First-in-man phase I trial of two schedules of the novel synthetic tetrahydroisoquinoline alkaloid PM00104 (Zalypsis) in patients with advanced solid tumours.

BACKGROUND: PM00104 binds guanines at DNA minor grooves, impacting DNA replication and transcription. A phase I study was undertaken to investigate safety, dose-limiting toxicities (DLTs), recommended phase II dose (RP2D), pharmacokinetics (PKs) and preliminary antitumour activity of PM00104 as a 1- or 3-h infusion three-weekly. METHODS: Patients with advanced solid tumours received PM00104 in a dose escalation trial, as guided by toxicity and PK data. RESULTS: A total of 47 patients were treated; 27 patients on the 1-h schedule (0.23-3.6 mg m(-2)) and 20 patients on the 3-h schedule (1.8-3.5 mg m(-2)). Dose-limiting toxicities comprised reversible nausea, vomiting, fatigue, elevated transaminases and thrombocytopenia, establishing the 1-h schedule RP2D at 3.0 mg m(-2). With the 3-h schedule, DLTs of reversible hypotension and neutropenia established the RP2D at 2.8 mg m(-2). Common PM00104-related adverse events at the RP2D comprised grade 1-2 nausea, fatigue and myelosuppression. In both schedules, PKs increased linearly, but doses over the 1-h schedule RP2D resulted in higher than proportional increases in exposure. A patient with advanced urothelial carcinoma had RECIST shrinkage by 49%, and three patients had RECIST stable disease ≥6 months. CONCLUSION: PM00104 is well tolerated, with preliminary evidence of antitumour activity observed. The 1-h 3-weekly schedule is being assessed in phase II clinical trials.

The insulin-like growth factor-I receptor inhibitor figitumumab (CP-751,871) in combination with docetaxel in patients with advanced solid tumours: results of a phase Ib dose-escalation, open-label study.

BACKGROUND: This phase Ib trial assessed safety, tolerability, and maximum tolerated dose (MTD) of figitumumab (CP-751,871), a fully human monoclonal antibody targeting the insulin-like growth factor type 1 receptor (IGF-IR), in combination with docetaxel. METHODS: Patients with advanced solid tumours were treated with escalating dose levels of figitumumab plus 75 mg m(-2) docetaxel every 21 days. Safety, efficacy, pharmacokinetics (PKs), and biomarker responses were evaluated. RESULTS: In 46 patients, no dose-limiting toxicities were attributable to the treatment combination. Grade 3 and 4 toxicities included neutropaenia (n=28), febrile neutropaenia (n=11), fatigue (n=10), leukopaenia (n=7), diarrhoea (n=5), hyperglycaemia, lymphopaenia, cellulitis, DVT, and pain (all n=1). The MTD was not reached. Four partial responses were observed; 12 patients had disease stabilisation of > or =6 months. Pharmacokinetic and biomarker analyses showed a dose-dependent increase in plasma exposure, and complete sIGF-IR downregulation at doses of >or =3 mg kg(-1). Pharmacokinetics of docetaxel in combination was similar to when given alone. Out of 18 castration-resistant prostate cancer patients, 10 (56%) had > or =5 circulating tumour cells (CTCs) per 7.5 ml of blood at baseline: 6 out of 10 (60%) had a decline from > or =5 to <5 CTCs and 9 out of 10 (90%) had a > or =30% decline in CTCs after therapy. CONCLUSIONS: Figitumumab and docetaxel in combination are well tolerated. Further evaluation is warranted.

Phase II, two-stage, single-arm trial of the histone deacetylase inhibitor (HDACi) romidepsin in metastatic castration-resistant prostate cancer (CRPC).

