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Background\ud Aortic dissection is a rare but potentially catastrophic condition. Misdiagnosis of aortic dissection is not uncommon as symptoms can overlap with other diagnoses.\ud \ud Objective\ud We conducted a systematic review to better understand the factors contributing to incorrect diagnosis of this condition.\ud \ud Methods\ud We searched MEDLINE and EMBASE for studies that evaluated the misdiagnosis of aortic dissection. The rate of misdiagnosis was pooled and results were narratively synthesized.\ud \ud Results\ud A total of 12 studies with were included with 1663 patients. The overall rate of misdiagnosis of aortic dissection was 33.8%. The proportion of patients presenting with chest pain, back pain and syncope were 67.5%, 24.8% and 6.8% respectively. The proportion of patients with pre-existing hypertension was 55.4%, 30.5% were smokers while the proportion of patients with coronary artery disease, previous cardiovascular surgery or surgical trauma and Marfan syndrome was 14.7%, 5.8%, and 3.7%, respectively. Factors related to misdiagnosis included the presence of symptoms and features associated with other diseases (such as acute coronary syndrome, stroke and pulmonary embolism), the absence of typical features (such as widened mediastinum on chest X-ray) or concurrent conditions such congestive heart failure. Factors associated with more accurate diagnosis included more comprehensive history taking and increased use of imaging.\ud \ud Conclusions\ud Misdiagnosis in patients with an eventual diagnosis of aortic dissection affects 1 in 3 patients. Clinicians should consider aortic dissection as differential diagnosis in patients with chest pain, back pain and syncope. Imaging should be used early to make the diagnosis when aortic dissection is suspected.

Chest pain is one of the most common reasons for patients to present to healthcare professionals. One of the main challenges with the management of chest pain is the wide differential diagnosis, ranging from minor chest trauma to potentially life-threatening acute myocardial infarction. In a patient-centered health service pathway, the aim is to assess, investigate, diagnose, and treat patients in the safest and most accurate, time, and cost-efficient manner. This report describes the concept of clinical pathways and their importance. It iterates different perspectives of the investigation of chest pain and the barriers to understanding the clinical sequence of events. By considering the patient, clinician, and healthcare service perspective, it is possible to critically evaluate the current stable chest pain pathway. This exercise gives consideration into the way in which patient care could be improved.

Background: To explore the relationship between comorbidity burden and mortality, peri-procedural complications, and length of stay in patients treated with TAVR in the National Inpatient Sample (NIS). Patients undergoing transcatheter aortic valve replacement (TAVR) often have multiple comorbidities. Whilst the impact of individual comorbid conditions on clinical outcomes following TAVR has been previously assessed, the impact of more global measures of comorbidity remains unknown in this cohort. To explore the relationship between comorbidity burden and mortality, peri-procedural complications, and length of stay in patients treated with TAVR NIS. Methods: TAVR procedures were identified between 2011 and 2014 and comorbidities were defined by the Elixhauser classification system (ECS) consisting of 30 comorbidity measures. Endpoints included in-hospital mortality, periprocedural complications, and length of stay. Patients were classified based on their ECS in five categories (ECS I < 0, ECS II = 0, ECS III = 1–5, ECS IV = 6–13, ECS V ≥ 14). Results: A total of 40,604 TAVR patients were identified. Mean age was 81.2 ± 8.5 years. Patients with ECS category V accounted for more than 40% of the cohort and experienced almost a 2.5-fold increase in in-hospital mortality (OR 2.42, 95% CI: 1.28–4.56), acute kidney injury (OR: 6.23, 95% CI: 4.13–9.41), major bleeding (OR: 2.26, 95% CI: 1.71–2.99), post-procedural stroke or TIA (OR: 2.02, 95% CI: 1.08–3.78). It was also associated with a mean 4.14-day increased length of stay (95% CI: 3.67 to 4.65) compared to patients with lower ECS category after adjusting for confounding factors. Conclusions: Our study of over 40,000 TAVRs shows that Elixhauser comorbidity score was independently associated with higher mortality, periprocedural complications, and length of stay. Global comorbidity burden is an important consideration for risk stratification in patients undergoing TAVR.

Fetal heart rate variability (FHRV) is a key index of antenatal and intrapartum fetal well-being. FHRV is well established to be mediated by both arms of the autonomic nervous system, but it remains unknown whether higher centers in the forebrain contribute to FHRV. We tested the hypothesis that selective forebrain ischemia would impair the generation of FHRV. Sixteen chronically instrumented near-term fetal sheep were subjected to either forebrain ischemia induced by bilateral carotid occlusion or sham-ischemia for 30 min. Time, frequency, and nonlinear measures of FHRV were assessed during and for seven days after ischemia. Ischemia was associated with profound suppression of electroencephalographic (EEG) power, which remained suppressed throughout the recovery period ( P < 0.001). During the first 5 min of ischemia, multiple time and frequency domain measures were increased (all P < 0.05) before returning back to sham levels. A delayed increase in sample entropy was observed during ischemia ( P < 0.05). For the first 3 h after ischemia, there was moderate suppression of two measures of FHRV (very-low frequency power and the standard deviation of RR-intervals, both P < 0.05) and increased sample entropy ( P < 0.05). Thereafter, all measures of FHRV returned to control levels. In conclusion, profound forebrain ischemia sufficient to lead to severe neural injury had only transient effect on multiple measures of FHRV. These findings suggest that the forebrain makes a limited contribution to FHRV. FHRV therefore primarily originates in the hindbrain and is unlikely to provide meaningful information on forebrain neurodevelopment or metabolism.

