Noninvasive assessment of organ-specific and shared pathways in multi-organ fibrosis using T1 mapping.

Fibrotic diseases affect multiple organs and are associated with morbidity and mortality. To examine organ-specific and shared biologic mechanisms that underlie fibrosis in different organs, we developed machine learning models to quantify T1 time, a marker of interstitial fibrosis, in the liver, pancreas, heart and kidney among 43,881 UK Biobank participants who underwent magnetic resonance imaging. In phenome-wide association analyses, we demonstrate the association of increased organ-specific T1 time, reflecting increased interstitial fibrosis, with prevalent diseases across multiple organ systems. In genome-wide association analyses, we identified 27, 18, 11 and 10 independent genetic loci associated with liver, pancreas, myocardial and renal cortex T1 time, respectively. There was a modest genetic correlation between the examined organs. Several loci overlapped across the examined organs implicating genes involved in a myriad of biologic pathways including metal ion transport (SLC39A8, HFE and TMPRSS6), glucose metabolism (PCK2), blood group antigens (ABO and FUT2), immune function (BANK1 and PPP3CA), inflammation (NFKB1) and mitosis (CENPE). Finally, we found that an increasing number of organs with T1 time falling in the top quintile was associated with increased mortality in the population. Individuals with a high burden of fibrosis in ≥3 organs had a 3-fold increase in mortality compared to those with a low burden of fibrosis across all examined organs in multivariable-adjusted analysis (hazard ratio = 3.31, 95% confidence interval 1.77-6.19; P = 1.78 × 10-4). By leveraging machine learning to quantify T1 time across multiple organs at scale, we uncovered new organ-specific and shared biologic pathways underlying fibrosis that may provide therapeutic targets.

Clonal haematopoiesis of indeterminate potential predicts incident cardiac arrhythmias.

BACKGROUND AND AIMS: Clonal haematopoiesis of indeterminate potential (CHIP), the age-related expansion of blood cells with preleukemic mutations, is associated with atherosclerotic cardiovascular disease and heart failure. This study aimed to test the association of CHIP with new-onset arrhythmias. METHODS: UK Biobank participants without prevalent arrhythmias were included. Co-primary study outcomes were supraventricular arrhythmias, bradyarrhythmias, and ventricular arrhythmias. Secondary outcomes were cardiac arrest, atrial fibrillation, and any arrhythmia. Associations of any CHIP [variant allele fraction (VAF) ≥ 2%], large CHIP (VAF ≥10%), and gene-specific CHIP subtypes with incident arrhythmias were evaluated using multivariable-adjusted Cox regression. Associations of CHIP with myocardial interstitial fibrosis [T1 measured using cardiac magnetic resonance (CMR)] were also tested. RESULTS: This study included 410 702 participants [CHIP: n = 13 892 (3.4%); large CHIP: n = 9191 (2.2%)]. Any and large CHIP were associated with multi-variable-adjusted hazard ratios of 1.11 [95% confidence interval (CI) 1.04-1.18; P = .001] and 1.13 (95% CI 1.05-1.22; P = .001) for supraventricular arrhythmias, 1.09 (95% CI 1.01-1.19; P = .031) and 1.13 (95% CI 1.03-1.25; P = .011) for bradyarrhythmias, and 1.16 (95% CI, 1.00-1.34; P = .049) and 1.22 (95% CI 1.03-1.45; P = .021) for ventricular arrhythmias, respectively. Associations were independent of coronary artery disease and heart failure. Associations were also heterogeneous across arrhythmia subtypes and strongest for cardiac arrest. Gene-specific analyses revealed an increased risk of arrhythmias across driver genes other than DNMT3A. Large CHIP was associated with 1.31-fold odds (95% CI 1.07-1.59; P = .009) of being in the top quintile of myocardial fibrosis by CMR. CONCLUSIONS: CHIP may represent a novel risk factor for incident arrhythmias, indicating a potential target for modulation towards arrhythmia prevention and treatment.

