Peter W. Pflugfelder

The role of donor age and ischemic time on survival following orthotopic heart transplantation

BACKGROUND The advances in immunotherapy, along with a liberalization of eligibility criteria have contributed significantly to the ever increasing demand for donor organs. In an attempt to expand the donor pool, transplant programs are now accepting older donors as well as donors from more remote areas. The purpose of this study is to determine the effect of donor age and organ ischemic time on survival following orthotopic heart transplantation (OHT). METHODS From April 1981 to December 1996 372 adult patients underwent OHT at the University of Western Ontario. Cox proportional hazards models were used to identify predictors of outcome. Variables affecting survival were then entered into a stepwise logistic regression model to develop probability models for 30-day- and 1-year-mortality. RESULTS The mean age of the recipient population was 45.6 +/- 12.3 years (range 18-64 years: 54 < or = 30; 237 were 31-55; 91 > 56 years). The majority (329 patients, 86.1%) were male and the most common indications for OHT were ischemic (n = 180) and idiopathic (n = 171) cardiomyopathy. Total ischemic time (TIT) was 202.4 +/- 84.5 minutes (range 47-457 minutes). In 86 donors TIT was under 2 hours while it was between 2 and 4 hours in 168, and more than 4 hours in 128 donors. Actuarial survival was 80%, 73%, and 55% at 1, 5, and 10 years respectively. By Cox proportional hazards models, recipient status (Status I-II vs III-IV; risk ratio 1.75; p = 0.003) and donor age, examined as either a continuous or categorical variable ([age < 35 vs > or = 35; risk ratio 1.98; p < 0.001], [age < 50 vs > or = 50; risk ratio 2.20; p < 0.001], [age < 35 vs 35-49 versus > or = 50; risk ratio 1.83; p < 0.001]), were the only predictors of operative mortality. In this analysis, total graft ischemic time had no effect on survival. However, using the Kaplan-Meier method followed by Mantel-Cox logrank analysis, ischemic time did have a significant effect on survival if donor age was > 50 years (p = 0.009). By stepwise logistic regression analysis, a probability model for survival was then developed based on donor age, the interaction between donor age and ischemic time, and patient status. CONCLUSIONS Improvements in myocardial preservation and peri-operative management may allow for the safe utilization of donor organs with prolonged ischemic times. Older donors are associated with decreased peri-operative and long-term survival following. OHT, particularly if graft ischemic time exceeds 240 minutes and if these donor hearts are transplanted into urgent (Status III-IV) recipients.

Frequency of angiographic detection and quantitative assessment of coronary arterial disease one and three years after cardiac transplantation

The reported high incidence of coronary atherosclerosis in many transplant series led us to critically review our experience in 83 patients who have had selective coronary angiography at greater than or equal to 1 years after transplantation. Angiograms were reviewed for evidence of coronary vascular disease, and quantitative analysis of multiple coronary artery segments was performed in serial films. Qualitative analysis revealed only 3 of 83 patients with any angiographic abnormality at follow-up, 1 with minimal luminal irregularities in the right coronary artery at 1 year, a second with a 50% diameter stenosis of the proximal left anterior descending artery and minimal irregularity of the proximal circumflex artery at 1 year and a third patient who developed a new 30% diameter eccentric proximal right coronary artery stenosis at 3-year follow-up. The cumulative incidence of graft vascular disease assessed angiographically was therefore 2% at 1 year and 4% at 3 years. Quantitative analysis, however, showed a significant decrease in coronary artery luminal diameter over time. The mean left main coronary artery diameter decreased from 5.4 +/- 0.9 mm at 1 year to 4.7 +/- 0.8 mm at 3 years (p = 0.0007).(ABSTRACT TRUNCATED AT 250 WORDS)

Importance of chronic aspiration in recipients of heart-lung transplants.

In a series of eleven recipients of heart-lung transplants (HLT), five have obliterative bronchiolitis. Five of the eleven patients have chronic cough as well as slower than normal gastric emptying and/or oesophageal dysmotility; all five have evidence of bronchiectasis and three have obliterative bronchiolitis. Three of the patients improved after the introduction of treatment to prevent reflux, and another, who had a large phytobezoar, improved after pyloroplasty. In patients with chronic cough after HLT, with or without dyspeptic symptoms or recurring pulmonary sepsis, investigation of oesophageal motility and gastric emptying should be undertaken.

Early detection of canine myocardial infarction by magnetic resonance imaging in vivo.

