Cardiac sarcoidosis: diagnosis and management.

Cardiac sarcoidosis is one of the most serious and unpredictable aspects of this disease state. Heart involvement frequently presents with arrhythmias or conduction disease, although myocardial infiltration resulting in congestive heart failure may also occur. The prognosis in cardiac sarcoidosis is highly variable, which relates to the heterogeneous nature of heart involvement and marked differences between racial groups. Electrocardiography and echocardiography often provide the first clue to the diagnosis, but advanced imaging studies using positron emission tomography and MRI, in combination with nuclear isotope perfusion scanning are now essential to the diagnosis and management of this condition. The identification of clinically occult cardiac sarcoidosis and the management of isolated and/or asymptomatic heart involvement remain both challenging and contentious. Corticosteroids remain the first treatment choice with the later substitution of immunosuppressive and steroid-sparing therapies. Heart transplantation is an unusual outcome, but when performed, the results are comparable or better than heart transplantation for other disease states. We review the epidemiology, developments in diagnostic techniques and the management of cardiac sarcoidosis.

A prospective observational study of stroke volume responsiveness to a passive leg raise manoeuvre in healthy non-starved volunteers as assessed by transthoracic echocardiography.

Current guidelines for intra-operative fluid management recommend the use of increments in stroke volume following intravenous fluid bolus administration as a guide to subsequent fluid therapy. To study the physiological premise of this paradigm, we tested the hypothesis that healthy, non-starved volunteers would develop an increment in their stroke volume following a passive leg raise manoeuvre. Subjects were positioned supine and stroke volume was measured by transthoracic echocardiography at baseline, 30 s, 1 min, 3 min and 5 min after passive leg raise manoeuvre to 45°. Stroke volume was measured at end-expiration during quiet breathing, as the mean of three sequential measurements. Seventeen healthy volunteers were recruited; one volunteer in whom it was not possible to obtain Doppler measurements and a further five for reasons of poor Doppler image quality were not included in the study. Mean (SD) percentage difference from baseline to the largest change in stroke volume was 5.7 (9.6)% (p = 0.16). Of the 11 volunteers evaluated, five (45%) had stroke volume increases of greater than 10%. Mean (SD) maximum percentage change in cardiac index was 14.8 (9.7)% (p = 0.004). A wide variation in baseline stroke volume and response to the passive leg raise manoeuvre was seen, suggesting greater heterogeneity in the normal population than current clinical guidelines recognise.

Narrow complex (supraventricular) tachycardias.

Patients experiencing a narrow complex tachycardia are usually at a lower risk than those in whom a broad complex tachycardia occurs. Therefore, in the UK cardiologists are frequently involved in broad complex dysrhythmias at an early stage, while general physicians and general practitioners will often have greater involvement in the management of patients with narrow complex arrhythmias. We describe the management of narrow complex arrhythmias likely to be encountered, including the ubiquitous atrial fibrillation.

Risk factors for cardiovascular disease in IDDM. A study of identical twins.

Patients with insulin-dependent diabetes mellitus (IDDM) have an excess mortality, predominantly attributable to cardiovascular disease. To determine the effect of IDDM on potential risk factors for cardiovascular mortality, we studied subjects from the British Diabetic Twin Study Group. Forty-five identical twin pairs discordant for IDDM were recruited in addition to 45 matched nondiabetic singleton control subjects. All were selected to be normotensive and to have normal albumin excretion rates. Four variables differed significantly between the diabetic twins and their nondiabetic identical co-twins: diabetic twins had higher systolic blood pressure (sBP) ([mean +/- SD] 127 +/- 17 vs. 123 +/- 18 mmHg, P < 0.05), high-density lipoprotein (HDL) cholesterol (1.36 +/- 0.31 vs. 1.25 +/- 0.29 mM, P < 0.05) and fibrinogen (3.23 +/- 0.81 vs. 2.98 +/- 0.71 mg/ml, P < 0.05) but lower factor VII (114 +/- 34 vs. 122 +/- 31%, P < 0.05). All four of these risk factors were significantly correlated (P < 0.001) within the identical twin pairs, as were the other risk factors. These significant correlations within twins for the risk factors studied reflects the impact of shared genetic and environmental influences. IDDM affects sBP, HDL cholesterol, fibrinogen, and factor VII, but only sBP and fibrinogen are affected adversely.