Genetics of myocardial interstitial fibrosis in the human heart and association with disease.

Myocardial interstitial fibrosis is associated with cardiovascular disease and adverse prognosis. Here, to investigate the biological pathways that underlie fibrosis in the human heart, we developed a machine learning model to measure native myocardial T1 time, a marker of myocardial fibrosis, in 41,505 UK Biobank participants who underwent cardiac magnetic resonance imaging. Greater T1 time was associated with diabetes mellitus, renal disease, aortic stenosis, cardiomyopathy, heart failure, atrial fibrillation, conduction disease and rheumatoid arthritis. Genome-wide association analysis identified 11 independent loci associated with T1 time. The identified loci implicated genes involved in glucose transport (SLC2A12), iron homeostasis (HFE, TMPRSS6), tissue repair (ADAMTSL1, VEGFC), oxidative stress (SOD2), cardiac hypertrophy (MYH7B) and calcium signaling (CAMK2D). Using a transforming growth factor ß1-mediated cardiac fibroblast activation assay, we found that 9 of the 11 loci consisted of genes that exhibited temporal changes in expression or open chromatin conformation supporting their biological relevance to myofibroblast cell state acquisition. By harnessing machine learning to perform large-scale quantification of myocardial interstitial fibrosis using cardiac imaging, we validate associations between cardiac fibrosis and disease, and identify new biologically relevant pathways underlying fibrosis.

BMI-adjusted adipose tissue volumes exhibit depot-specific and divergent associations with cardiometabolic diseases.

For any given body mass index (BMI), individuals vary substantially in fat distribution, and this variation may have important implications for cardiometabolic risk. Here, we study disease associations with BMI-independent variation in visceral (VAT), abdominal subcutaneous (ASAT), and gluteofemoral (GFAT) fat depots in 40,032 individuals of the UK Biobank with body MRI. We apply deep learning models based on two-dimensional body MRI projections to enable near-perfect estimation of fat depot volumes (R2 in heldout dataset = 0.978-0.991 for VAT, ASAT, and GFAT). Next, we derive BMI-adjusted metrics for each fat depot (e.g. VAT adjusted for BMI, VATadjBMI) to quantify local adiposity burden. VATadjBMI is associated with increased risk of type 2 diabetes and coronary artery disease, ASATadjBMI is largely neutral, and GFATadjBMI is associated with reduced risk. These results - describing three metabolically distinct fat depots at scale - clarify the cardiometabolic impact of BMI-independent differences in body fat distribution.

Silhouette images enable estimation of body fat distribution and associated cardiometabolic risk.

Inter-individual variation in fat distribution is increasingly recognized as clinically important but is not routinely assessed in clinical practice, in part because medical imaging has not been practical to deploy at scale for this task. Here, we report a deep learning model trained on an individual's body shape outline-or "silhouette" -that enables accurate estimation of specific fat depots of interest, including visceral (VAT), abdominal subcutaneous (ASAT), and gluteofemoral (GFAT) adipose tissue volumes, and VAT/ASAT ratio. Two-dimensional coronal and sagittal silhouettes are constructed from whole-body magnetic resonance images in 40,032 participants of the UK Biobank and used as inputs for a convolutional neural network to predict each of these quantities. Mean age of the study participants is 65 years and 51% are female. A cross-validated deep learning model trained on silhouettes enables accurate estimation of VAT, ASAT, and GFAT volumes (R2: 0.88, 0.93, and 0.93, respectively), outperforming a comparator model combining anthropometric and bioimpedance measures (ΔR2 = 0.05-0.13). Next, we study VAT/ASAT ratio, a nearly body-mass index (BMI)-and waist circumference-independent marker of metabolically unhealthy fat distribution. While the comparator model poorly predicts VAT/ASAT ratio (R2: 0.17-0.26), a silhouette-based model enables significant improvement (R2: 0.50-0.55). Increased silhouette-predicted VAT/ASAT ratio is associated with increased risk of prevalent and incident type 2 diabetes and coronary artery disease independent of BMI and waist circumference. These results demonstrate that body silhouette images can estimate important measures of fat distribution, laying the scientific foundation for scalable population-based assessment.