This study was undertaken to assess the ability of proton magnetic resonance imaging (MRI) to detect myocardial ischemia shortly after coronary artery occlusion. Fifteen dogs were studied before and serially for up to 6 hr after anterior descending or circumflex coronary artery ligation in vivo by gated MRI with a 0.15 tesla resistive magnet (resonant frequency of hydrogen 6.25 MHz). Image acquisition was by single-spin echo, with echo times (TE) of 30 msec and TE 60 msec, and modified inversion recovery pulse sequences. Excellent anatomic definition was observed. By 4 hr after coronary artery occlusion the signal in the infarct zone increased to 36 +/- 20% greater than that in the adjacent normal myocardium for the TE 30 msec sequence (p less than .01) and to 116 +/- 100% for the TE 60 msec sequence (p less than .05). The most intense increase in signal was noted with the TE 60 msec pulse sequence and because normal myocardium is not well visualized by this technique, acutely ischemic myocardium was clearly delineated. Inversion recovery imaging did not show areas of ischemia. Changes seen on MR images correlated well with the location of ischemic changes noted on microscopic examination of the excised hearts. MRI thus provides a noninvasive means for detection of ischemia early in the course of myocardial infarction.

Hemodynamic profiles at rest and during supine exercise after orthotopic cardiac transplantation

To characterize the spectrum of hemodynamic findings after orthotopic cardiac transplantation, 20 healthy heart transplant recipients with no evidence of cardiac dysfunction by noninvasive testing were studied for 1 to 51 months (mean 15) following surgery. After routine endomyocardial biopsy, right-sided heart pressures and thermodilution cardiac outputs were measured at rest (supine) and during symptom-limited, graded supine exercise. In addition, the effect of respiration on right atrial pressures and waveforms was determined at rest (supine, legs down), and after passive leg raising (volume loading). During exercise, striking increases of pulmonary artery, pulmonary artery wedge and right atrial pressures were seen. The mean pulmonary artery pressure rose 45% during the first stage of exercise (p less than 0.001) and by peak exercise it had increased 87% above resting values. The pulmonary artery wedge pressure increased significantly with passive leg elevation (p less than 0.001) and during the first stage of exercise rose 61% above baseline values. By peak exercise the mean pulmonary artery wedge pressure was more than double the resting value. Similarly, the right atrial mean pressure increased significantly (p less than 0.001) with passive leg elevation and nearly tripled at peak exercise. All values promptly returned to near baseline after exercise. The cardiac output increased 98% during exercise. During early exercise, the rise in cardiac output was mediated primarily by an increase in stroke volume. At rest, there was an abnormal response in right atrial mean pressure during slow deep inspiration in 7 individuals with legs down and in 12 after passive leg elevation (volume loading), including 4 of 10 patients studied beyond 1 year.(ABSTRACT TRUNCATED AT 250 WORDS)

Enhanced detection of cardiac allograft arterial disease with intracoronary ultrasonographic imaging

Intracoronary ultrasonographic imaging was performed in 60 patients 0.3 to 9 years (mean 2.9 +/- 1.9) after heart transplantation. By using a 1.8 mm intravascular ultrasonographic catheter, 192 (80%) of 240 angiographically visualized major epicardial coronary arteries (right, left main, anterior descending, and circumflex) were imaged by ultrasonography. Coronary luminal irregularities were detected in 15% of arteries by angiography compared with 34% by ultrasonography (p < 0.0001). The typical abnormality detected by ultrasonography consisted of crescentic and/or concentric intimal and medial thickening. Calcification in vascular lesions was rare (< 1% of arteries studied). Although the prevalence of angiographic abnormalities tended to be time dependent, ultrasonographic abnormalities were more strongly associated with donor age (normal, 22 +/- 8 years, vs abnormal, 33 +/- 10 years; p < 0.0001). Cardiac allograft coronary arterial disease is significantly underestimated by contrast angiography. Intravascular ultrasonography may provide a useful adjunct for identification and serial follow-up of this significant problem.

Clinical consequences of angiotensin-converting enzyme inhibitor withdrawl in chronic heart failure: A double-blind, placebo-controlled study of quinapril☆

Objectives. This study was performed to the efficacy, safety and clinical consequences of abrupt cessation of quinapril therapy in a placebo-controlled,, randomized, double-blind withdrawal trial. Background. Angiotensin-converting enzyme inhibitor therapy has assumed a pivotal role in the treatment of chronic heart failure. Quinnpril hydrochloride, a nonsulfydryl angiotensinconverting enzyme inhibitor, has shown beneficial clinical effects in previous studies. Methods. After ≥ 10 weeks of single-blind quinapril therapy, 224 patients with New York Heart Association class II or III heart failure were randomized in double-blind fashion to continue quinapril (n = 114) or to receive placebo (n = 110) for 16 weeks. Changes in treadmill exercise time, New York Heart Association functional class, quality of life and symptoms of heart failure were assessed. Results. Patients withdrawn to placebo had a significant deterioration in exercise tolerance (median change -16 s with placebo vs. +3 s with quinapril, p = 0.015). New York Heart Association fractional class (p = 0.004) and quality of life were improved and and symptoms of congestive heart failure were lessened in those remaining on quinapril therapy compared with those receiving placebo. During double-blind treatment, 18 patients were withdrawn from the placebo group because of worsening heart failure compared with 5 patients withdrawn from quinapril treatment (p < 0.001). Rather than a precipitous deterioration of clinical status or early incidence of adverse events, withdrawal from quinapril was associated with steady worsening of heart failure, beginning 4 to 6 weeks after randomization to placebo. Conclusions. Quinapril is effective and safe for maintaining clinical stability in patients with moderate congestive heart failure. Withdrawal of quinapril from patients with heart failure results in a slow progressive decline in clinical status.