BACKGROUND There has been a revival of balloon aortic valvuloplasty (BAV) for severe aortic stenosis, as a result of an increasing number of patients undergoing trans-catheter aortic valve implantation (TAVI). However, there has not been universal adoption of BAV as a standalone, nor bridging therapy. METHODS A retrospective analysis of the practice at our institution between June 2009 and May 2016 was performed. Demographic, clinical, procedural, and follow-up data on all patients were collected. RESULTS A total of 200 patients with a median age of 82 years and severe symptomatic aortic stenosis underwent BAV from June 2009 to May 2016. All patients had appreciable comorbidity with a mean logistic Euro SCORE of 48 ± 11 and mean standard Euro SCORE 15 ± 4. BAV was performed for palliation in 118 (59%), as a bridging therapy for TAVI in 55 (27.5%) and bridging to surgical AVR in 27 patients (13.5%), respectively. Major complications occurred in 14 patients (7%) including 2 in-patient deaths (1%). A statistically significant improvement in symptoms and a decrease in trans-valvular gradient were observed. CONCLUSION BAV is an effective treatment strategy, either as a bridge to definitive therapy or as a palliative procedure, with an acceptable mortality. BAV is associated with a significant improvement in symptoms and is valuable as a palliative treatment in high-risk patients, where no other invasive option is available.

Giant coronary artery aneurysms are extremely rare entities, and the authors are aware of only 13 case reports of such aneurysms of the circumflex artery. This case report is provided to add evidence of the natural history and pathophysiology and describe the successful surgical treatment of this condition.

OBJECTIVES: This review aims to evaluate the adverse outcomes for patients after treatment with covered stents. BACKGROUND: Coronary perforation is a potentially fatal complication of percutaneous coronary revascularization which may be treated using covered stents. Studies have evaluated long-term outcomes among patients who received these devices, but hitherto no literature review has taken place. METHODS: We conducted a systematic review of adverse outcomes for patients after treatment with covered stents. Data from studies were pooled and outcomes were compared according to stent type. RESULTS: A total of 29 studies were analyzed with data from 725 patients who received covered stents. The proportion of patients with chronic total occlusions, vein graft percutaneous coronary intervention (PCI), intracoronary imaging and rotational atherectomy were 16.9, 11.5, 9.2, and 6.6%, respectively. The stents used were primarily polytetrafluoroethylene (PTFE) (70%) and Papyrus (20.6%). Mortality, major adverse cardiovascular events, pericardiocentesis/tamponade and emergency surgery were 17.2, 35.3, 27.1, and 5.3%, respectively. Stratified analysis by use of PTFE, Papyrus and pericardial stents, suggested no difference in mortality (p = .323), or target lesion revascularization (p = .484). Stent thrombosis, pericardiocentesis/tamponade and emergency coronary artery bypass surgery (CABG) occurred more frequently in patients with PTFE stent use (p = .011, p = .005, p = .012, respectively). In-stent restenosis was more common with pericardial stent use (

The West Midlands Transplant First Project has identified different approaches to coronary angiography. Some units routinely delay angiography until patients are established on dialysis, in order to reduce the risk of contrast nephropathy. However, this causes a significant delay to transplant

Objectives: To identify factors associated with outcomes following rotational atherectomy (RA). Background: RA is an effective way to mechanically modify heavily calcified lesions before stenting; however its outcomes are not well defined. Methods and Results: Retrospective evaluation of all patients who underwent RA in three large UK centers (Leeds General Infirmary (LGI), Royal Infirmary of Edinburgh (RIE) and University Hospital of North Staffordshire (UHNS)) from March 2005 to January 2013. Five hundred and eighteen patients had RA with median follow-up period of 22 months. About 68.3% were male, 28.7% had DM and 34.6% were treated because of ACS. Stents were deployed in 97.3% of the patients while 30.7% of the procedures were performed transradially. Maximum burr was ≤1.75 mm in 85.5% and the mean SYNTAX score was 19.5 ± 11.6. Peri-procedural complications occurred in 6.4% and vascular access complications in 1.9%. Outcomes in the follow-up period were: MACE 17.8%, cardiac death 7.1%, MI 11.7%, TVR 7.5%, all-cause death 13.7%, definite stent thrombosis (ST) 1.4% and stroke 2.9%. Patients with intermediate and high SYNTAX scores were more likely to suffer MACE, cardiac death, MI, all-cause death and ST. Patients with a SYNTAX score >32 were also more likely to have a peri-procedural complication. Multiple logistic regression analysis showed that the presence of PVD (P = 0.026, OR = 2.0), DM (P = 0.008, OR = 2.1), ACS presentation (P = 0.011, OR = 2.1) and SYNTAX score ≥23 (P = 0.02, OR = 1.9) had a significant association with MACE. Conclusions: RA is safe and effective, with high rate of procedural success and relatively low incidence of MACE. PVD, DM, ACS presentation and SYNTAX score were significant predictors for MACE. © 2016 Wiley Periodicals, Inc.