Genetic analysis of right heart structure and function in 40,000 people.

Congenital heart diseases often involve maldevelopment of the evolutionarily recent right heart chamber. To gain insight into right heart structure and function, we fine-tuned deep learning models to recognize the right atrium, right ventricle and pulmonary artery, measuring right heart structures in 40,000 individuals from the UK Biobank with magnetic resonance imaging. Genome-wide association studies identified 130 distinct loci associated with at least one right heart measurement, of which 72 were not associated with left heart structures. Loci were found near genes previously linked with congenital heart disease, including NKX2-5, TBX5/TBX3, WNT9B and GATA4. A genome-wide polygenic predictor of right ventricular ejection fraction was associated with incident dilated cardiomyopathy (hazard ratio, 1.33 per standard deviation; P = 7.1 × 10-13) and remained significant after accounting for a left ventricular polygenic score. Harnessing deep learning to perform large-scale cardiac phenotyping, our results yield insights into the genetic determinants of right heart structure and function.

Inherited basis of visceral, abdominal subcutaneous and gluteofemoral fat depots.

For any given level of overall adiposity, individuals vary considerably in fat distribution. The inherited basis of fat distribution in the general population is not fully understood. Here, we study up to 38,965 UK Biobank participants with MRI-derived visceral (VAT), abdominal subcutaneous (ASAT), and gluteofemoral (GFAT) adipose tissue volumes. Because these fat depot volumes are highly correlated with BMI, we additionally study six local adiposity traits: VAT adjusted for BMI and height (VATadj), ASATadj, GFATadj, VAT/ASAT, VAT/GFAT, and ASAT/GFAT. We identify 250 independent common variants (39 newly-identified) associated with at least one trait, with many associations more pronounced in female participants. Rare variant association studies extend prior evidence for PDE3B as an important modulator of fat distribution. Local adiposity traits (1) highlight depot-specific genetic architecture and (2) enable construction of depot-specific polygenic scores that have divergent associations with type 2 diabetes and coronary artery disease. These results - using MRI-derived, BMI-independent measures of local adiposity - confirm fat distribution as a highly heritable trait with important implications for cardiometabolic health outcomes.

Cohort design and natural language processing to reduce bias in electronic health records research.

Electronic health record (EHR) datasets are statistically powerful but are subject to ascertainment bias and missingness. Using the Mass General Brigham multi-institutional EHR, we approximated a community-based cohort by sampling patients receiving longitudinal primary care between 2001-2018 (Community Care Cohort Project [C3PO], n = 520,868). We utilized natural language processing (NLP) to recover vital signs from unstructured notes. We assessed the validity of C3PO by deploying established risk models for myocardial infarction/stroke and atrial fibrillation. We then compared C3PO to Convenience Samples including all individuals from the same EHR with complete data, but without a longitudinal primary care requirement. NLP reduced the missingness of vital signs by 31%. NLP-recovered vital signs were highly correlated with values derived from structured fields (Pearson r range 0.95-0.99). Atrial fibrillation and myocardial infarction/stroke incidence were lower and risk models were better calibrated in C3PO as opposed to the Convenience Samples (calibration error range for myocardial infarction/stroke: 0.012-0.030 in C3PO vs. 0.028-0.046 in Convenience Samples; calibration error for atrial fibrillation 0.028 in C3PO vs. 0.036 in Convenience Samples). Sampling patients receiving regular primary care and using NLP to recover missing data may reduce bias and maximize generalizability of EHR research.

Selection of 51 predictors from 13,782 candidate multimodal features using machine learning improves coronary artery disease prediction.

