Stroke and mortality rates after off-pump vs. pump-assisted/no-clamp coronary artery bypass grafting.

BACKGROUND: Ascending aorta manipulation during on-pump coronary artery bypass grafting (CABG) surgery can release embolic matter and may cause stroke. Strategies for lowering the stroke rate associated with coronary artery bypass grafting surgery include off-pump surgery without cardiopulmonary bypass and pump-assisted surgery with minimal aortic manipulation (i.e., without aortic cross-clamping). We examined whether one approach is superior to the other in reducing stroke and perioperative mortality rates. METHODS: We reviewed consecutive elective, urgent, and emergency off-pump/no-bypass and pump-assisted/no-clamp coronary artery bypass grafting procedures performed by a single surgeon at our institution from June 2011 through October 2017. RESULTS: Of 570 patients analyzed, 395 (69.3%) underwent off-pump/no-bypass surgery, 43 (7.5%) underwent pump-assisted/no-clamp surgery, and 132 (23.2%) transitioned mid-procedure from off-pump/no-bypass to pump-assisted/no-clamp surgery. Patients who were >70 years old, were female, or had diabetes, cardiomegaly, or a history of myocardial infarction or congestive heart failure were more likely to undergo pump-assisted/no-clamp surgery or the combined technique. None of the pump-assisted/no-clamp patients had a stroke, versus 0.3% of the off-pump/no-bypass patients and 0.8% of the combination patients. Stroke and in-hospital mortality rates did not differ by technique. CONCLUSIONS: A hybrid strategy incorporating off-pump, pump-assisted, and combined off-pump/pump-assisted techniques achieved very low stroke rates in patients undergoing coronary revascularization. Perioperative mortality was similar for all three techniques. Avoiding aortic clamping may be crucial for decreasing CABG-related stroke rates. Off-pump/no-bypass surgery had no significant advantage over the pump-assisted/no-clamp or combined techniques in reducing the stroke rate after coronary artery bypass grafting surgery.

Mechanical Cardiac Support With an Implantable Direct Cardiac Compression Device: Proof of Concept.

PURPOSE: We examined the hemodynamic effects of a new, implantable, direct cardiac assist device in an ovine heart failure model. DESCRIPTION: The device, which encompasses both left and right ventricles, is inserted through the pericardial apex and self-expands to encompass the heart without suturing. The intact pericardium anchors the device in place. The device has 2 concentric chamber layers: an internal chamber layer filled with fluid to conform to the heart and an external chamber layer filled with air that provides external compression and negative pressure to aid relaxation. EVALUATION: The device was implanted in 7 sheep with heart failure induced by microsphere embolization. Cardiac performance was assessed for 6 to 8 hours. The cardiac assist device provided cardiac systolic and diastolic assistance, as shown by pressure tracings of the left ventricle and aorta, pulmonary artery flow, and +dP/dt. Central venous pressure decreased during cardiac assistance. No anatomic damage was noted postmortem. CONCLUSIONS: Systolic and diastolic cardiac assistance can be achieved with this device that compresses and relaxes in synchrony with the native cardiac cycle.

The influence of preoperative dialysis on survival after continuous-flow left ventricular assist device implantation.

OBJECTIVES: Dialysis is considered a contraindication to continuous-flow left ventricular assist device (CF-LVAD) implantation. We evaluated clinical outcomes and survival in carefully selected, low-risk patients with renal failure who required dialysis before CF-LVAD implantation. METHODS: We extracted medical record data of patients who underwent CF-LVAD placement at our centre between 1 January 2006 and 31 August 2017, with 2 clinical scenarios: those who required long-term (>14 days) dialysis and those who required short-term (≤14 days) dialysis immediately before implantation. Demographic, clinical and intraoperative characteristics and survival outcomes were assessed. RESULTS: Of 621 patients who underwent CF-LVAD implantation during the study period, 31 underwent dialysis beforehand. Of these, 17 required long-term dialysis (13 haemodialysis, 4 peritoneal dialysis), and 14 underwent short-term haemodialysis. Compared with the long-term dialysis patients, the short-term dialysis patients were more likely to be Interagency Registry for Mechanically Assisted Circulatory Support profile 1-2 (92.9% vs 70.6%; P < 0.001), to have needed preoperative mechanical circulatory support (78.6% vs 70.6%; P < 0.01) and to have higher in-hospital mortality (85.7% vs 29.4%; P = 0.01). Patients stable on long-term dialysis had acceptable overall survival and markedly better 6-month and 1-year survival than those with short-term dialysis before implantation (64.7% vs 14.3% and 58.8% vs 7.1%, respectively; P < 0.001). CONCLUSIONS: Carefully selected patients who are stable on long-term dialysis have acceptable survival rates after CF-LVAD implantation. Patients with acute renal failure had much poorer outcomes than those with chronic end-stage renal disease.