There are few scenarios in the cardiac catheterization laboratory quite as dramatic as a coronary artery perforation. While some instances of this mishap are subtle, others are quite dramatic. Fortunately this occurrence is rare, but carries with it a significant risk of serious adverse events. The potential for harm may be reduced by the brisk identification of the problem within the catheter laboratory, together with early implementation of treatment. A clear understanding of the mechanism, implications, and management of this complication are essential tools for the capable interventional cardiologist.

Background Aortic stenosis (AS) is a common valvular abnormality and transcatheter aortic valve implantation (TAVI) is being increasingly used to treat patients considered too high risk for conventional surgery. We aimed to assess the prevalence of comorbid conditions in patients undergoing TAVI using the Charlson Comorbidity Index (CCI) and to assess their impact on clinical and procedural outcomes. Methods We analysed 158 patients who underwent a TAVI at our institution between June 2009 and September 2015 to define their co-morbid burden as measured with CCI, and study its impact on procedural characteristics and mortality at 30 days. Results One hundred fifty-eight (158) patients with a mean age of 82 ± 8 years and a mean CCI score of 2.67 underwent a TAVI. Only 12/158 patients had a CCI of 0. The commonest cardiovascular comorbidities were previous myocardial infarction (24%), congestive heart failure (15%) and diabetes mellitus (23%) whilst the commonest non-cardiovascular comorbidities were renal disease (46%) and chronic obstructive pulmonary disease (COPD) (29%). After multivariable adjustment, CCI was not independently associated with adverse clinical outcomes. The addition of CCI to scoring systems such as Logistic EuroScore (LES) and Society of Thoracic Surgeons (STS) risk models improved the area under the curve from 0.75 (95%CI: 0.44–1.00) and 0.83 (95%CI: 0.64–1.00) to 0.78 (95%CI: 0.53–1.00) and 0.89 (95%CI: 0.78–1.00) respectively. Conclusions The burden of comorbid conditions in patients undergoing TAVI is significant. The CCI score was not independently associated with a higher risk of death but can be useful in addition to LES and STS risk models in informing decision making on the selection of patients for TAVI.

The cost of inpatient percutaneous coronary interventions (PCI) procedure is related to length of stay (LOS). It is unknown, how LOS may be associated with readmission rates and costs of index PCI and readmissions in elective PCI. This study aims to evaluate rates, predictors, causes, and costs associated with 30-day unplanned readmissions according to lLOS in patients, who underwent elective PCI. We included patients in the Nationwide Readmission Database, who were admitted to hospital from 2010 to 2014, who underwent uncomplicated elective PCI. LOS was defined as 0, 1, 2, and ≥3 days. A total of 324,345 patients were included in the analysis and the 30-day unplanned readmission was 4.75%, 4.67%, 6.44%, and 9.42% in the LOS groups 0, 1, 2, and ≥3 days, respectively. Prolonged LOS was associated with increased average total 30-day cost (index and readmission cost, 0 days $15,063, 1 day $14,693, 2 days $18,136, and ≥3 days $24,336). Compared with 0 days, the odds of readmissions were greater for 2 days (odds ratio 1.41, 95% confidence interval 1.07 to 1.87, p = 0.016) and ≥3 days (odds ratio 1.70, 95% confidence interval 1.28 to 2.24, p

Transcatheter aortic valve replacement over the last few years has revolutionized the way severe aortic stenosis patients are being managed [ [1] , [2] , [3] , [4] ]. Randomized clinical trials commonly excluded bicuspid aortic valves and pure native severe aortic regurgitation [ 2 , 4 ]. We present a case with severe acute aortic regurgitation complicated by refractory pulmonary oedema successfully managed by transfemoral transcatheter aortic valve replacement using a Sapien 3 valve.