Current cardiovascular risk assessment tools use a small number of predictors. Here, we study how machine learning might: (1) enable principled selection from a large multimodal set of candidate variables and (2) improve prediction of incident coronary artery disease (CAD) events. An elastic net-based Cox model (ML4HEN-COX) trained and evaluated in 173,274 UK Biobank participants selected 51 predictors from 13,782 candidates. Beyond most traditional risk factors, ML4HEN-COX selected a polygenic score, waist circumference, socioeconomic deprivation, and several hematologic indices. A more than 30-fold gradient in 10-year risk estimates was noted across ML4HEN-COX quintiles, ranging from 0.25% to 7.8%. ML4HEN-COX improved discrimination of incident CAD (C-statistic = 0.796) compared with the Framingham risk score, pooled cohort equations, and QRISK3 (range 0.754-0.761). This approach to variable selection and model assessment is readily generalizable to a broad range of complex datasets and disease endpoints.

Regulation of Nuclear Hormone Receptors by MYCN-Driven miRNAs Impacts Neural Differentiation and Survival in Neuroblastoma Patients.

MYCN amplification and MYC signaling are associated with high-risk neuroblastoma with poor prognosis. Treating these tumors remains challenging, although therapeutic approaches stimulating differentiation have generated considerable interest. We have previously shown that the MYCN-regulated miR-17∼92 cluster inhibits neuroblastoma differentiation by repressing estrogen receptor alpha. Here, we demonstrate that this microRNA (miRNA) cluster selectively targets several members of the nuclear hormone receptor (NHR) superfamily, and we present a unique NHR signature associated with the survival of neuroblastoma patients. We found that suppressing glucocorticoid receptor (GR) expression in MYCN-driven patient and mouse tumors was associated with an undifferentiated phenotype and decreased survival. Importantly, MYCN inhibition and subsequent reactivation of GR signaling promotes neural differentiation and reduces tumor burden. Our findings reveal a key role for the miR-17∼92-regulated NHRs in neuroblastoma biology, thereby providing a potential differentiation approach for treating neuroblastoma patients.

Laparoscopic bilateral adrenalectomy following failed hypophysectomy.

BACKGROUND: Laparoscopic adrenalectomy has recently been shown to be a safe and effective means of treating adrenal pathology with much lower morbidity than the traditional approach. The majority of reports in the literature involve removal of adrenal tumors. Although open bilateral adrenalectomy has been utilized for persistent Cushing's syndrome following attempted hypophysectomy, there is little data available describing the application of laparoscopic adrenal surgery to this problem. METHODS: Four patients with persistent Cushing's syndrome after attempted treatment with hypophysectomy underwent laparoscopic bilateral adrenalectomy at our institution. One procedure was done transabdominally in the supine position. Three procedures were done transabdominally using sequential lateral decubitus positions. RESULTS: All procedures were completed laparoscopically. The mean operative time was 4.6 h (range 3.9-5.25). Repositioning and reprepping the patients resulted in a slight increase in operative time, but visualization was improved using the lateral decubitus position. Average blood loss: 156 cc (range 50-300). One patient required early reoperation for bleeding from the left adrenal bed, which was controlled laparoscopically. Three patients were eating the following day and were discharged on postoperative days 1, 2, and 5. The fourth patient remained hospitalized for 18 days due to problems unrelated to surgery. After a mean follow-up of 10 months, all patients have done well and have no clinical or biochemical evidence of recurrent disease. CONCLUSION: Our clinical experience indicates that laparoscopic bilateral adrenalectomy is a viable treatment option for Cushing's syndrome following failed hypophysectomy.

Intraoperative vascular endoscopy: early and late results.

