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Biomedical subjects

R H Falk

Publications and source records attributed to R H Falk.

At least 19 recordsLinked to original sources
PubMed1998

Etiology and complications of atrial fibrillation: insights from pathology studies.

Atrial fibrillation (AF) is an arrhythmia associated with a wide variety of cardiac conditions, and it carries a risk of thromboembolism which varies with the underlying disease. The prevalence of AF increases markedly with age, and a review of histopathologic studies reveals that normal aging produces histologic changes in atrial conduction that may lead to the development of atrial arrhythmias. The diverse pathologic causes of AF also result in histologic abnormalities, and an examination of the relation of the etiology of the arrhythmia to pathologic changes suggests a possible reason for the varying risk of thrombus formation. The interaction between the histologic abnormalities and the presence of triggers of AF may also play an important role in the onset and maintenance of this common condition.

Aged↗
PubMed1998

Dose-intensive melphalan with blood stem-cell support for the treatment of AL (amyloid light-chain) amyloidosis: survival and responses in 25 patients.

AL (amyloid light-chain) amyloidosis is an uncommon plasma cell disorder in which depositions of amyloid light-chain protein cause progressive organ failure and death in a median of 13 months. Autologous stem-cell transplantation is effective therapy for multiple myeloma and therefore, we evaluated its efficacy for AL amyloidosis. Patients with adequate cardiac, pulmonary, and renal function had stem cells mobilized with granulocyte-colony stimulating factor and were treated with dose-intensive intravenous melphalan (200 mg/m2). Response to therapy was determined by survival and improvement of performance status, complete response or persistence of the clonal plasma cell disorder, and change in the function of organs involved with amyloid at baseline. We enrolled 25 patients with a median age of 48 years (range, 29-60), all of whom had biopsy-proven amyloidosis with clonal plasma cell disorders. Twenty-two (88%) were Southwest Oncology Group performance status 1 or 2 within a year of diagnosis, and 16 (64%) had received no prior therapy. Predominant amyloid-related organ involvement was cardiac (n = 8), renal (n = 7), hepatic (n = 6), neuropathic (n = 3), and lymphatic (n = 1). Fifteen patients had one or two organ systems involved, whereas 10 had three or more involved. With a median follow-up of 24 months (12-38), 17 of 25 patients (68%) are alive, and the median survival has not been reached. Thirteen of 21 patients (62%) evaluated 3 months posttransplant had complete responses of their clonal plasma cell disorders. Currently, two thirds of the surviving patients (11 of 17) have experienced improvements of amyloid-related organ involvement in all systems, whereas 4 of 17 have stable disease. The improvement in the median performance status of the 17 survivors at follow-up (0 [range, 0-3]) is statistically significant versus baseline (2 [range, 1-3]; P < . 01). Significant negative prognostic factors with respect to overall survival include amyloid involvement of more than two major organ systems and predominant cardiac involvement. Three patients have experienced relapses of the clonal plasma cell disorder at 12 and 24 months. Dose-intensive therapy should currently be considered as the preferred therapy for patients with AL amyloidosis who meet functional criteria for autologous transplantation.

Adult↗
PubMed1998

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.

Adult↗
PubMed1998

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.

Adult↗
PubMed1997

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.

Aged↗
PubMed1997

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.

Adult↗
PubMed1997

Signal-averaged electrocardiography in patients with AL (primary) amyloidosis.

One hundred thirty-three patients with biopsy-proven AL amyloidosis were studied with echocardiography, Holter recording, 12-lead electrocardiography, and signal-averaged electrocardiograms. Features from these tests were analyzed in relation to their effect on mortality. Late potentials were more frequent in patients with echocardiographic evidence of cardiac amyloidosis (31%) compared with patients with normal echocardiograms (9%, p < 0.003). One hundred six of the 133 patients died during follow-up, of which 34 were nonsudden cardiac deaths and 33 were sudden deaths. Abnormal echocardiograms and signal-averaged electrocardiograms were each predictive of all-cause cardiac death (p < 0.0001 ) and sudden cardiac death (p < 0.0001). Abnormal signal-averaged electrocardiograms were also independently predictive of sudden death in the subgroup of patients with an abnormal echocardiogram (p < 0.05). Thus late potentials are predictive of sudden death in patients with AL amyloidosis and provide independent prognostic information in patients with echocardiographic evidence of amyloid involvement.

Adult↗
PubMed1997

Intravenous dofetilide, a class III antiarrhythmic agent, for the termination of sustained atrial fibrillation or flutter. Intravenous Dofetilide Investigators.