Objectives: We sought to characterize UK-wide balloon aortic valvuloplasty (BAV) experience in the TAVI era. Background: BAV for acquired calcific aortic stenosis is in a phase of renaissance, largely due to the development of transcatheter aortic valve implantation (TAVI). Methods: Data from 423 patients at 14 centers across the UK were analyzed. Results: Patients were aged 80.9 6 9.5 years; 52.5% were male. Mean logistic EuroScore was 27.3% 6 16.8%. Mean peak transaortic gradient fell from 62.0 6 26.3 to 28.3 6 16.2 mm Hg. Aortic valve area increased from 0.58 6 0.19 to 0.80 6 0.25 cm 2 echocardiographically. Procedural complication rate was 6.3%, comprising death (2.4%), blood transfusion � 2 U (1.2%), cardiac tamponade (1.0%), stroke (1.0%), vascular surgical repair (1.0%), coronary embolism (0.5%), and permanent pacemaker (0.2%). Mortality was 13.8% at 30 days and 36.3% at 12 months. Subsequently, 18.3% of patients underwent TAVI and 7.0% sAVR, with improved survival compared to those who had no further intervention (logrank < 0.0001). Multivariate Cox proportional hazard analysis demonstrated that survival was adversely effected by the presence of coronary artery disease (HR 1.53, 95%CI 1.08‐2.17, P 5 0.018), poor LV function (HR 1.54, 95%CI 1.09‐2.16, P 5 0.014), and either urgent (HR 1.70, 95%CI 1.18‐2.45; P 5 0.004) or emergent presentation (HR 3.72, 95%CI 2.27‐6.08; P < 0.0001). Conclusion: Balloon aortic valvuloplasty offers good immediate hemodynamic efficacy at an acceptable risk of major complications. Medium-term prognosis is poor in the absence of definitive therapy. V C 2013 Wiley Periodicals, Inc.

Background Preimplantation balloon aortic valvuloplasty ( BAV ) is considered a routine procedure during transcatheter aortic valve implantation ( TAVI ) to facilitate prosthesis implantation and expansion; however, it has been speculated that fewer embolic events and/or less hemodynamic instability may occur if TAVI is performed without preimplantation BAV . The aim of this study was to systematically review the clinical outcomes associated with TAVI undertaken without preimplantation BAV . Methods and Results We conducted a search of Medline and Embase to identify studies that evaluated patients who underwent TAVI with or without preimplantation BAV for predilation. Pooled analysis and random‐effects meta‐analyses were used to estimate the rate and risk of adverse outcomes. Sixteen studies involving 1395 patients (674 with and 721 without preimplantation BAV ) fulfilled the inclusion criteria. Crude device success was achieved in 94% (1311 of 1395), and 30‐day all‐cause mortality occurred in 6% (72 of 1282) of patients. Meta‐analyses evaluating outcomes of strategies with and without preimplantation BAV showed no statistically significant differences in terms of mortality (relative risk [ RR ] 0.61, 95% CI 0.32–1.14, P =0.12), safety composite end point ( RR 0.85, 95% CI 0.62–1.18, P =0.34), moderate to severe paravalvular leaks ( RR 0.68, 95% CI 0.23–1.99, P =0.48), need for postdilation ( RR 0.86, 95% CI 0.66–1.13, P =0.58), stroke and/or transient ischemic attack ( RR 0.72, 95% CI 0.30–1.71, P =0.45), and permanent pacemaker implantation ( RR 0.80, 95% CI 0.49–1.30, P =0.37). Conclusions Our analysis suggests that TAVI procedures with or without preimplantation BAV were associated with similar outcomes for a number of clinically relevant end points. Further studies including a large number of patients are needed to ascertain the impact of TAVI without preimplantation BAV as a standard practice.

Background— There are limited data on outcomes of patients with previous coronary artery bypass grafting (CABG) presenting with ST-segment–elevation myocardial infarction (STEMI) and undergoing primary percutaneous coronary intervention (PPCI). We report outcomes in patients with STEMI undergoing PPCI with or without previous CABG surgery in a large real-world, all-comer population. Methods and Results— Clinical, demographic, procedural, and outcomes data were collected for all patients undergoing PPCI in England and Wales from January 2007 to December 2012. All-cause mortality at 30 days and 1 year were evaluated in the whole and a propensity-matched cohort. Of 79 295 patients with STEMI studied, 2658 (3.4%) patients had prior CABG, of whom 44% (n=1168) underwent PPCI to native vessels and 56% (n=1490) to bypass grafts. There were significant differences in the demographic, clinical, and procedural characteristics of these groups. Patients with prior CABG (with primary PCI to native artery or graft) had higher mortality at 30 days (6.2% with PPCI to native artery, 6.1% with PPCI to bypass graft) than patients with no prior CABG (4.5%; P Conclusions— A prior history of CABG in patients presenting with STEMI and undergoing PPCI does not independently confer additional risk of mortality, although it is a marker of other high-risk features.