In a prospective study, 60 consecutive cases of vascular endoscopy were analyzed to examine the role of angioscopy in infrainguinal vascular procedures. A total of 52 patients had 60 separate vascular endoscopy procedures performed as an adjunct to various vascular procedures; results of intraoperative arteriography were available in 38 of 60 cases. All patients were followed for at least 42 months. The 19 patients who underwent thrombectomy with angioscopy were compared with 19 age-matched control subjects who underwent infrainguinal thrombectomy without angioscopy to evaluate the influence of angioscopy on primary and secondary patency rates. Angioscopy allowed observation of 50 lesions; angiography failed to detect three. These findings altered surgical management in 24 cases (40%). Primary patency rates for the control and experimental thrombectomy groups were 38.8% and 6.5% at 42 months, respectively (p = 0.010 based on log-rank test). Secondary patency rates for the control and experimental groups at 42 months were 63.8% and 49%, respectively (p = 0.521). The limb salvage rate was 89% at 42 months for both groups (p = 0.973). Angioscopy provides the clinician with a direct view while he or she is performing vascular procedures. However, there was no statistical improvement in secondary patency and limb salvage rates. Furthermore, the use of angioscopy during thrombectomy may increase the propensity for subsequent intervention as evidenced by the frequency of changes in surgical management and the lower primary patency rate.

Laparoscopic Collis gastroplasty is the treatment of choice for the shortened esophagus.

BACKGROUND: The shortened esophagus has long been recognized as a potential complicating factor for reflux surgery or the repair of paraesophageal hernias. We discuss the incidence of shortened esophagus encountered in a prospective series of laparoscopic hiatal hernia repairs and present our current operative strategies for dealing with this problem, including a new technique for preforming a cut Collis gastroplasty for severe cases. METHODS: A prospectively gathered database on laparoscopic fundoplications (n = 213) and giant paraesophageal hernia repairs (n = 25) revealed 34 (14%) patients who had shortened esophagus as defined by the gastroesophageal (GE) junction being > 5 cm above the hiatus. Presentation preoperative diagnosis, operative times, techniques, and outcomes were evaluated. RESULTS: Three categories of dissection were determined from review of the operative data of these 34 patients. Category I (a normal esophagus easily brought into the abdominal cavity with minimal dissection) occurred in 30% of patients. Category II occurred in 50% of patients and was defined as shortened esophagus requiring extensive mediastinal dissection to allow the GE junction to be brought 2 cm below the diaphragm. Category III patients (20%) were unable, in spite of extensive dissection, to have their GE junction sufficiently reduced to permit fundoplication. Four of these patients had a simple cural closure and gastropexy. Three patients underwent an endoscopic Collis gastroplasty to lengthen the esophagus and allow a tension-free fundoplication. Patients who had a type I or type III dissection with Collis gastroplasty did uniformly well. Patients having type II dissections or no fundoplication had a higher rate of postoperative hernia recurrences and reflux disease. CONCLUSION: Approximately 14% of patients presenting for surgical treatment of gastroesophageal reflux disease or paraesophageal hernias demonstrate a shortened esophagus. While 30% of these patients are easily treated laparoscopically, 20% to 70% may benefit from an esophageal lengthening procedure. Proper utilization of the Collis gastroplasty should minimize the incidence of postoperative dysphagia, postoperative acid reflux, and hiatal hernia recurrence.

Carbon dioxide pneumothorax in laparoscopic surgery.

BACKGROUND: We conducted this animal study to investigate the cardiopulmonary effects of carbon dioxide pneumothorax during laparoscopic surgery and determine what intervention, if any, is necessary for this phenomenon. METHODS: A swine animal model was used (n = 8). Animals were anesthetized and underwent peritoneal insufflation with carbon dioxide. A laceration was created in the left diaphragm. pO2, pCO2, oxygen saturation, peak inspiratory pressure (PIP), systolic blood pressure, and heart rate were measured and subjected to statistical analysis. RESULTS: Significant changes were noted in the pO2, O2 saturation, pCO2, and PIP upon creation of the pneumothorax. Trends were also noted in the heart rate and the systolic blood pressure. The physiologic changes could be corrected by noninvasive means and without terminating the procedure. CONCLUSIONS: Carbon dioxide pneumothorax produces reproducible cardiopulmonary changes in laparoscopic surgery. These changes are easily monitored and the resulting cardiopulmonary changes can be treated without invasive means.