BACKGROUND: Histone deacetylase blockade can promote heat shock protein 90 (HSP90) acetylation, abrogating androgen receptor signaling. A phase II trial of the histone deacetylase inhibitor (HDACi) romidepsin was conducted in patients with progressing, metastatic, castration-resistant prostate cancer (CRPC). PATIENTS AND METHODS: A dose of 13 mg/m(2) was administered i.v. over 4 h on days 1, 8 and 15 every 28 days. The primary end point was rate of disease control defined as no evidence of radiological progression at 6 months. A sample size of 16 assessable patients in stage 1 and nine assessable patients in stage 2 was selected; progression to stage 2 required one or more patients with disease control in stage 1 (H(o) = 0.10, H(a) = 0.30; alpha and beta = 0.10). RESULTS: Thirty-five patients were enrolled. Two patients achieved a confirmed radiological partial response (RECIST) lasting > or = 6 months, along with a confirmed prostate-specific antigen decline of > or = 50%. Eleven patients experienced toxicity necessitating early discontinuation. The commonest adverse events were nausea (30 patients; 85.7%), fatigue (28 patients; 80.0%), vomiting (23 patients; 65.7%) and anorexia (20 patients; 57.1%). There was no significant cardiac toxicity. CONCLUSIONS: At the dose and schedule selected, romidepsin demonstrated minimal antitumor activity in chemonaive patients with CRPC. Further studies of improved HDACi, alone and in combination with other therapies, should nevertheless be investigated.

Circulating tumour cell (CTC) counts as intermediate end points in castration-resistant prostate cancer (CRPC): a single-centre experience.

BACKGROUND: The purpose of this study was to evaluate the association of circulating tumour cell (CTC) counts, before and after commencing treatment, with overall survival (OS) in patients with castration-resistant prostate cancer (CRPC). EXPERIMENTAL DESIGN: A 7.5 ml of blood was collected before and after treatment in 119 patients with CRPC. CTCs were enumerated using the CellSearchSystem. RESULTS: Higher CTC counts associated with baseline characteristics portending aggressive disease. Multivariate analyses indicated that a CTC >or=5 was an independent prognostic factor at all time points evaluated. Patients with baseline CTC >or=5 had shorter OS than those with <5 [median OS 19.5 versus >30 months, hazard ratio (HR) 3.25, P=0.012]; patients with CTC >50 had a poorer OS than those with CTCs 5-50 (median OS 6.3 versus 21.1 months, HR 4.1, P<0.001). Patients whose CTC counts reduced from >or=5 at baseline to <5 following treatment had a better OS compared with those who did not. CTC counts showed a similar, but earlier and independent, ability to time to disease progression to predict OS. CONCLUSION: CTC counts predict OS and provide independent prognostic information to time to disease progression; CTC dynamics following therapy need to be evaluated as an intermediate end point of outcome in randomised phase III trials.

A case-crossover study on transient risk factors of work-related eye injuries.

OBJECTIVES: To investigate modifiable risk and preventive factors of work-related eye injuries. METHODS: A case-crossover study conducted to explore the associations between transient risk factors and work-related eye injuries. Patients seen at seven medical centres in Taiwan with work-related eye injuries over a 4-year period were enrolled in the study. Clinical information was collected from medical charts and detailed information on exposure to eight potentially modifiable factors during the 60 minutes prior to the occurrence of each injury, as well as during the same time interval on the last work day prior to the injury, were obtained using questionnaire surveys. Matched-pair interval analysis was adopted to assess the odds ratios (ORs) for work-related eye injuries given exposure to the eight modifiable factors. RESULTS: A total of 283 subjects were interviewed. Most of these injured workers were young, male, and self-employed or small enterprise workers. The most common injury type was photokeratitis (33.2%), mainly caused by welding (30.4%). The OR for a work-related eye injury was increased with the performance of an unfamiliar task (57.0), operation of a faulty tool or piece of equipment (48.5), distractions (24.0), being rushed (13.0), or fatigued (10.0), and a poor work environment (4.3). Wearing eye protection devices was found to have a significant protective effect on workers who might otherwise have been exposed to eye injuries (OR = 0.4; 95% CI 0.2 to 0.7). CONCLUSION: Potential modifiable risk and preventive factors for work-related eye injuries were identified using a case-crossover study. This information should be helpful in the development of preventive strategies.

Serum lipid and apolipoprotein distributions in Hong Kong Chinese.