Background Published data relating to arterial access site selection and radiation exposure during coronary procedures suggest radial access may lead to increased radiation exposure, but this is based on poorly controlled studies. We sought to measure radiation exposure to patients and operators during elective coronary angiography (CA) according to access site, with other procedure related variables controlled for. We also investigated the specific effect of operator expertise in relation to radiation exposure. Methods 100 consecutive patients undergoing first time elective CA were recruited prospectively. An expert transradial (TR) and an expert transfemoral (TF) operator performed 25 cases each via their default route. A trainee cardiologist with intermediate experience in both access sites performed 25 cases via each route. Angiographic projections were standardised and optimised radiation protection was utilised for all procedures. The primary endpoints were operator and patient exposure, quantified by effective dose (ED) and dose area product (DAP) respectively. Secondary endpoints included fluoroscopy time (FT) and time to patient ambulation. Results The trainee operator recorded higher values for radiation exposure in radial and femoral cases when compared to the expert operators. There were no significant differences in radiation exposure during CA to operator or patient according to access site when standardised by operator experience. For the trainee, ED for TR and TF procedures was 8.8 ± 4.3 μSv and 8.5 ± 6.5 μSv ( P = .86) and DAP was 25.4 ± 4.8 Gycm 2 vs 25.2 ± 8.3 Gycm 2 ( P = .9). For the expert TR and TF operators, ED was 6.4 ± 4.7 μSv vs 6.1 ± 5.6 μSv ( P = .85) and DAP was 21.7 ± 6.5 Gycm 2 vs 22.4 ± 8.0 Gycm 2 , ( P = .74). There was no significant difference in FT in relation to access site. Time to ambulation was significantly longer with TF access. Conclusion The use of TR access has no adverse effect on radiation exposure or FT for diagnostic CA, but does allow for quicker ambulation compared to TF access. The magnitude of radiation exposure is related to operator expertise for both access sites. The results of previous studies reflect the effect of uncontrolled patient and operator variables and not access site selection.

To identify factors associated with outcomes following rotational atherectomy (RA).RA is an effective way to mechanically modify heavily calcified lesions before stenting; however its outcomes are not well defined.Retrospective evaluation of all patients who underwent RA in three large UK centers (Leeds General Infirmary (LGI), Royal Infirmary of Edinburgh (RIE) and University Hospital of North Staffordshire (UHNS)) from March 2005 to January 2013. Five hundred and eighteen patients had RA with median follow-up period of 22 months. About 68.3% were male, 28.7% had DM and 34.6% were treated because of ACS. Stents were deployed in 97.3% of the patients while 30.7% of the procedures were performed transradially. Maximum burr was ≤1.75 mm in 85.5% and the mean SYNTAX score was 19.5 ± 11.6. Peri-procedural complications occurred in 6.4% and vascular access complications in 1.9%. Outcomes in the follow-up period were: MACE 17.8%, cardiac death 7.1%, MI 11.7%, TVR 7.5%, all-cause death 13.7%, definite stent thrombosis (ST) 1.4% and stroke 2.9%. Patients with intermediate and high SYNTAX scores were more likely to suffer MACE, cardiac death, MI, all-cause death and ST. Patients with a SYNTAX score32 were also more likely to have a peri-procedural complication. Multiple logistic regression analysis showed that the presence of PVD (P = 0.026, OR = 2.0), DM (P = 0.008, OR = 2.1), ACS presentation (P = 0.011, OR = 2.1) and SYNTAX score ≥23 (P = 0.02, OR = 1.9) had a significant association with MACE.RA is safe and effective, with high rate of procedural success and relatively low incidence of MACE. PVD, DM, ACS presentation and SYNTAX score were significant predictors for MACE. © 2016 Wiley Periodicals, Inc.

Currently available tools to assist clinicians with prediction of neurodevelopmental outcome of preterm infants are inadequate. Modified cotside electroencephalography (EEG) has the ability to produce quantitative electrophysiologic measures. These measures may be useful in future prediction of outcome.To determine patterns of change in quantitative EEG measures in preterm infants during their first week after birth.Observational.Preterm infants born at less than 32 weeks completed gestation surviving to discharge with unremarkable serial ultrasound scans.Changes in continuity, amplitude and spectral edge frequency measures of EEGs obtained over the first week after birth.Results of EEGs performed using a novel EEG device on 63 infants are reported here. Their median (range) gestation was 29 (24-31) weeks and birthweight was 1,235 (540-1,980) g. Quantitative measures of EEG continuity increased over the first week after birth from 72 (25-99)% to 92 (54-100)% at the 25 microV threshold, and from 39 (10-87)% to 64 (34-75)% at the 50 microV threshold, both p0.0001. There was a related 32% increase in median amplitude from 5.8 (2.6-10.6) microV on day 1 to 7.6 (4.3-9.4) microV on day 4, p=0.005. There was a trend for average spectral edge frequency to fall from 10.7 (9.3-12.9) Hz on day 1 to 9.9 (8.1-12.3) Hz on day 3, p=0.06. Each gestational tertile showed similar patterns.There are consistent changes in quantitative neurophysiologic measures over the first week after birth, and particularly measures of continuity over the first 4 days, in normal preterm infants.