Laparoscopic treatment of known choledocholithiasis.

BACKGROUND: Occasionally patients present to the surgeon with known common duct stones. These will frequently have been detected by imaging modalities: ultrasound, computed tomography (CT) scans, transhepatic cholangiogram (THC) or IV cholangiography. Occasionally there are stones that had failed attempts at endoscopic retrieval (ERCP). METHODS: A retrospective analysis of a prospectively gathered database of 77 laparoscopic common bile duct explorations was done to assess the incidence, treatments and outcomes of patients who had known common duct stones (CDS) before surgery. RESULTS: Eighteen patients (23%) were identified as having a preoperative diagnosis of CDS. All underwent a laparoscopic common bile duct exploration. This exploration was successful in all cases. Outcomes were good with a 4% complication rate and one case of retained common duct stones (4%). CONCLUSIONS: Before laparoscopic cholecystectomy, known choledocholithiasis was considered a surgical disease except in cases of acute cholangitis or the very morbidly ill. The ability to perform cholecystectomy laparoscopically made many practitioners avoid open common duct exploration and, instead, rely on ERCP as primary treatment for known or suspected common duct stones. As techniques of laparoscopic common duct exploration improve, the ability to deal with common duct pathology surgically has increased, offering new options for treatment of this patient population. We present our experience with 18 patients who presented with known choledocholithiasis and were treated laparoscopically with good results.

Histologic and morphologic effects of rotary atherectomy on human cadaver arteries.

Intimal splitting and medial dissection caused by balloon angioplasty and thermal burns and subintimal vacuolization caused by laser angioplasty have been proposed as potential causes of failure from these respective procedures. The purpose of this study was to evaluate the histologic and morphologic effects of a new high speed rotary atherectomy device (the Rotoblator) on human cadaver arteries. Fifteen stenotic human cadaver superficial femoral and popliteal arteries were harvested and atherectomized using the Rotoblator. Histologically, on cross-section, the atherectomized arteries exhibited a denuded endothelial layer, a smooth rounded luminal contour, minute plaque separation from the media, absence of plaque fragmentation, and variable remaining rim of atheromatous plaque. The media showed variable loss of the internal elastic lamina, normal remaining elastin, and normal smooth muscle cells. The adventitia was normal and completely intact in all sections with no media/adventitia separation or perforations. Scanning electron microscopy revealed endothelial peeling, etching from the atherectomy devices within the smooth muscle layer, and a tapered atherectomy distal endpoint. The arterial branches were preserved without evidence of any disruption of the branch artery orifice. Compared to balloon angioplasty and laser angioplasty, the Rotoblator atherectomy device appears to leave a smoother, more rounded luminal surface that may result in less risk of embolic complications and arterial wall damage.

Post-carotid endarterectomy hypertension: association with elevated cranial norepinephrine.

The cause and mechanism of post-carotid endarterectomy hypertension remains unknown. To determine the influence of the sympathetic and renin-angiotensin system, we measured cranial and peripheral plasma levels of catecholamine and renin in patients undergoing carotid endarterectomy. Baseline samples were drawn just before carotid clamping (sample I) and compared with study samples drawn immediately after clamp release (sample II), 2 to 6 hours after surgery (sample III), and then 18 to 24 hours after surgery (sample IV). The patients with post-carotid endarterectomy hypertension had an associated increase of cranial and peripheral norepinephrine levels in the postoperative hypertensive period whereas the patients without post-carotid endarterectomy hypertension did not. This association was most pronounced and statistically significant in cranial samples II (p = 0.032) and III (p = 0.005). Epinephrine and dopamine values did not correlate with post-carotid endarterectomy hypertension. Renin values were higher in cranial than in peripheral samples at time period 2 (p = 0.011), suggestive of a central nervous system Goldblatt phenomenon. However, the renin values did not correlate with post-carotid endarterectomy hypertension. We conclude that post-carotid endarterectomy hypertension is associated with elevated cranial norepinephrine levels, suggestive of a central nervous system sympathomimetic mechanism. Optimal prevention and treatment of this brief but frequently occurring hypertension should include a central-acting sympatholytic agent.