STUDY OBJECTIVE: The aim was to describe the distribution of lipids and apolipoproteins in the Chinese population in Hong Kong. DESIGN: This was a prospective, cross sectional, population based survey. SETTINGS: The study was conducted in a single, self referred, out patient screening centre. PARTICIPANTS: Altogether 825 Chinese adults aged > or = 20 years were screened. One hundred subjects who had previously had lipid measurement and 29 who were taking lipid modifying drugs were excluded but 289 men and 407 women remained for further analysis. MAIN RESULTS: Age standardised mean (SEM) lipids concentrations for Hong Kong Chinese were total cholesterol: men, 5.48 (0.05) mmol/l and women, 5.46 (0.06) mmol/l; triglycerides: men, 1.22 (1.03) mmol/l and women, 1.00 (1.03) mmol/l; high density lipoprotein (HDL) cholesterol: men, 1.25 (0.02) mmol/l and women, 1.42 (0.02) mmol/l; low density lipoprotein (LDL) cholesterol: men, 3.56 (0.05) mmol/l and women, 3.50 (0.06) mmol/l; apolipoprotein A-I (apo A-I): men, 1.34 (0.01) g/l and women, 1.46 (0.01) g/l; and apolipoprotein B (apo B): men, 1.15 (0.02) g/l and women, 1.06 (0.02) g/l. The total to HDL cholesterol ratios were men, 4.62 (0.07) and women, 4.10 (0.08); and apo B to apo A-I ratios (apo B/A) were men, 0.88 (0.02) and women, 0.75 (0.02). While levels of total cholesterol, LDL cholesterol, apo B, triglycerides, total/HDL cholesterol, and apo B/A were positively associated with age in both sexes and were higher in men before the age 50-59 years, they rose steeply thereafter in women to cross over the levels in men. In contrast, HDL cholesterol decreased with age while apo A-I remained constant, and both were consistently higher in women than in men in all age groups. CONCLUSIONS: Hong Kong Chinese have attained lipid profiles similar to those in other developed western populations. Environmental factors seem influential in this regard. Faced with the increasing coronary mortality of recent years, there should be a major effort to reduce the cholesterol concentrations in this population.

Cerebral haemorrhage in anticoagulated patients with non-septic mechanical valvular prosthesis.

Cerebral haemorrhage in anticoagulated patients with mechanical valvular prosthesis poses an uncommon but difficult management problem. Four such patients are presented: one patient had delayed haemorrhagic transformation of a preexisting cerebral infarct, one probably had de novo haemorrhage complicating hypertension and in two patients cerebral haemorrhage was associated with excessive anticoagulation. Conservative management including the use of fresh frozen plasma, delayed heparinisation and warfarinisation was used. Both patients with anticoagulant overdose died as a result of extensive haemorrhage despite the drainage of cerebellar haematoma in one patient. The remaining two patients survived with minimal neurological deficits. Diagnosis of the underlying cause of cerebral haemorrhage, and the timing of heparinisation and anticoagulation are discussed.

Mollaret's meningitis revisited. Report of a case with a review of the literature.

Recurrent aseptic meningitis of Mollaret is a rare condition. We report a Chinese patient with Mollaret's meningitis and describe the characteristic cytological changes in the cerebrospinal fluid. The diagnosis and treatment of this condition is discussed with a review of the English literature.

Bilateral coronary-artery-to-pulmonary-artery fistula coexistent with apical hypertrophic cardiomyopathy--a case report.

A sixty-four-year-old man presented with repolarization abnormalities on the electrocardiogram. Echocardiography and cardiac catheterization revealed that he had the rare combination of apical hypertrophic cardiomyopathy with bilateral coronary-artery-to-pulmonary-artery fistula. An exercise thallium scan was negative, suggesting that the marked electrocardiographic changes were most likely secondary to the apical myocardial hypertrophy, instead of to coronary-steal-induced ischemia.

Myocardial infarction complicating postsplenectomy thrombocytosis, with early left ventricular mural thrombus formation and cerebral embolism--a case report.

Thrombocytosis is a rare cause of ischemic cardiovascular and cerebrovascular events in patients with intrinsically normal coronary and cerebral vasculature. This report details the occurrence of inferior wall myocardial infarction (MI) consequent upon postsplenectomy thrombocytosis in a thirty-four-year-old man with angiographically normal coronary arteries. The MI was complicated by early left ventricular mural thrombus formation and embolic cerebral infarction. Combined anticoagulant and antiplatelet therapy was required to prevent the recurrence of ischemic events.

Mass balance, excretion and metabolism of [¹4C] ASA404 in cancer patients in a phase I trial.