Electrophysiologic abnormalities in AL (primary) amyloidosis with cardiac involvement.

OBJECTIVES: This study sought to determine the spectrum of electrophysiologic abnormalities found in patients with cardiac involvement due to AL (primary) amyloidosis and to evaluate the prognostic implications, particularly in relation to subsequent sudden death. BACKGROUND: Only case reports, but no series of invasive electrophysiologic studies, exist in patients with cardiac AL. METHODS: Twenty-five patients with biopsy-proven AL and cardiac involvement underwent standard invasive electrophysiologic studies. RESULTS: The function of the sinus and the atrioventricular node was preserved in most patients, but the infra-His (HV) conduction times were usually abnormal. The mean (+/-SD) HV interval for the 25 patients was 79 +/- 18 ms (range 50 to 110), and 23 patients (92%) had an abnormally prolonged interval (> 55 ms). Marked HV prolongation (> or = 80 ms) occurred in 12 patients, 6 of whom had an interval > or = 100 ms. Among the 23 patients who died during follow-up, HV prolongation was the sole independent predictor of sudden death by multivariate analysis (p = 0.05). CONCLUSIONS: Patients with cardiac AL are prone to disease in the His-Purkinje system. Prolongation of the HV interval is common and may not be suspected from the surface electrocardiogram in the presence of a narrow QRS complex. These patients have a high prevalence of sudden death, of which the HV interval is an independent predictor. The association of HV prolongation and sudden death is probably multifactorial, representing either a marker of severe myocardial infiltration with an increased propensity to lethal ventricular arrhythmias or electromechanical dissociation, or indicating severe conduction system disease eventually leading to complete atrioventricular block and bradycardic death.

Increased urinary albumin and retinol-binding protein in type I diabetes. A study of identical twins.

OBJECTIVE: Indexes of early renal glomerular and tubular dysfunction have been demonstrated in type I diabetes, but it remains uncertain whether such changes are genetically determined or are secondary to the disease process. We therefore undertook to study whether early markers of renal dysfunction are a consequence of type I diabetes or inherited. RESEARCH DESIGN AND METHODS: We estimated both urinary albumin excretion (UAE) and urinary retinol-binding protein (RBP) in 51 identical twin pairs discordant for type I diabetes and in 51 matched control subjects. RESULTS: UAE and RBP were significantly higher in the diabetic twins than in their nondiabetic co-twins (P < 0.0001 and P < 0.0002, respectively). Seven diabetic twins had elevated UAE, but none of the nondiabetic co-twins did. In a subgroup of 44 twins with normal UAE (albumin excretion rate < 20 micrograms/min), diabetic twins had both a higher albumin excretion function (median [range]; 0.64 [0.18-2.74] mg/mmol creatinine) than their nondiabetic co-twins (0.48 [0.24-1.40], P < 0.01) and higher levels of RBP excretion (10.4 [4.0-167.0] micrograms/mmol creatinine) than their nondiabetic co-twins (7.5 [0.97-23.0], P < 0.05). Values between twins of a pair were significantly correlated for RBP (r = 0.36, P < 0.05) but not for UAE (r = 0.13). CONCLUSIONS: These results suggest that in type I diabetes, an index of renal tubular function (RBP), but not glomerular function (UAE), is influenced by shared genetic and nongenetic factors. Type I diabetes can affect renal tubular function even when glomerular function is normal. We conclude that neither the increased UAE nor urinary RBP found in type I diabetes is inherited independently of the diabetes process.

Erythrocyte sodium-lithium countertransport activity in non-nephropathic diabetic twins.