The CorInnova Implantable Cardiac Assist System for Direct Cardiac Compression.

The CorInnova cardiac compression device (CorInnova, Inc., Houston, TX, USA) is designed to provide direct biventricular support, increase cardiac output, and improve ventricular unloading in patients with heart failure. Placed within the pericardium and surrounding both ventricles, the device has two concentric sets of thin-film polyurethane chambers: (1) inner (epicardial) saline-filled chambers that conform intimately to the epicardial surface, eradicating any gaps in the interface between the device and the heart; and (2) outer air-filled chambers cycled to provide epicardial compression during systole and negative epicardial pressure during diastole, consistent with physiological cardiac contraction and relaxation. A superelastic, collapsible Nitinol frame gives the device structure, enables minimally invasive self-deployment, and enhances diastolic filling. Preclinical testing has been extremely promising, with improvements in cardiac output and other cardiac parameters in animal heart failure models. This potentially transformative technology is moving rapidly toward first-in-human use. The CorInnova device may provide an effective device-based solution for patients with heart failure who currently have few or limited mechanical cardiac support options, including patients with biventricular cardiac failure, those with right heart failure, those who are older, and those who are of smaller size. It can be removed easily and requires minimal maintenance. An important, unique feature of this technology is that it provides mechanical cardiac assistance without blood contact or need for anticoagulation. The CorInnova device may be particularly important for those patients who have contraindications to anticoagulation due to allergy, neurological bleeds, or preexisting hemorrhage. No other mechanical circulatory support device addresses these underserved heart-failure populations.

Continuous-Flow Left Ventricular Assist Device Explantation After More Than 5 Years of Circulatory Support and Ventricular Reconditioning.

Continuous-flow left ventricular assist devices have proved to be effective, durable, life-saving tools in patients with end-stage heart failure. However, because of the risks associated with mechanical circulatory support (including stroke, infection, gastrointestinal bleeding, and device malfunction), the optimal goal of device therapy is myocardial recovery and device removal. Ventricular reconditioning and pump explantation after continuous-flow support have been reported; however, little is known about variables that govern the pace and degree of myocardial response in patients who experience such recovery. We describe our long-term pump-weaning strategy for a 25-year-old man who had a continuous-flow device implanted and then needed more than 5 years of support from it before developing cardiac reserve sufficient to enable pump explantation. To our knowledge, this is the longest period of uninterrupted continuous-flow device support to end in successful pump deactivation and a return to medical therapy. This case highlights the importance of actively and persistently pursuing a device-weaning strategy in all patients who need left ventricular assist device therapy.

Heterotopic Cardiac Transplantation: Long-term Results and Fate of the Native Heart.

BACKGROUND: The long-term results of heterotopic cardiac transplantation have not been well defined. Patient survival rates and the fate of the native heart remain unclear. METHODS: This study is a retrospective review of all 46 heterotopic cardiac transplantations performed at a single institution, the Texas Heart Institute in Houston, Texas, between 1982 and 2017. Four patients who underwent heterotopic transplantation as an emergency procedure for cardiogenic shock were excluded. Three of the procedures were repeat transplantations in patients who had previously undergone heterotopic transplantation; the 3 repeat transplantations were excluded, but the original procedures were not. Follow-up was 100% complete for mortality and 77% complete (30 of 39 patients) for assessment of preoperative indication for surgery and postoperative cardiac function. RESULTS: For the 39 patients, the 1-year, 5-year, and 10-year survival rates were 69%, 36%, and 21%, respectively. One patient remains alive 25 years after the transplantation procedure. The most frequent indication for heterotopic transplantation was pulmonary vascular resistance greater than 4 Wood units (n = 11), followed by weight greater than 112.5 kg (n = 7). In most patients, native heart left ventricular ejection fraction stabilized over time to between 10% and 30%. Sinus rhythm was preserved in 87% (26 of 30) of native hearts at long-term follow-up. CONCLUSIONS: Heterotopic cardiac transplantation is an acceptable procedure that should be considered for obese patients (especially those heavier than 112.5 kg) and patients with elevated pulmonary vascular resistance (especially those with pulmonary vascular resistance >4.0 Wood units). After heterotopic transplantation, native cardiac function appears to stabilize, and there is potential for native heart recovery.