Serial imaging of canine myocardial infarction by in vivo nuclear magnetic resonance

Anterior infarction was produced in eight dogs to characterize serial changes in nuclear magnetic resonance signal intensity within the infarct zone. Magnetic resonance imaging was done on the day of infarction, on day 4, 5 or 6, on day 13 and day 20 using a 0.15 tesla (6.25 MHz) resistive imager. Electrocardiographically triggered spin echo (30, 45 and 60 ms echo times) and inversion recovery (400 to 500 ms inversion time) pulse sequences were employed to obtain single slice images. On day 20, the excised hearts were sectioned and examined to determine infarct location and extent. In the spin echo images, signal intensity within the ischemic zone was visibly increased in seven of the eight dogs on the day of infarction, and in all dogs by days 4 to 6. Signal intensity remained elevated in all but two dogs at day 20. With inversion recovery imaging, changes in the infarct zone were highly variable; both ill defined increases and decreases in signal intensity were noted. With a 30 ms echo time, signal intensity in the infarct zone was increased on average 29.8 +/- 24.1% above that in normal myocardium on the day of infarction. The relative signal intensity increased to 62.4 +/- 23.5% during the first 2 weeks after infarction (p less than 0.05), then decreased to 12.0 +/- 18.5% by day 20 (p less than 0.05). Similar changes were detected in the images using the 45 and 60 ms echo times. Nuclear magnetic resonance imaging therefore is able to detect regions of myocardial infarction and follow evolutionary changes in signal intensity within the infarct zone with healing.

Cardiac phenotype and clinical outcome of familial amyloid polyneuropathy associated with transthyretin alanine 60 variant

AIMS Familial amyloid polyneuropathy (FAP) is a dominantly inherited multi-system disease associated with transthyretin (TTR) mutations. Previous series have predominantly described patients with the TTR variant Val30Met (V30M), which is the most prevalent cause of FAP worldwide. Here, we report the dominant cardiac phenotype and outcome of FAP associated with TTR Thr60Ala (T60A), the most common UK variant. METHODS AND RESULTS Sixty consecutive patients with FAP associated with TTR T60A (FAP T60A) were prospectively evaluated in two centres between 1992 and 2009. Median (range) age of symptom development was 63 (45-78) years. A family history of amyloidosis was present in only 37%. Autonomic and peripheral neuropathy were present in 44 and 32 patients, respectively, at diagnosis. Cardiac involvement was evident on echocardiography at diagnosis in 56 patients, but was associated with reduced QRS voltages on electrocardiography in only 16% evaluable cases. Seventeen patients received implantable anti-arrhythmic devices. Median survival was 6.6 years following onset of symptoms and 3.4 years from diagnosis, and correlated with serum N-terminal prohormone brain natriuretic peptide (NT-proBNP) concentration and certain echocardiographic parameters at the latter. Orthotopic liver transplantation (OLT), performed to eliminate the predominant hepatic source of variant TTR T60A protein, was performed in eight patients including one who received a concomitant cardiac transplant. Cardiac amyloidosis progressed in all lone OLT recipients, of whom four died within 5 years. CONCLUSION Cardiac amyloidosis is almost always present at diagnosis in FAP T60A, and is a major determinant of its poor prognosis. Outcome of liver transplantation in FAP T60A has been discouraging.

Cardiac dynamics during supine exercise in cyclosporine-treated orthotopic heart transplant recipients: Assessment by radionuclide angiography

The mechanisms by which the denervated heart responds to supine exercise were assessed by equilibrium gated radionuclide angiography in 18 cardiac transplant recipients 1 to 25 months (mean 11) after surgery. Results were compared with those in 15 normal subjects. Exercise duration among transplant recipients did not differ significantly from that in normal subjects. The heart rate at rest in transplant patients was 30% higher than in normal volunteers. Heart rate increased only 3% between rest and the first stage of exercise in transplant recipients compared with a 37% increase in the normal group (p less than 0.001). Cardiac output at rest was similar in both groups although the rate of rise of cardiac output and peak cardiac output were significantly lower among the transplant recipients. In early exercise, the means by which cardiac output increased in the transplant patients differed significantly from normal. In the transplant recipients, the left ventricular end-diastolic volume index increased 14% compared with a decrease of 2% in normal subjects (p less than 0.001) during the first stage of exercise. At the same time, the end-systolic volume index increased 6% in the transplant group but decreased 11% in normal subjects (p less than 0.001). These changes resulted in an overall increase in stroke volume by 20% in the transplant group compared with only a slight increase (+3%) in normal subjects (p less than 0.001) during the first stage of exercise. Among transplant recipients, the stroke volume index plateaued after the first stage of exercise, which, in combination with the blunted chronotropic response, resulted in a peak cardiac index 25% lower than that in normal subjects (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)