OBJECTIVE: It has proved difficult to separate the role of the diabetic state as distinct from its complications in causing the elevation in erythrocyte sodium-lithium (Na-Li) countertransport activity that has been observed in diabetes. The present study sought to isolate the impact of diabetes on the countertransporter by studying groups of non-nephropathic identical-twin pairs both discordant and concordant for diabetes. RESEARCH DESIGN AND METHODS: We studied erythrocyte Na-Li countertransport activity in 49 identical-twin pairs who were discordant for IDDM and 26 identical twin pairs who were concordant for IDDM. Similar numbers of healthy control subjects, matched with the nondiabetic twins from the discordant pairs in respect to sex, BMI, and age were also studied. RESULTS: The clinical and laboratory characteristics of both sets of twins were very similar to those of the control subjects with the exception that whole-blood glucose and glycated hemoglobin concentrations were higher in diabetic twins, whether from discordant or concordant pairs (P < 0.001), and that systolic blood pressure (P < 0.05) and serum HDL cholesterol (P < 0.05) were higher in the discordant diabetic twins than in their nondiabetic co-twins. Median (95% CI) Na-Li countertransport activities (in millimoles of lithium released from 1 liter of erythrocytes per hour) in the nondiabetic discordant twin [0.237 (0.192-0.284)], the diabetic discordant twin [0.284 (0.254-0.326)], and the concordant twin [0.262 (0.207-0.358)] groups were similar to each other and higher than in the control subjects [0.172 (0.138-0.203)]. Countertransport activities in the discordant diabetic twins correlated significantly with their nondiabetic co-twins (r = 0.34; P = 0.015; n = 49), as did those between the concordant diabetic twin pairs (r = 0.68; P < 0.005; n = 26); activity levels were not related to either disease duration or blood glucose control. CONCLUSIONS: An elevation in Na-Li countertransport activity has been noted in non-nephropathic normotensive twin pairs both discordant and concordant for IDDM. The potential genetic contribution to the altered behavior of the countertransporter was similar in both types of twins studied, and individual Na-Li countertransport activities were not significantly related to either duration of diabetes or metabolic control.

A hairy fall: syncope resulting from topical application of minoxidil.

We describe the case of a young man who developed syncope after using a high strength formulation of topical minoxidil as a hair growth restorer. Other potential cardiovascular and endocrine causes were excluded, and his symptoms resolved on discontinuation of the product. While syncope is a recognised side effect of using this powerful systemic antihypertensive agent, few cases are documented in the literature, which we illustrate in our discussion.

Progression of ventricular wall thickening after liver transplantation for familial amyloidosis.

BACKGROUND: Familial amyloidosis (FAP) is characterized by the progression of neurologic and cardiac impairment ultimately leading to death within 7 to 15 years after the onset of the disease. Liver transplantation represents the only definitive therapy for this disease and has been performed since 1990. METHODS: To determine the effect of liver transplantation on disease progression, electrocardiography and Doppler echocardiography were performed and blindly analyzed on 11 patients with FAP who were followed 0.8 to 8.6 years before liver transplantation and 0.8 to 4.1 years after liver transplantation. RESULTS; After liver transplantation, five patients showed progression of left ventricular wall thickening with increased left ventricular mass, and three of these five showed a reduction in electrocardiographic voltage despite abolition of the mutant protein from the serum. Of the five patients showing progressive wall thickening, four had the transthyretin variant Glu 42 Gly and one patient had the Ala 36 Pro variant; none of the remaining six patients, all of whom possessed the Val 30 Met variant, showed echocardiographic changes. Although 9 of the 11 patients have shown symptomatic improvement in neurologic symptoms, 1 patient has developed heart failure and a second patient has suffered a sudden cardiac death. CONCLUSIONS: After liver transplantation, patients with FAP should have regular clinical evaluations including electrocardiographic and echocardiographic examinations to look for continued deterioration in heart structure or function.

Effect of orthotopic liver transplantation on the progression of familial amyloidotic polyneuropathy.