Ten-Year Survival With a Continuous-Flow Left Ventricular Assist Device and Aortic Valve Closure.

We report the long-term survival of a 46-year-old man supported with a HeartMate II continuous-flow left ventricular assist device after complex repair of a bicuspid aortic valve, anomalous left main coronary artery, and dilated aorta. He has been maintained on an anticoagulation regimen of warfarin and low-dose aspirin without problems for 10 years, during which he has worked continuously and productively. Device flow has been kept at 10,000 rpm. Possible contributors to this long-term success include proper alignment of the device inflow cannula, pericardial patch closure of the left ventricular outflow tract, and, notably, the remarkable freedom from mechanical failure of the continuous-flow left ventricular assist device. Whether the higher flow rate produced by the pericardial patch closure contributes to pump longevity is unknown and merits further investigation.

Low Incidence of Pump-Related Infections in Jarvik 2000 Ventricular Assist Device Recipients with a Subcostal Driveline Exit Site.

Driveline infection has been a persistent problem with mechanical cardiac assist devices. The reported incidence of infection has been low in patients who receive a Jarvik 2000 continuous-flow left ventricular assist device when a skull-pedestal driveline exit site is used. We evaluated whether this is also true when a subcostal driveline exit site is used. We reviewed baseline demographic variables, postimplantation vital signs, laboratory values, and culture results in patients who underwent Jarvik 2000 implantation at our center from April 2000 through October 2009, including follow-up through June 2014. All patients had a subcostal driveline exit site. We defined device-related infection as a positive blood or wound culture associated with a medical or surgical device intervention. Event and time-to-event rates were calculated. Eighty-one patients received 89 Jarvik 2000 devices, all as bridges to transplantation. The median support duration was 69 days (interquartile range, 27-153 d; range, 2-2,249 d). Five superficial driveline infections and one incision-site infection occurred (0.002 events per patient-year of support). The median time from pump implantation to onset of driveline infection was 30 days; the incision-related infection occurred at 44 days. The Jarvik 2000 has a low incidence of infection when implanted with use of a subcostal driveline exit site. The incidence of pump infections is particularly low. Using a subcostal driveline exit site may be as effective in preventing infections as using a skull-pedestal driveline exit site. We detail our findings in this report.

Surgical approach to continuous-flow left ventricular assist device explantation: A comparison of outcomes.

OBJECTIVE: Ventricular reconditioning and device weaning in select patients with continuous-flow left ventricular assist devices (CF LVADs) has been shown to be feasible. However, little is known regarding the outcomes associated with different surgical methods of device removal. We examined the effect of surgical explantation approach on early and late outcomes. METHODS: We retrospectively reviewed data from all patients who underwent successful ventricular weaning and CF LVAD explantation at our center. Patients were stratified by surgical approach. Descriptive univariate statistics, multivariate regression, and survival analyses were performed. Patients were censored by transplant, device reimplantation, or end of follow-up. RESULTS: Twenty-seven patients were identified who underwent successful removal of a CF LVAD (25 HeartMate II, 2 HeartWare) after 532 ± 424 days of support (range, 42-1937 days). Four approaches were used that vary primarily in the degree of retained pump material: complete pump removal with plug ventriculotomy closure (n = 13; 48%), pump housing explant with ligation of the inflow and outflow grafts (n = 7; 26%), ligation of the outflow graft and driveline transection (n = 5; 19%), and driveline transection alone (n = 2; 7%). Mean overall postexplant survival was 1286 ± 947 days (range, 143-3072 days). Overall time-to-event and survival analyses showed no significant association between surgical approach and postoperative length of stay (P = .7), stroke (P = .12), reoperation (P = .4), or survival (P = .12). CONCLUSIONS: For patients who receive device therapy, pump deactivation and removal represents a favorable outcome. All methods are feasible and produce similar early and late survival and clinical outcomes.