PURPOSE: To determine the mass balance, excretion and metabolism of the small molecule flavonoid tumour vascular disrupting agent ASA404 in patients with advanced cancer. METHODS: Seven cancer patients were given a single dose of 3,000 mg [(14)C] ASA404 by intravenous infusion over 20 min prior to collection of samples of plasma, urine and faeces. Pharmacokinetic samples were analysed by HPLC, liquid scintillation counting, mass spectrometry, glusulase treatment and comparison to authentic standards. Descriptive pharmacokinetic parameters were generated by noncompartmental analysis. RESULTS: Mass balance was achieved (mean recovery of radioactivity in excreta = 86.9% of the dose) with balanced excretion between urine (mean recovery of radioactivity in urine = 53.9% of dose) and faeces (mean recovery of radioactivity in faeces = 33.3% of dose). ASA404 was eliminated as parent drug, three known metabolites (6-methylhydroxy-ASA404, ASA404 acyl glucuronide and 6-methylhydroxy-ASA404 acyl glucuronide) and two novel metabolites (an ASA404 dimer and an ASA404 dimer glucuronide conjugate). Unchanged ASA404 was the major radioactivity component detected in plasma within the first 24 h after dosing. At later time points, irreversibly protein bound ASA404 and all of the metabolites that had been detected in excreta contributed to total plasma radioactivity. CONCLUSION: This study defined the substantial excretion of ASA404, mainly as metabolites, in both urine (over half of the dose) and faeces (about one-third of the dose) after intravenous administration. Two novel metabolites were identified that were not reported by previous studies using nonradioactive techniques.

A phase Ib study of pertuzumab, a recombinant humanised antibody to HER2, and docetaxel in patients with advanced solid tumours.

Pertuzumab represents the first in a new class of targeted therapeutics known as HER dimerisation inhibitors. We conducted a phase Ib study to determine the maximum-tolerated dose, the dose limiting toxicities (DLT), and pharmacokinetic (PK) interaction of docetaxel when administered in combination with pertuzumab. Initially, two dose levels of docetaxel (60 and 75 mg m(-2)) were explored in combination with a fixed dose of 1050 mg of pertuzumab; then two dose levels of docetaxel (75 and 100 mg m(-2)) were explored in combination following a fixed dose of 420 mg of pertuzumab with a loading dose of 840 mg. Both drugs were administered intravenously every 3 weeks. The latter dose of pertuzumab was allowed after an amendment to the original protocol when phase II data suggesting no difference in toxicity or activity between the 2 doses became available. Two patients out of two treated at docetaxel 75 mg m(-2) in combination with pertuzumab 1050 mg suffered DLT (grade 3 diarrhoea and grade 4 febrile neutropaenia). Two out of five patients treated at docetaxel 100 mg m(-2) in combination with pertuzumab 420 mg with a loading dose of 840 mg suffered DLT (grade 3 fatigue and grade 4 febrile neutropaenia). Stable disease was observed at four cycles in more than half of the patients treated and a confirmed radiological partial response with a >50% decline in PSA in a patient with hormone refractory prostate cancer were observed. There were no pharmacokinetic drug-drug interactions. The recommended phase II dose of this combination was docetaxel 75 mg m(-2) and 420 mg pertuzumab following a loading dose of 840 mg.

SERPIN regulation of factor XIa. The novel observation that protease nexin 1 in the presence of heparin is a more potent inhibitor of factor XIa than C1 inhibitor.

In the present studies we have made the novel observation that protease nexin 1 (PN1), a member of the serine protease inhibitor (SERPIN) superfamily, is a potent inhibitor of the blood coagulation Factor XIa (FXIa). The inhibitory complexes formed between PN1 and FXIa are stable when subjected to reducing agents, SDS, and boiling, a characteristic of the acyl linkage formed between SERPINs and their cognate proteases. Using a sensitive fluorescence-quenched peptide substrate, the K(assoc) of PN1 for FXIa was determined to be 7.9 x 10(4) m(-)(1) s(-)(1) in the absence of heparin. In the presence of heparin, this rate was accelerated to 1.7 x 10(6), M(-)(1) s(-)(1), making PN1 a far better inhibitor of FXIa than C1 inhibitor, which is the only other SERPIN known to significantly inhibit FXIa. FXIa-PN1 complexes are shown to be internalized and degraded by human fibroblasts, most likely via the low density lipoprotein receptor-related protein (LRP), since degradation was strongly inhibited by the LRP agonist, receptor-associated protein. Since FXIa proteolytically modifies the amyloid precursor protein, this observation may suggest an accessory role for PN1 in the pathobiogenesis of Alzheimer's disease.

Propylthiouracil hypersensitivity with circumstantial evidence for drug-induced reversible sensorineural deafness: a case report.