BACKGROUND: Familial amyloidotic polyneuropathy (FAP) is an autosomal dominant inherited disease associated with a mutant form of the protein transthyretin (TTR). It is characterized clinically by the systemic deposition of amyloid fibrils resulting in organ dysfunction and, ultimately, death. The majority of TTR is produced in the liver, and transplantation of the liver has been shown to ameliorate this source of mutant TTR, arresting the progression of this fatal disease. METHODS: Thirteen patients with FAP have undergone successful liver transplant surgery at our center since 1992. The impact of liver transplantation on amyloid-related polyneuropathy, cardiovascular, and gastrointestinal dysfunction is reported in this study. Three patients who died before cardiovascular and neurological follow-up are excluded from the analysis. RESULTS: Ten of 13 patients (77%) remain alive an average of 49 months (range, 17-64 months) after transplantation. Three patients suffered sudden death, with autopsy documentation of amyloid deposits involving the conduction system of the heart. Liver transplantation was performed more quickly, required less blood, and a shorter postoperative hospital stay in these patients, compared with patients with cirrhosis. Neurological and nutritional symptoms improved in the majority of affected patients. Those patients with echocardiographic evidence of ventricular wall and valve thickening before transplantation progressed postoperatively despite neurologic improvement. CONCLUSIONS: Liver transplantation offers the only cure for the genetic defect causing FAP and appears to result in subjective and objective improvement in neurological dysfunction. Patients with preexisting cardiovascular abnormalities progress despite transplantation; therefore, consideration for combined heart-liver transplantation may be warranted in this subset of patients.

Features and prognosis of exertional syncope in light-chain associated AL cardiac amyloidosis.

Syncope is common in AL amyloid heart disease and in almost 1/3 of our patients who experienced syncope, it was precipitated by physiologic stress. Stress-precipitated syncope was associated with a poor prognosis in such patients, both in terms of their median survival of 2 months and was frequently a precursor of sudden cardiac death.

Electrocardiography and Doppler echocardiography in secondary (AA) amyloidosis.

The fibrils in AL and AA amyloidosis, although similar in appearance, have different biochemical composition and staining characteristics. Whereas electrocardiographic and echocardiographic features of heart involvement in AA amyloidosis resemble those for AL amyloidosis, our findings support the concept that the constituent amyloid fibrils may play a decisive role in the clinical pattern and significance of heart infiltration.

Right ventricular dilation in primary amyloidosis: an independent predictor of survival.

This study was designed to characterize the geometry and function of the right ventricle and its prognostic significance in patients with primary (AL) cardiac amyloidosis. AL amyloidosis is an infiltrative systemic disease that can result in thickening of heart structures and rapidly progressive congestive heart failure due to restrictive ventricular physiology and eventual systolic dysfunction. Thirty-seven patients with AL amyloid heart involvement and 20 normal control subjects were evaluated using 2-dimensional and Doppler echocardiography. Based on the ratio of left-to-right end-diastolic ventricular chamber areas, patients were classified into 2 groups: 25 patients with disproportionate right ventricular (RV) dilation (left ventricular to RV ratio < or = 2) and 12 with a ventricular area ratio > 2. Patients with a relatively dilated right ventricle (ratio < or = 2) had a shorter median survival (4 months) compared with patients with an area ratio > 2 (10 months, p <0.003). Of multiple clinical, echocardiographic, and Doppler features entered into a multifactorial model, a ventricular area ratio < or = 2 remained the only independent predictor of survival. Patients with AL amyloid heart disease represent a heterogeneous population with regard to both prognosis and the relative degree of right to left ventricular dilation. RV dilation in patients with amyloid heart disease appears to be associated with more severe involvement and is associated with a very poor prognosis with a median survival of only 4 months.

Kinetic characteristics of the erythrocyte sodium-lithium countertransporter in subjects with coronary artery disease.

Sodium-lithium countertransport activity, external affinity for sodium (kNa) and maximal rate of turnover (Vmax), were characterized in 21 male subjects (aged 45 to 65 years) with angiographically proven coronary artery disease; these were compared with a matched group of healthy controls. No significant differences in countertransport activity were noted between the coronary artery disease patients and the healthy controls. By contrast, the median [range] kNa in the coronary artery disease group (8.5 [2.6 to 30.5] mmol/L Na) was significantly lower than that in the controls (59.9 [5.9 to 240.5] mmol/L Na; P < .0001). This reduction was accompanied by a significantly lower mean Vmax (controls 0.403 +/- 0.187 v coronary artery disease group 0.248 +/- 0.121 mmol Li/L RBC/h; P < .01). The findings suggest that disturbed behavior of the sodium-lithium countertransporter is not confined to hypertension but may represent a broader-based membrane dysfunction associated with vascular disease.