Thyrotoxicosis-facilitated bridge to recovery with a continuous-flow left ventricular assist device.

The HeartMate II is a continuous-flow left ventricular assist device that can be explanted from patients after cardiac recovery. We implanted a HeartMate II in a 21-year-old man who had idiopathic cardiomyopathy. A year later, he developed thyrotoxicosis, presumably secondary to amiodarone administered for ventricular fibrillation. Four months after the diagnosis of thyrotoxicosis, thyroid hormone levels had returned to normal, and native cardiac function had improved remarkably. After a support period of 24 months, the HeartMate II was explanted. Six years later, the patient continues to be in New York Heart Association functional Class I. Amiodarone-induced thyrotoxicosis may have contributed to myocardial recovery.

Long-term results of complex left ventricular reconstruction surgery: case report.

Left ventricular reconstruction is advocated as a surgical option for patients with severe congestive heart failure. Despite initial enthusiasm for this procedure, reports of long-term results are sparse. Herein, we describe a particularly gratifying case of left ventricular reconstruction in a 43-year-old man, who continues to have excellent left ventricular function 10 years postoperatively. This approach may be a reasonable alternative to cardiac transplantation in patients who lack other treatment options.

Arteriovenous malformation and gastrointestinal bleeding in patients with the HeartMate II left ventricular assist device.

BACKGROUND: In this study we investigated gastrointestinal (GI) bleeding and its relationship to arteriovenous malformations (AVMs) in patients with the continuous-flow HeartMate II (HMII) left ventricular assist device (LVAD). METHODS: The records of 172 patients who received HMII support between November 2003 and June 2010 were reviewed. Patients were considered to have GI bleeding if they had 1 or more of the following symptoms: guaiac-positive stool; hematemesis; melena; active bleeding at the time of endoscopy or colonoscopy; and blood within the stomach at endoscopy or colonoscopy. The symptom(s) had to be accompanied by a decrease of >1 g/dl in the patient's hemoglobin level. The location of the bleeding was identified as upper GI tract, lower GI tract or both according to esophagogastroduodenoscopy, colonoscopy, small-bowel enteroscopy or mesenteric angiography. Post-LVAD implantation anti-coagulation therapy consisted of warfarin, aspirin and dipyridamole. RESULTS: Thirty-two of the 172 patients (19%) had GI bleeding after 63 ± 62 (range 8 to 241) days of HMII support. Ten patients had GI bleeding from an AVM; these included 3 patients who had 2 bleeding episodes and 2 patients who had 5 episodes each. Sixteen patients had upper GI bleeding (10 hemorrhagic gastritis, 4 gastric AVM, 2 Mallory-Weiss syndrome), 15 had lower GI bleeding (6 diverticulosis, 6 jejunal AVM, 1 drive-line erosion of the colon, 1 sigmoid polyp, 1 ischemic colitis) and 1 had upper and lower GI bleeding (1 colocutaneous and gastrocutaneous fistula). All GI bleeding episodes were successfully managed medically. CONCLUSIONS: Arteriovenous malformations can cause GI bleeding in patients with continuous-flow LVADs. In all cases in this series, GI bleeding was successfully managed without the need for surgical intervention.

Percutaneous repair or surgery for mitral regurgitation.

BACKGROUND: Mitral-valve repair can be accomplished with an investigational procedure that involves the percutaneous implantation of a clip that grasps and approximates the edges of the mitral leaflets at the origin of the regurgitant jet. METHODS: We randomly assigned 279 patients with moderately severe or severe (grade 3+ or 4+) mitral regurgitation in a 2:1 ratio to undergo either percutaneous repair or conventional surgery for repair or replacement of the mitral valve. The primary composite end point for efficacy was freedom from death, from surgery for mitral-valve dysfunction, and from grade 3+ or 4+ mitral regurgitation at 12 months. The primary safety end point was a composite of major adverse events within 30 days. RESULTS: At 12 months, the rates of the primary end point for efficacy were 55% in the percutaneous-repair group and 73% in the surgery group (P=0.007). The respective rates of the components of the primary end point were as follows: death, 6% in each group; surgery for mitral-valve dysfunction, 20% versus 2%; and grade 3+ or 4+ mitral regurgitation, 21% versus 20%. Major adverse events occurred in 15% of patients in the percutaneous-repair group and 48% of patients in the surgery group at 30 days (P<0.001). At 12 months, both groups had improved left ventricular size, New York Heart Association functional class, and quality-of-life measures, as compared with baseline. CONCLUSIONS: Although percutaneous repair was less effective at reducing mitral regurgitation than conventional surgery, the procedure was associated with superior safety and similar improvements in clinical outcomes. (Funded by Abbott Vascular; EVEREST II ClinicalTrials.gov number, NCT00209274.).

