodothyronine concentrations, n = 219). We found that overall measures of heart rate variability and those specific for cardiac vagal modulation were attenuated in patients with overt hyperthyroidism compared with normal subjects; measurements of overall heart rate variability remained low in those with low levels of serum thyrotropin but returned to normal in patients with biochemical euthyroidism. Measurements of HRT (onset and slope) were also decreased in patients with overt hyperthyroidism, but HRT slope returned to normal values with antithyroid treatment. This study is the first to evaluate HRT in overt and treated hyperthyroidism.

Hyperthyroidism and cardiovascular morbidity and mortality.

Hyperthyroidism is a common disorder affecting multiple systems in the body. The cardiovascular effects are among the most striking. The availability of effective treatments for hyperthyroidism has led to the widespread perception that it is a reversible disorder without any long-term consequences. Recent evidence suggests, however, that there may be adverse outcomes. Long-term follow-up studies have revealed increased mortality from cardiovascular and cerebrovascular disease in those with a past history of overt hyperthyroidism treated with radioiodine, as well as those with subclinical hyperthyroidism. Thyroid hormones are known to exert direct effects on the myocardium, as well as the systemic vasculature and predispose to dysrhythmias, especially supraventricular. Atrial fibrillation (AF) is a recognized complication of overt hyperthyroidism, and subclinical hyperthyroidism is also known to be a risk factor for development of AF. Supraventricular dysrhythmias, particularly atrial fibrillation, in older patients may account for some of the excess cardiovascular and cerebrovascular mortality described, especially because AF is known to predispose to embolic phenomena.

Indications and nonindications for ablation of atrioventricular conduction in the elderly: is it sensible to destroy normal tissue?

Atrial fibrillation is common in later life. The goals of therapy are maintenance/restoration of sinus rhythm and control of ventricular rate when atrial fibrillation occurs. The only nonpharmacologic therapy of proven benefit is atrioventricular junction ablation and pacing, but this approach is irreversible and requires clear guidelines for patient selection. In paroxysmal atrial fibrillation, ablation and pacing carries a high risk of progression to permanent atrial fibrillation within 6 months but is indicated only when at least two appropriate drug strategies have failed. In persistent atrial fibrillation, ablation and pacing will inevitably result in permanent atrial fibrillation; this may influence the decision for pacemaker type and the timing of the procedure. In permanent atrial fibrillation, there is clear evidence for benefit, especially in those with reduced left ventricular function. In conclusion, ablation and pacing offers symptomatic and functional benefit to patients with drug-refractory atrial fibrillation. Timing of the intervention relates to response to other pharmacologic therapy.

Cardiovascular manifestations of hyperthyroidism before and after antithyroid therapy: a matched case-control study.

OBJECTIVES: This study sought to prospectively evaluate the prevalence of cardiovascular abnormalities in patients with overt hyperthyroidism before and after antithyroid therapy. BACKGROUND: Overt hyperthyroidism is associated with recognized cardiovascular effects believed to be reversed by antithyroid therapy; however, increasing data suggest significant long-term cardiovascular mortality. METHODS: A total of 393 (312 women, 81 men) consecutive unselected patients with overt hyperthyroidism were recruited and compared with 393 age- and gender-matched euthyroid control subjects. Hyperthyroid patients were re-evaluated after antithyroid therapy. Findings in patients and matched control subjects were compared at presentation, after treatment when patients had subclinical hyperthyroidism biochemically, and when patients were rendered biochemically euthyroid. All had a structured cardiovascular history and examination, including measurements of blood pressure (BP) and pulse rate. All had resting 12-lead electrocardiogram and 24-h digital Holter monitoring of cardiac rhythm. RESULTS: A higher prevalence of cardiovascular symptoms and signs, as well as abnormal hemodynamic parameters, was noted among hyperthyroid patients at recruitment compared with control subjects. Cardiac dysrhythmias, especially supraventricular, were more prevalent among patients than among control subjects. Palpitation and dyspnea, postural decrease in systolic pressure, and atrial fibrillation (AF) remained more prevalent in treated hyperthyroid subjects with subclinical hyperthyroidism compared with control subjects, and remained more prevalent after restoration of euthyroidism. Predictors for successful reversion to sinus rhythm in those with AF associated with hyperthyroidism were lower BP measurements at recruitment and an initial hypothyroid state induced by antithyroid therapy. Mortality was higher in hyperthyroid subjects than in control subjects after a mean period of follow-up of 66.6 months. CONCLUSIONS: Cardiovascular abnormalities are common in patients with overt hyperthyroidism at presentation, but some persist despite effective antithyroid therapy.