Objective. Current methods for early identification of cerebral white matter injury in the premature infant at the bedside are inadequate. This study investigated the utility of advanced spectral analysis of the neonatal electroencephalogram (EEG) in the early diagnosis of white matter injury in the premature infant. The critical measurement used, suggested largely by previous studies in animal models, was the spectral edge frequency (SEF), calculated here as the frequency below which 90% of the power in the EEG exists. Methods. Fifty-nine very low birth weight infants (87% of eligible infants) had electrodes placed over the central and parietal regions (C3, P3, C4, and P4 sites according to the 10-20 international system) for the collection of EEG amplitude, intensity, and SEF. All averaged signals were analyzed off-line using software (Chart Analyzer; BrainZ Instruments, Auckland, NZ). All infants had a magnetic resonance imaging scan at term to identify the presence and severity of white matter injury. Results. There was no significant difference between conventional EEG amplitude and intensity for infants with or without evidence of white matter injury. However, premature infants with increasingly severe white matter injury had progressively lower SEFs compared with infants who did not exhibit white matter injury. Conclusions. These data suggest that SEF-based measures are useful for defining the presence and severity of white matter injury at the bedside.

ObjectivesThis study characterizes the histology of myocardium predicted to be hibernating using three different imaging techniques to explain the discordance among them.BackgroundBoth radionuclide and functional imaging techniques were used to assess myocardial hibernation. The former have high sensitivity and the latter high specificity for predicting functional recovery.MethodsNineteen patients underwent thallium-201 and 99m-technetium tetrofosmin myocardial perfusion imaging, and dobutamine magnetic resonance imaging (MRI), prior to coronary bypass grafting. Criteria for predicted hibernation for each technique were defined before operation. Postoperative criteria for scar and true hibernation were also defined. Biopsies were analyzed for myocyte volume fraction (MVF), glycogen deposition and pathologic cell features.ResultsThallium was most sensitive in predicting hibernation (88%) and MRI most specific (84%); and, although there was good agreement between thallium and tetrofosmin (85%), agreement between MRI and thallium (59%) or tetrofosmin (59%) was poor. For each technique, MVF was higher in segments predicted to be hibernating rather than scar (p < 0.05). The MVF was higher where both thallium and MRI predicted hibernation (0.77 ± 0.07) than in segments predicted by thallium alone (0.69 ± 0.13, p < 0.05). Proven hibernating segments had a higher MVF than scar (0.72 ± 0.11 vs. 0.6 ± 0.26, p < 0.05).ConclusionsPreservation of myocyte fraction is an important determinant of functional recovery after revascularization. A higher myocyte fraction is required to maintain contractile reserve than to achieve significant tracer uptake. This explains the higher sensitivity of radionuclide imaging compared with dobutamine MRI in the identification of myocardial hibernation.

We read with interest the letter from Dr. Dastidar and colleagues in which they express their views and compare our report of the randomized CvLPRIT (Complete Versus Lesion-Only Primary PCI Trial) [(1)][1] with their in-house clinical experience. They suggest that the trial was not run according to

Objective. Cerebral hypothermia has been shown to reduce damage from experimental hy-poxia-ischemia if started shortly after reperfusion. However, in the newborn infant it may not be feasible to determine prognosis so soon after exposure to asphyxia. The aim of this study was to determine whether head cooling, delayed until shortly before the onset of postasphyxial seizure activity, is neuroprotective. Methods. Unanesthetized near-term fetal sheep in utero were subjected to 30 minutes of cerebral ischemia. Later, at 5.5 hours, they were randomized to either cooling (n = 7) or sham cooling (n = 10) for 72 hours. Intrauterine cooling was induced by circulating cold water through a coil around the fetal head. The water temperature was titrated to reduce fetal extradural temperature from 39.1 ± 0.1°C to between 30°C and 33°C, while maintaining esophageal temperature >37°C. Results. Cerebral cooling suppressed the secondary rise in cortical impedance (a measure of cytotoxic edema), but did not prevent delayed seizures, 8 to 30 hours after ischemia. Transient metabolic changes including increased plasma lactate and glucose levels were seen with a moderate sustained rise in blood pressure. This severe cerebral insult resulted in depressed residual parietal electroencephalographic activity after 5 days recovery (−14.2 ± 1.5 decibels), associated with a watershed distribution of neuronal loss (eg, 94 ± 4% in parasagittal cortex and 77 ± 4% in the lateral cortex). Hypothermia was associated with better recovery of electroencephalographic activity (−8.9% ± 1.8 decibels) and substantially reduced neuronal loss in the parasagittal cortex (46 ± 13%), the lateral cortex (9 ± 4%), and other regions except the cornu ammonis sectors 1 and 2 of the hippocampus. Conclusions. Delayed selective head cooling begun before the onset of postischemic seizures and continued for 3 days may have potential to significantly improve the outcome of moderate to severe hypoxic-ischemic encephalopathy.