Computed electroencephalographic topographic brain mapping. A new and accurate monitor of cerebral circulation and function for patients having carotid endarterectomy.

To determine the usefulness of computed electroencephalographic (EEG) topographic (CET) brain mapping to monitor neurologic function during carotid endarterectomy (CEA), 46 consecutive patients having CEA were monitored preoperatively, intraoperatively, and immediately postoperatively by CET brain mapping and simultaneous 16-lead EEG. Preoperative studies revealed that 7 of 16 asymptomatic patients, 5 of 11 patients with amaurosis fugax, and 8 of 12 patients with transient ischemic attacks (TIAs) had abnormal CET brain mapping suggestive of previous subclinical stroke. EEG was abnormal in only 8 of the 20 patients with abnormal CET brain mapping. Intraoperatively during carotid cross-clamping, ischemic changes were seen on CET brain mapping in 23 patients whereas EEG detected these changes in only 13 patients. Ischemic changes detected by intraoperative CET brain mapping were more likely to occur in patients with previous stroke (six of seven) than in patients without previous stroke (17 of 39), p less than 0.05. Patients with changes detected by intraoperative CET brain mapping had an average carotid back-pressure of 38 mm Hg, in contrast to 57 mm Hg for patients without CET brain mapping changes, p less than 0.05. After endarterectomy, CET brain mapping revealed new ischemic changes in one patient who awoke with a mild stroke and in one patient who had TIAs and amaurosis fugax within 6 hours of surgery. We conclude that CET brain mapping is a sensitive, accurate, and useful noninvasive monitor of cerebral circulation and function for patients having CEA.(ABSTRACT TRUNCATED AT 250 WORDS)

Removal of focal atheromatous lesions by angioscopically guided high-speed rotary atherectomy. Preliminary experimental observations.

A new high-speed rotary atherectomy device, inserted over a guide wire and directed with an angioscope, offers the potential of restoring patency of outflow vessels by "boring out" the atheromatous lesion of the orifices of runoff vessels. The device was tested on 68 cadaver arteries with atheromatous lesions involving the superficial femoral, popliteal, and tibial arteries. This was performed with either free segments or in situ with the device placed through a popliteal arteriotomy. The gross results of rotary atherectomy were assessed by angioscopy, angiography, or both. The luminal surfaces were studied with scanning electron microscopy and transverse sections of vessels were studied with light microscopy. The pulverized atheroma, in colloidal suspension, was analyzed for particle size by Coulter counter. The effect of a colloidal suspension of atheromatous particles on distal capillary circulation was measured in animal experiments. Obstructive lesions were successfully removed in 36 of 37 stenotic arteries (97%) and 18 of 31 completely occluded arteries (58%), an overall efficacy of 54 of 68 (79%). In successfully atherectomized arteries, angioscopy and angiography demonstrated a widely patent, smooth, polished surface. Light microscopy demonstrated removal of the diseased intima with maintenance of the outer media and adventitia. The pulverized atheroma particles were generally smaller than red blood cells and injection of the colloidal atheroma into canine femoral arteries failed to produce local tissue injury. We conclude that in the human cadaver this atherectomy device effectively enlarges and recanalizes obstructed superficial femoral, popliteal, and tibial arteries.(ABSTRACT TRUNCATED AT 250 WORDS)