OBJECTIVES: This study sought to determine the safety and efficacy of a single bolus of intravenous dofetilide, a pure class III antiarrhythmic agent, for the termination of sustained atrial fibrillation or flutter. BACKGROUND: Dofetilide is a highly selective blocker of the rapid component of the delayed rectifier current causing action potential prolongation. These effects, and preliminary clinical data, suggest that it may be effective in the treatment of atrial fibrillation and flutter. METHODS: Ninety-one patients with sustained atrial fibrillation (75 patients) or flutter (16 patients) were entered into a double-blind, randomized multicenter study of one of two doses of dofetilide (4 or 8 micrograms/kg body weight) or placebo. RESULTS: Dofetilide effectively terminated the arrhythmia in 31% of patients receiving 8 micrograms/kg, a statistically significant difference from those receiving 4 micrograms/kg (conversion rate 12.5%, p < 0.05) or placebo (no conversion, p < 0.01). Patients with atrial flutter had a greater response to dofetilide (54% conversion rate) than those with atrial fibrillation (14.5% conversion rate, p < 0.001). CONCLUSIONS: Intravenous dofetilide can convert sustained atrial fibrillation or flutter to sinus rhythm. However, its efficacy is greater in flutter--a response that contrasts with the poorer response seen with class I agents. This finding potentially represents an important advance in the pharmacologic termination of atrial flutter.

Anti-Arrhythmia Agents↗
PubMed1997

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.

Aged↗
PubMed1997

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.

Amyloidosis↗
PubMed1996

Dose-intensive melphalan with blood stem cell support for the treatment of AL amyloidosis: one-year follow-up in five patients.

The morbidity and lethality of AL amyloidosis is caused by the deposition of lg light chains as fibrillar amyloid protein in vital organs, disrupting their function, and not by the generally low burden of clonal plasma cells that produce the paraproteins. Survival of patients with AL amyloidosis is no more than 1 to 2 years from the time of diagnosis with current management approaches. Clearly, more effective therapies are needed for this rapidly lethal disease. Five patients were treated with dose-intensive melphalan and blood stem cell support and followed for a period of 1 year. Patients were diagnosed with AL amyloidosis by tissue biopsy and categorized by performance status and organ involvement. Their plasma cell dyscrasias were evaluated with immunofixation electrophoresis of serum and urine specimens, quantitative serum lgs, and immunohistochemical staining of bone marrow biopsy specimens. After treatment with dose-intensive intravenous melphalan followed by infusion of autologous growth-factor-mobilized blood stem cells, clinical evaluations and plasma cell studies were repeated at 3 and 12 months. Three men and 2 women aged 38 to 53 years were treated. Median performance status (SWOG) was 2 (1 to 3), and clinical presentations included nephrotic syndrome (n = 1), symptomatic cardiomyopathy (n = 1), gastrointestinal involvement with polyneuropathy (n = 2), and hepatomegaly (n = 1). With a median follow-up of 13 months (12 to 17 months), all five patients are well and have shown stable or improved performance status and clinical remission of organ-related dysfunction, including a 50% reduction in daily proteinuria with no change in creatinine, reversal of symptoms of cardiomyopathy and reductions of posterior wall and septal thickening, reversal of polyneuropathy and gastric atony, and resolution of hepatomegaly by computed tomographic scan. In 3 of the 5 patients (60%) at 12 months after treatment, plasma cell dyscrasias could not be detected. Dose-intensive chemotherapy with intravenous melphalan and growth-factor-mobilized blood stem cell support is feasible therapy for patients with AL amyloidosis, even when there is clinical evidence of cardiac involvement. At least some patients with AL amyloidosis achieve complete remission of their plasma cell dyscrasia, improvement in performance status, and clinical remission of organ-specific disease after this form of treatment.

Adult↗
PubMed1996

Resolution of heart failure in patients with AL amyloidosis.

BACKGROUND: Patients with AL amyloidosis and congestive heart failure have a very poor prognosis. To date, the recovery of these patients has not been described in detail. OBJECTIVE: To determine the frequency and characteristics regression of disease in patients with congestive heart failure due to AL amyloidosis. DESIGN: Review of patients with systemic AL amyloidosis. SETTING: An international referral center for amyloidosis in the United States. PATIENTS: 140 patients with congestive heart failure due to Al amyloidosis who were seen between 1983 and 1994. MEASUREMENTS: Functional status, Doppler echocardiography, and objective measurements of disease activity. RESULTS: 3 of 140 patients (2.1%) had marked resolution of congestive heart failure and evidence for remission of disease activity. All 3 had been treated with melphalan. CONCLUSIONS: Melphalan appears to have had a favorable effect in 3 patients with AL amyloidosis and heart failure. The abolition of light chains that was seen in these 3 patients suggests that light-chain toxicity may play a role in the genesis of heart failure in patients with AL amyloidosis.

Amyloidosis↗