Off-pump coronary artery bypass and avoidance of hypothermic cardiac arrest improves early left ventricular function in patients with systolic dysfunction.

OBJECTIVE: Off-pump coronary artery bypass surgery (OPCAB) and beating-heart coronary artery bypass grafting (BH-CAB) performed with cardiopulmonary bypass support are used with increasing frequency in the treatment of coronary artery occlusive disease. The utility of OPCAB and BH-CAB in treating high-risk patients has been studied, but the effects of these procedures on ventricular function have not been thoroughly investigated. METHODS: Data were collected from a database encompassing all patients who underwent isolated coronary revascularization performed by a single surgeon between August 2002 and March 2007. All procedures (n = 507) began as OPCAB operations, but 99 were converted to BH-CAB during surgery. Each patient's ejection fraction (EF) was measured preoperatively and postoperatively (median, 5.0 days after surgery). RESULTS: We found that although the BH-CAB patients tended to be in worse health and to have a lower preoperative EF than the OPCAB patients, both groups of patients had similar improvements in postoperative EF (6.8% vs 5.4%; p = 0.65). In addition, multivariable linear regression showed that a lower preoperative EF, age ≥ 70 years, and cardiomegaly predicted less postoperative EF improvement after coronary revascularization by either OPCAB or BH-CAB. CONCLUSIONS: Both OPCAB and BH-CAB procedures produce significant and similar short-term improvement in EF in patients with coronary disease. This change in EF may account for the subjective clinical improvements seen early after both procedures.

Improved left ventricular unloading and circulatory support with synchronized pulsatile left ventricular assistance compared with continuous-flow left ventricular assistance in an acute porcine left ventricular failure model.

OBJECTIVE: Controversy exists regarding the optimal pumping method for left ventricular assist devices. The purpose of this investigation was to test the hypothesis that pulsatile left ventricular assist synchronized to the cardiac cycle provides superior left ventricular unloading and circulatory support compared with continuous-flow left ventricular assist devices at the same level of ventricular assist device flow. METHODS: Seven male pigs were used to evaluate left ventricular assist device function using the TORVAD synchronized pulsatile-flow pump (Windmill Cardiovascular Systems, Inc, Austin, Tex) compared with the Bio-Medicus BPX-80 continuous-flow centrifugal pump (Medtronic, Inc, Minneapolis, Minn). Experiments were carried out under general anesthesia, and animals were instrumented via a median sternotomy. Hemodynamic measurements were obtained in the control state and with left ventricular assistance using the TORVAD and BPX-80 individually. Left ventricular failure was induced with suture ligation of the mid-left anterior descending coronary artery, and hemodynamic measurements were repeated. RESULTS: During left ventricular assist device support, mean aortic pressure and total cardiac output were higher and left atrial pressure was lower with pulsatile compared with continuous flow at the same ventricular assist device flow rate. During ischemic left ventricular failure, pulsatile left ventricular support resulted in higher total cardiac output (5.58 ± 1.58 vs 5.12 ± 1.19, P < .05), higher mean aortic pressure (67.8 ± 14 vs 60.2 ± 10, P < .05), and lower left atrial pressure (11.5 ± 3.5 vs 13.9 ± 6.0, P < .05) compared with continuous flow at the same left ventricular assist device flow rate. CONCLUSION: Synchronized, pulsatile left ventricular assistance produces superior left ventricular unloading and circulatory support compared with continuous-flow left ventricular assist at the same flow rates.

Selective left anterior descending shunting provides effective off-pump myocardial protection.