Severe adverse reactions to propylthiouracil occur in 1-5% of patients. Three major side effects, namely agranulocytosis, hepatotoxicity and drug-induced hypersensitivity, have been described though these syndromes are not distinct entities and there can be overlaps in the clinical manifestations. The drug-induced hypersensitivity may be an immune-mediated reaction with multiorgan involvement in which a combination of polyarthritis, cutaneous vasculitis and fever is common. We report a patient with propylthiouracil-induced hypersensitivity with an unusual combination of high spiking fever, migratory polyarthritis, reversible sensorineural deafness, normochromic normocytic anaemia, leucocytosis and hepatotoxicity associated with polyclonal activation of multiple autoantibodies. This case illustrates the highly variable clinical manifestations of the syndrome. The prompt recovery upon withdrawal of the drug indicates the importance of early diagnosis.

Elective stenting of unprotected left main coronary disease.

For the 12-mo period of 1995, we encountered seven consecutive patients with symptomatic unprotected left main coronary stenosis requiring revascularization. There were five males and two females, age ranging 48-76 years. One patient was referred to coronary bypass surgery. Of the remaining six patients, three refused surgery and the other three, including one with previous bypass surgery and two with previous interventional procedures, preferred percutaneous revascularization. All six had successful elective stenting of their left main coronary stenoses with the new short Palmaz-Schatz stents, P084 and PS104. There were no complications and all remained totally asymptomatic at 3-14 months followup. We conclude that with proper patient selection and the availability of appropriate stents, elective stenting of unprotected left main coronary stenosis is safe with good immediate and medium term results.

Incessant automatic ventricular tachycardia complicating acute coxsackie B myocarditis.

A 13-year-old girl presented with incessant ventricular tachycardia complicating acute Coxsackie B3 myocarditis. Electrophysiologic assessment revealed that the tachycardia could not be terminated, overdrive suppressed or accelerated by programmed electrical stimulation, but was transiently slowed by intravenous adenosine triphosphate and had marked spontaneous and sympathoautonomic-mediated fluctuation in the tachycardia cycle length. These features were atypical of reentry and triggered automaticity and suggested that abnormal automaticity was the likely tachycardia mechanism. Intravenous amiodarone slowed the ventricular tachycardia, but the patient eventually succumbed from rapidly progressive left ventricular failure. Postmortem pathohistologic examination confirmed the diagnosis of acute myocarditis.

The use of implantable sensors for the control of pacemaker mediated tachycardias: a comparative evaluation between minute ventilation sensing and acceleration sensing dual chamber rate adaptive pacemakers.

The role of implantable sensors to control pacemaker mediated tachycardias was investigated in 16 patients with two different dual chamber rate adaptive (DDDR) pacemakers, which sensed eiter minute ventilation (DDDR-Meta, nine patients) or body acceleration (Relay, seven patients). Successive atrial sensed events beyond a programmable rate occurring in the absence of detection of exercise by the sensors were considered to represent retrograde conduction or atrial arrhythmias, and the pacemakers responded by either a mode shift from DDDR to ventricular rate adaptive (VVIR) pacing (DDDR-Meta) or by tracking at an interim rate, the so-called conditional ventricular tracking limit (CVTL, Relay). In the unipolar atrial sensing mode, myopotential sensing (MPI) and external chest wall stimulations (CWS) at 250 beats/min were induced to be preferentially sensed by the atrial channel to simulate the conditions of atrial arrhythmias. In the DDD mode, these maneuvers resulted in ventricular responses of 88 +/- 3 beats/min and 110 +/- 3 beats/min for MPI and CWS, respectively. The pacing rate was significantly reduced in the DDDR mode with the sensors correctly detecting and responding to the sensed abnormal atrial signals (68 +/- 5 beats/min during MPI and 71 +/- 5 beats/min during CWS, P less than 0.005 compared with the corresponding DDD rate). One patient with a Relay pacemaker developed spontaneous atrial flutter and the ventricular tracking responses were 140 and 85 beats/min in the DDD and DDDR pacing modes, respectively. Thus MPI and CWS are useful bedside testing methods to assess pacemaker response during atrial arrhythmias. The use of implantable sensors to judge the appropriateness of atrial rate is a new approach to the management of pacemaker mediated tachycardias.

Atrial arrhythmia management with sensor controlled atrial refractory period and automatic mode switching in patients with minute ventilation sensing dual chamber rate adaptive pacemakers.