Kinetic behavior of the erythrocyte sodium-lithium countertransporter in nonnephropathic diabetic twins.

Elevated erythrocyte sodium-lithium countertransport activity occurs in diabetes and may be genetically mediated. The relation of this abnormality to the disease and its complications is unclear. To remove confounding genetic factors and the impact of complications, we studied sodium-lithium countertransport activity together with its kinetic components, maximal rate of turnover (Vmax) and external affinity for sodium (kNa), in identical-twin pairs discordant for insulin-dependent diabetes who were normotensive and had no evidence of nephropathy. Fifteen twin pairs were studied along with the same number of healthy control subjects matched with the twins for gender, age, and body mass index. Clinical and laboratory characteristics of the twins and controls were similar, with the exception that whole blood glucose and glycated hemoglobin concentrations were higher in diabetic twins (P < .001). Comparison of countertransport activity between nondiabetic and diabetic twin groups failed to uncover any significant differences (P = .30, Wilcoxon). Similarly, there were no differences in countertransport activity between the nondiabetic twin group and the controls (P = .38, Mann-Whitney). Furthermore, no associations were noted between residual activity values and residual data of any of the other clinical or laboratory characteristics measured. Comparison of Vmax between nondiabetic and diabetic twin groups showed a significant elevation in the diabetic twins (0.515 + 0.220 v 0.439 + 0.229 mmol Li/L RBC x h, P = .049, paired t test). By contrast, no significant differences were noted between the nondiabetic twin group and the controls (P = .15, unpaired t test). Comparison of kNa between nondiabetic and diabetic twin groups found no significant differences in kNa (P = .42, Wilcoxon). Similarly, there were no differences in kNa between nondiabetic twins and controls (P = .14, Mann-Whitney). Neither the residual data for Vmax nor kNa showed any association with the residual data of any of the other clinical or laboratory characteristics measured. When intertwin correlations were examined, all three parameters describing the behavior of the sodium-lithium countertransporter showed significant intertwin correlations (activity, r = .51, P = .04; Vmax, r = .82, P = .001; kNa, r = .76, P = .001). In conclusion, the diabetic state has a small effect on the Vmax of the sodium-lithium countertransporter. Failure to consider the complex nature of the activity measurement is likely to have been partly responsible for earlier confusion with regard to the effect of diabetes on the countertransporter, since experimental conditions varied between studies and individual kinetic components were not measured. The associations between twins in this study with respect to Vmax and kNa indicate a genetic influence on both constants of the countertransporter. Vmax appears also to be sensitive to certain as yet unidentified environmental factors.

Heart failure in a district general hospital: are target doses of beta-blockers realistic?

BACKGROUND: Carvedilol therapy reduces mortality in patients with chronic heart failure. Multi-centre studies suggest a low first dose failure rate and high levels of tolerability to carvedilol. Little is known, however, concerning the eligibility and tolerance to treatment with carvedilol within a district general hospital setting. AIM: To evaluate the eligibility and tolerance of patients with heart failure to carvedilol within a district general hospital. DESIGN: Prospective clinical audit analysis. METHODS: We assessed 100 heart failure patients eligibility to commence carvedilol therapy. In those who satisfied clinical criteria, we evaluated first dose failure rate, target dose achievement, reasons for intolerance, heart rate and blood pressure reduction and resource requirements over a six-month period. RESULTS: Of 100 patients, 16% had contra-indications to commence carvedilol and 22% were receiving a beta-blocker as part of their existing heart failure therapy. Although 62% satisfied eligibility criteria, 1% refused therapy, thus 61% were initiated on carvedilol. The first dose failure rate was 11.5% and 6.6% of patients achieved 'target dose'. Mean heart rate and systolic blood pressure reductions were 15 (SE 1.2)bpm and 17 (SE 1.7) mmHg, respectively. Resource requirements included 155 hours of work-time for a trained heart failure specialist nurse and doctor. CONCLUSIONS: In the general setting, eligible patients appear to display a high first dose failure rate, poor tolerance to higher doses and achievement of a 'target dose' of carvedilol. Responses to adrenergic blockade were similar to previously published data, irrespective of the final tolerated dose, suggesting that the concept of achieving a 'target dose' may not be clinically useful. Guidelines and treatment protocols for heart failure should reflect not only what is considered gold standard, but also what is practical in general hospitals.