Background —The regional wall motion impairment and predisposition to arrhythmias in human ventricular hibernation may plausibly result from abnormal intercellular propagation of the depolarizing wave front. This study investigated the hypothesis that altered patterns of expression of connexin43, the principal gap junctional protein responsible for passive conduction of the cardiac action potential, contribute to the pathogenesis of hibernation. Methods and Results —Patients with poor ventricular function and severe coronary artery disease underwent thallium scanning and MRI to predict regions of normally perfused, reversibly ischemic, or hibernating myocardium. Twenty-one patients went on to coronary artery bypass graft surgery, during which biopsies representative of each of the above classes were taken. Hibernation was confirmed by improvement in segmental wall motion at reassessment 6 months after surgery. Connexin43 was studied by quantitative immunoconfocal laser scanning microscopy and PC image software. Analysis of en face projection views of intercalated disks revealed a significant reduction in relative connexin43 content per unit area in reversibly ischemic (76.7±34.6%, P P P P =.012) and normal (100±31.5%, P P Conclusions —These results indicate progressive reduction and disruption of connexin43 gap junctions in reversible ischemia and hibernation. Abnormal impulse propagation resulting from such changes may contribute to the electromechanical dysfunction associated with hibernation.

The role of C-type natriuretic peptide (CNP) and its guanylyl cyclase-linked receptors in mediating salt secretion by the rectal gland of the spiny dogfish shark ( Squalus acanthias) was investigated using HS-142–1, a competitive inhibitor of the binding of natriuretic peptides to their guanylyl cyclase receptors. CNP binds to receptors and activates guanylyl cyclase in rectal gland membranes in a way that is inhibited by HS-142–1. Guanylyl cyclase activation in rectal gland membranes is far more sensitive to CNP than to atrial natriuretic peptide, whereas the reverse is true for membranes derived from mammalian (rabbit) renal collecting duct cells. HS-142–1 inhibited the stimulatory effect of CNP on ouabain-inhibitable oxygen consumption by rectal gland tubules. In explanted rectal glands continuously perfused with blood from intact donor sharks, HS-142–1 inhibited the increase in salt secretion normally provoked by infusing isotonic saline solutions into the donor animal. These results strongly support the view that CNP released into the systemic circulation in response to volume expansion mediates the secretion of chloride by the rectal gland via receptors linked to guanylyl cyclase.

Objective: We assessed the effects of coronary bypass grafting on left ventricular (LV) function, exercise capacity and symptom profile in patients with LV impairment and evaluated the role of identifying myocardial hibernation in a prospective non-randomised study. Methods: Of 120 patients screened, 47 patients with LV ejection fraction B 35% and three vessel coronary artery disease were studied. All underwent stress:redistribution and separate day rest:redistribution Tl-201 imaging together with cine MRI at enrolment, and cine MRI at follow-up. Group 1, 30 patients undergoing bypass surgery, underwent symptom limited treadmill exercise testing with peak VO2 measurement, and symptom profile evaluation less than 3 months before, and 3‐6 months after operation. Revascularisation was assessed by post-operative Tl-201 imaging and repeat coronary angiography. Group 2, 17 patients treated on medical therapy alone underwent symptom profile assessment at enrolment and follow-up for those who survived. Segmental hibernation was defined as the equivalent of greater than 50% of maximal Tl-201 uptake where wall motion was severely impaired on resting imaging. Patients were considered to be hibernating where two of nine LV segments fulfilled these criteria. Results: In group 1, five patients died (17%), peri-or post-operatively, two defaulted and 23 attended follow-up studies. In group 2, three patients died prior to follow-up (18%). In the surgical group there was an increase in mean LVEF from 24.098% to 29.7911% (PB0.05) while in the medical group there was a fall from 25.79 10% to 20.698% (PB0.05). In group 1, the mean NYHA dyspnoea grade improved from 2.7 to 1.4 while in the medical group it was unchanged, 2.6 to 2.5. In patients with myocardial hibernation identified pre-operatively, 18:19 (95%) improved LVEF after CABG compared with 2:4 (50%) of patients without hibernation. 17:19 (86%) patients with hibernation improved NYHA dyspnoea class compared with 2:4 (50%) of patients without. 60:93 (65%) of hibernating segments improved function after revascularisation while 47:53 (89%) hibernating segments showed no improvement on medical therapy alone. Conclusion: In patients with severe LV impairment with myocardial hibernation, coronary artery bypass grafting improves both global and regional systolic LV function, and symptom profile. Medical treatment of patients with LV impairment and myocardial hibernation does not improve LV contractile function or symptoms. Both surgical and medical therapy carry a high mortality rate. © 1997 Elsevier Science B.V.

Background Some patients with hypertrophic obstructive cardiomyopathy may gain symptomatic relief from a reduction in the extent of obstruction to left ventricular outflow. We present the outcome of the first series of patients treated with an alternative method of gradient reduction using catheter techniques. Methods and Results Eighteen patients were treated with selective intracoronary alcohol injection to induce localized septal infarction. Patients underwent echocardiographic measurement of left ventricular dimensions and Doppler echocardiographic evaluation of left ventricular outflow tract gradients before the procedure, on the first postoperative day, and at a median follow-up of 3 months after the procedure. In addition, patients underwent exercise testing and symptom evaluation before and 3 months after nonsurgical septal reduction. There was a significant reduction in left ventricular outflow tract obstruction after the procedure (preprocedure, 67 mm Hg [95% CI, 48 to 87 mm Hg]; postprocedure, 25 mm Hg [95% CI, 16 to 34 mm Hg]; P =.0006), which persisted at 3-month follow-up (22 mm Hg [95% CI, 12 to 32 mm Hg]; P =.001). This was associated with a significant improvement in symptoms. There was a small but not significant increase in exercise capacity (n=10; preprocedure, 418 seconds [95% CI, 273 to 563 seconds]; postprocedure, 452 seconds [95% CI, 283 to 621 seconds). Left ventricular dimensions were not significantly altered by nonsurgical septal reduction. Conclusions Nonsurgical septal reduction significantly reduces left ventricular outflow tract obstruction and improves symptoms in some patients with hypertrophic obstructive cardiomyopathy. The technique may provide an alternative to surgical myomectomy in selected patients.