Although a long postventricular atrial refractory period (PVARP) may prevent the occurrence of pacemaker mediated tachycardias and inadvertent tracking of atrial arrhythmias in dual chamber (DDD) pacing, the maximum upper rate will necessarily be compromised. We tested the feasibility of using minute ventilation sensing in a dual chamber rate adaptive pacemaker (DDDR) to shorten the PVARP during exercise in 13 patients with bradycardias (resting PVARP = 463 +/- 29 msec) to avoid premature upper rate behavior. Graded treadmill exercise tests in the DDD and DDDR modes at this PVARP resulted in maximum ventricular rates of 98 +/- 8 and 142 +/- 3 beats/min, respectively (P < 0.0001), due to chronotropic incompetence and upper rate limitation in the DDD mode, both circumvened with the use of sensor. In order to stimulate atrial arrhythmias, chest wall stimulation was applied for 30 seconds at a rate of 250 beats/min at a mean unipolar atrial sensitivity of 0.82 mV. Irregular ventricular responses occurred in the DDD mode (the rates at a PVARP of 280 and 463 +/- 29 msec were, respectively 92 +/- 5 and 66 +/- 3 msec; P < 0.0001). In the DDDR mode at a PVARP of 463 +/- 29 msec, regular ventricular pacing at 53 +/- 2 beats/min occurred due to mode switching to VVIR mode in the presence of repetitive sensed atrial events within the PVARP. One patient developed spontaneous atrial fibrillation on follow-up, which was correctly identified by the pacemaker algorithm, resulting in mode switch from DDDR to regular VVIR pacing and preservation of rate response. In conclusion, sensor controlled PVARP allows a long PVARP to be used at rest without limiting the maximum rate during exercise. In addition, to offer protection against retrograde conduction, a long PVARP and mode switching also limit the rate during atrial arrhythmias and allow regular ventricular rate responses according to the physiological demands.

Bidirectional tachycardia induced by herbal aconite poisoning.

This report details the clinical, electrocardiographic, and electropharmacological characteristics of an unusual case of bidirectional tachycardia induced by aconites present in a Chinese herbal decoction consumed by a previously healthy subject. The tachycardia showed marked susceptibility to vagotonic maneuvers, cholinesterase inhibition, and adenosine triphosphate. The incessant nature of the tachycardia, rapid recurrence after transient suppression, and failure to respond to direct current cardioversion suggested an automatic tachycardia mechanism consistent with known data on the cellular electrophysiological mechanism of aconitine-mediated arrhythmogenesis. A fascicular or ventricular myocardial origin of the tachycardia with alternating activation patterns, or dual foci with alternate discharge, appeared most plausible. The rootstocks of aconitum plants have been commonly employed in traditional Chinese herbal recipes for "cardiotonic" actions and for relieving "rheumatism." Multiple pitfalls could occur during the processing of these herbs that might have predisposed to aconite poisoning. The need for strict control and surveillance of herbal substances with low margins of safety is highlighted.

Ventricular rate-adaptive pacing in the elderly.

The role of ventricular rate-adaptive pacing (VVIR) in the elderly was investigated in 12 patients with a mean age of 85 +/- 2 years (range 75-95 years) with implanted activity-initiated VVIR pacemakers. Although four patients had significant extracardiac diseases, all were capable of independent walking and self care. The pacing rate achieved during structured daily activities (walking, climbing stairs, washing, bed-making and scrubbing floors) were compared with those achieved by 10 age-matched healthy subjects. Apart from the more strenuous activities (ascending stairs and floor-scrubbing), the pacing rates achieved by the patients were comparable to those of the healthy subjects and occurred within an appropriate time. In a 4-weekly randomized, double-blind crossover protocol in the VVI and VVIR pacing modes, all patients underwent assessments in a 12-min walking distance test, a 24 h non-invasive ambulatory blood pressure recording and a symptomatic documentation. During VVIR pacing, the 12-min walking distance was significantly improved compared to VVI pacing (556 +/- 52 vs. 545 +/- 55 m, P less than 0.05). There was no difference between the recorded blood pressure and symptom scores between the two pacing modes, although most patients preferred VVIR pacing (P less than 0.05). It is concluded that VVIR pacing in this elderly population can improve exercise capacity, and the patients' preference for the VVIR mode was documented despite the absence of a measurable difference in symptomatology.