The clinical features of immunoglobulin light-chain (AL) amyloidosis with heart involvement.

We reviewed clinical presentation, investigations, therapy, prognosis and outcome of 232 patients with primary (AL) cardiac amyloidosis. There were 142 men and 90 women. Median age at presentation was 59 years (range 29-85). AL heart disease was unusual both in patients under the age of 40 (3.0%) and in non-Caucasians (6.5%). Fatigue and weakness were the commonest presenting symptoms. Hallmark features of periorbital ecchymoses and macroglossia were present in 12.5% and 27.2%, respectively. AL cardiac amyloidosis was unusual in isolation (3.9%), and most frequently patients had features of multiorgan dysfunction; heavy proteinuria and features of malabsorption predominating in this respect. Heart involvement represents the worst prognostic indicator, with a median survival from diagnosis of 1.08 years, falling to 0.75 years with the onset of heart failure. Current therapeutic procedures appear to prolong survival, with left ventricular wall thickness, mass and ejection fraction on echocardiography and late potentials on signal averaged electrocardiography of use in prognostic stratification. Cardiac involvement from AL amyloidosis is rapidly fatal. It should be suspected in all patients with heart failure who have wall thickening on echo, normal chamber sizes, low EKG voltages and evidence suggesting a multisystem disease.

Home inotrope treatment for intractable heart failure following heart transplantation.

A 49 year old man developed intractable heart failure three years after undergoing heart transplantation. Coronary angiography showed no evidence of graft vascular disease. An initial cardiac biopsy identified one episode of rejection which responded to augmented immunosuppressive treatment. The patient became inotrope dependent and has now survived at home for 22 months using an ambulatory delivery system for intravenous adrenaline (epinephrine), without significant complications. There has been a noticeable improvement in symptoms and left ventricular systolic performance, both clinically and as seen through echocardiographic and radiographic examination. This improvement was substantiated by the results of cardiac catheterisation, which showed a return to normal left ventricular filling pressure and cardiac output. The case is noteworthy because this treatment has allowed a patient who otherwise would have been hospital bound to return to the community. With the current shortage of organs, he would have been unlikely to receive a second transplant. The clinical features and outcome, and social, medicolegal, and financial issues are discussed.

Familial and primary (AL) cardiac amyloidosis: echocardiographically similar diseases with distinctly different clinical outcomes.

OBJECTIVE: To determine whether patients with myocardial amyloidosis due either to AL (primary) amyloid or familial amyloid have distinguishing echocardiographic or electrocardiographic features; and to compare the prevalence of heart failure and survival in the two types of amyloidosis in relation to echocardiographic findings. DESIGN: Blinded group comparison of randomly selected cases of cardiac amyloidosis. SETTING: International referral centre for amyloid research and treatment. PATIENTS: 36 patients with cardiac amyloid heart disease, of whom 12 had familial and 24 had primary AL amyloidosis. RESULTS: Familial and AL echocardiograms were morphologically indistinguishable, with similar left ventricular wall thickness, mean (SD) 15.4 (2.3) nu 15.8 (2.5) mm, respectively; right ventricular wall thickness was also similar between amyloid types: 9.6 (2.8) nu 9.7 (6.5) mm, respectively. Doppler indices of left and right ventricular function, left ventricular volume, and ejection fraction were also similar. Low voltage electrocardiograms (< 0.5 mV) were more common in the AL (16/24, 67%) than in the familial group (4/12, 25%), P < 0.05. The one year survival for familial and AL forms was 92% (11/12) nu 38% (6/24), respectively, with virtually all deaths due to cardiac causes. CONCLUSIONS: Although cardiac involvement is echocardiographically indistinguishable, cardiac mortality is very different between the two forms of amyloidosis. Preservation of electrocardiographic voltage in familial amyloidosis suggests that the particular biochemical characteristics of distinct types of amyloid fibril have different pathological effects on the myocardium. This distinction becomes critical in the evaluation, treatment, and management of patients who have a diagnosis within the spectrum of the protein deposition diseases.