Multi-center clinical experience with a lumenless, catheter-delivered, bipolar, permanent pacemaker lead: implant safety and electrical performance.

PURPOSE: Reduced lead diameter and reliability can be designed into transvenous permanent pacing leads through use of redundant insulation and removal of the stylet lumen. The model 3830 lead (Medtronic Inc., Minneapolis, MN, USA) is a bipolar, fixed-screw, steroid-eluting, lumenless, 4.1-Fr pacing lead. Implantation can be performed in a variety of right heart sites using a deflectable catheter (Model 10600, Medtronic). Lead performance and safety were studied. METHODS: Two prospective trials of 338 implanted subjects from 56 global sites were conducted. Electrical and safety data were obtained at implant, pre-discharge, and up to 18 months post-implant. Leads were implanted at traditional and alternate right heart sites. RESULTS: The study enrolled 338 subjects (204 males, 70.6 +/- 11.6 years) followed-up for a mean of 10.2 months (range, 0-21.6). Mean P-wave amplitudes ranged from 3.2 mV at 3 months to 2.9 mV at 18 months, while mean atrial pulse width thresholds at 2.5 V ranged from 0.07 ms at 3 months to 0.09 ms at 18 months. Mean R-wave amplitudes ranged from 11.3 mV to 11.1 mV and mean ventricular pulse width thresholds at 2.5 V ranged from 0.10 ms to 0.14 ms. There were 22 ventricular and 12 atrial lead complications within 3 months post-implant. Survival from lead-related complications improved to a clinically acceptable rate in the cohort of patients when revised implant techniques were employed. CONCLUSIONS: With the use of recommended implant techniques, the study results support the electrical efficacy and safety of a catheter-delivered, lumenless lead in traditional or alternate right atrium or right ventricle sites through 18 months post-implant.

Randomized trials for selective site pacing: do we know where we are going?

Clinical evidence is accumulating that pacing from traditional right-sided sites (right ventricular apex and right atrial appendage) may be associated with long-term detriment to left ventricular function and promotion of atrial arrhythmias. Large numbers of small studies, some randomized, have addressed the effects of pacing from nontraditional or alternate sites, but the studies have varied in design such that comparison of results is often difficult. Many studies show data from acute studies only, although more recently longer-term data have started to become available; definition and description of pacing site also varies, adding further to the difficulties in comparing data. This article attempts to examine the randomized studies available to date, and to consider how future studies may contribute to our understanding of the effects of pacing from traditional and selected, specific sites on the right side of the heart.

Selective site pacing: defining and reaching the selected site.

Selective site right ventricular pacing has been suggested as an approach to reduce the incidence of ventricular dysfunction and hopefully influence the morbidity resulting from traditional right ventricular apical pacing. Pacing from the right ventricular apex allows a stable ventricular rate, and together with atrial pacing and sensing, helps maintain atrioventricular synchrony but does not allow physiological activation of the left ventricle. Traditional atrial pacing sites like the right atrial appendage may encourage atrial tachyarrhythmias, whereas lead placement in right atrial septal sites may reduce the frequency of symptomatic atrial tachyarrhythmia episodes, especially when combined with prevention algorithms. Researchers attempting to pace the heart from these selective sites have been hindered by the lack of uniform definitions of where these sites actually lie and the inadequacy of tools to consistently reach these locations and verify correct placement. This lack of definition consensus may have contributed to the apparent conflict of data, particularly in the right ventricle. There is an urgent need for a standardization of terms and identifying measures for selective pacing sites.