BACKGROUND: Coronary artery shunting during off-pump coronary artery bypass OPCAB procedures has been addressed only infrequently. To assess the protective effect of shunting, we examined CABG patients' postoperative cardiac enzyme levels and preoperative and postoperative ejection fractions. METHODS: During OPCAB, we selectively shunted the left anterior descending coronary artery (LAD) to provide myocardial protection when ischemia developed. We prospectively gathered data from 408 consecutive patients who underwent OPCAB. Data on shunt status were available for 386 of these patients. A "flow-through" shunt providing perfusion to the distal LAD was used whenever ST-segment elevations greater than 2 mm occurred or when patients had hemodynamic compromise unexplained by cardiac manipulation. Ejection fraction was assessed 1 to 3 days preoperatively and again 3 to 10 days postoperatively. Creatine kinase (muscle/brain) levels were assessed postoperatively for 24 hours. RESULTS: During OPCAB, 99 patients required shunting for presumed ischemia. Thirty-day cardiac mortality was 1.4% (4 of 296 without a shunt; 0 of 90 with a shunt). In patients without a LAD shunt, the mean peak creatine kinase index was 5.3; in patients who needed a shunt, the index was 5.2. Mean ejection fraction improved from 0.536 to 0.589 in the shunted patients and from 0.53.5 to 0.586 in the nonshunted patients. CONCLUSIONS: Selective shunting of the LAD during OPCAB provides effective protection against myocardial ischemia when ischemia is detected by electrocardiogram or when hypotension develops that is unexplained by cardiac manipulation.

Surgical revision after percutaneous mitral repair with the MitraClip device.

BACKGROUND: Percutaneous mitral repair with the MitraClip device (Evalve, Menlo Park, CA) has been reported. Preserving conventional surgical options in the event of percutaneous treatment failure is important. We describe surgical treatment at varying intervals after the MitraClip procedure in 32 patients. METHODS: One hundred seven patients with moderate-to-severe or severe mitral regurgitation who were either symptomatic (91%) or, if asymptomatic (9%), had evidence of left ventricular dysfunction were enrolled as part of the Endovascular Valve Edge-to-Edge REpair STudy (EVEREST) phase I registry study or as "roll-in" subjects in the EVEREST II study. Thirty-two of the 107 patients (30%) underwent surgery after an attempted MitraClip procedure. RESULTS: Of the 32 patients undergoing post-clip mitral valve surgery, 23 patients (72%) had one or more clips implanted and 9 patients (28%) received no clip implant. The indications for mitral valve surgery in the 23 patients with a clip included partial clip detachment (n = 10), residual or recurrent mitral regurgitation greater than 2+ (n = 9), and other (atrial septal defect [n = 2], device malfunction [n = 1], and incorrectly diagnosed mitral stenosis [n = 1]). Twenty-seven of 31 patients (87%) underwent the surgical procedure planned before surgery (planned procedure unknown in 1 patient). Four of 25 patients (16%) with planned repair underwent mitral valve replacement. CONCLUSIONS: Standard surgical options were preserved in patients who had surgery after percutaneous repair with the MitraClip device. Successful repair was feasible in the majority of patients after the MitraClip procedure, with repair performed as late as 18 months after clip implantation.

Location and density of alpha- and beta-adrenoreceptor sub-types in myocardium after mechanical left ventricular unloading.

BACKGROUND: We hypothesized that not all subtypes of alpha- and beta-adrenoreceptors undergo similar upregulation and redistribution in human myocardium after mechanical unloading with an assist device. METHODS: We obtained core biopsy samples of the left ventricle in 19 patients before and after removal of a Jarvik or Thoratec left ventricular assist device (LVAD) to study the effect of mechanical unloading on the distribution of alpha- and beta-adrenoreceptors. Fresh, embedded tissue sections were incubated with receptor blockers and antibodies before the fluorescent labeling of receptors. Images were obtained by fluorescence deconvolution microscopy, and composite tissue renditions were made from the stacked images. Multiple adrenoreceptor subtypes were studied. RESULTS: We saw a reversal of myocyte hypertrophy in all patients, but the upregulation of receptors was not seen in all post-LVAD tissue samples. Furthermore, we noted receptor relocalization from an initial punctate/clumped pattern to a normal homogeneous distribution in many patients. Significant differences were seen in the distribution of beta(2)- and alpha(1)-receptors and in alpha(1A) subtypes. CONCLUSIONS: In this study we show not only the expected reversal of myocyte hypertrophy and the increase in adrenoreceptors after ventricular unloading, but also the relocalization of specific receptor subtypes.