Aims: Primary percutaneous coronary intervention (PPCI) is the preferred strategy for acute ST-segment elevation myocardial infarction (STEMI), with evidence of improved clinical outcomes compared to fibrinolytic therapy. However, there is no consensus on how best to manage multivessel coronary disease detected at the time of PPCI, with little robust data on best management of angiographically significant stenoses detected in non-infarct-related (N-IRA) coronary arteries. CVLPRIT will determine the optimal management of N-IRA lesions detected during PPCI. Methods and results: CVLPRIT (Complete Versus culprit-Lesion only PRimary PCI Trial) is an open-label, prospective, randomised, multicentre trial. STEMI patients undergo verbal “assent” on presentation. Patients are included when angiographic MVD has been detected, and randomised to culprit (IRA)-only PCI (n=150) or in-patient complete multivessel PCI (n=150). Cumulative major adverse cardiac events (MACE) - all-cause mortality, recurrent MI, heart failure, need for revascularisation (PCI or CABG) will be recorded at 12 months. Secondary endpoints include safety endpoints of confirmed ischaemic stroke, intracranial haemorrhage, major non-intracranial bleeding, and repair of vascular complications. A cardiac magnetic resonance (CMR) substudy will provide mechanistic data on infarct size, myocardial salvage index and microvascular obstruction. A cost efficacy analysis will be undertaken. Conclusions: The management of multivessel coronary artery disease in the setting of PPCI for STEMI, including the timing of when to perform non-culprit-artery revascularisation if undertaken, remains unresolved. CVLPRIT will yield mechanistic insights into the myocardial consequence of N-IRA intervention undertaken during the peri-infarct period.

We describe a novel treatment for hypertrophic obstructive cardiomyoparhy, in which septal reduction is achived via transluminal induction of focal septal infarction. The results of the first three patients treated in this fashion have been recently reported; in this preliminary series, intraventricular pressure gradients could be dramatically reduced by the creation of a localized infarction of the ventricular septum. The procedure is well tolerated and effective in reducing the obstruction to left ventricular ourflow. Further studies are underway to fully evaluate the usefulness of the technique. (J Interven Cardiol 1996;9:393–397)

This study evaluates changes in ischaemic threshold over a 5-year period in patients with stable angina pectoris, who did not suffer any intervening cardiac event. Changes in ischaemic threshold are related to alterations in symptomatic status and ambulatory ischaemia. Over long-term follow-up, there is a significant fall in ischaemic threshold in such patients (mean heart rate at onset of ischaemia fell from 104 +/- 17.8 to 97 +/- 17.4 bpm: P0.001), but this is not matched by a worsening of either symptoms or ischaemia during daily life. In the 68% of patients that had a reduction in ischaemic threshold ofor = 5 bpm, 68% had either definite reduction or no change in symptoms and 84% had either reduction, abolition or no change in transient ischaemic activity. The dissociation between ischaemic threshold, ambulatory ischaemia and symptoms has implications for long-term monitoring and management of the patient with stable angina.

Hypoxic-ischemic injuries can evolve over several days, and recent studies suggest that further neuronal death may occur 6 to 72 h later. Because cerebral temperature is an important determinant of outcome during the primary injury, we investigated the effect of temperature, on outcome, during the later phases of injury. Hypoxic-ischemic injury was induced in 21-d-old rats by unilateral ligation of the right carotid artery followed by exposure to 15 min of hypoxia of 8% O2 at 34 degrees C. Cerebral temperature changes were induced by modifying environmental temperature. The rats were divided into four treatment groups: group 1 (n = 15) remained at 34 degrees C for 72 h; group 2 (n = 14) were kept at 34 degrees C for 6 h and then at 22 degrees C for the remaining 66 h; group 3 (n = 17) remained at 22 degrees C for 6 h and 34 degrees C for the next 66 h; group 4 (n = 16) remained at 22 degrees C for 72 h. Rats kept at 22 or 34 degrees C had cortical temperatures of 35.5 +/- 0.1 degrees C and 37.9 +/- 0.2 degrees C, respectively. Histologic outcome was assessed 72 h after hypoxia. The area of cortical infarction was reduced in group 4 compared with groups 1-3 (p < or = 0.05). Striatal damage was reduced in group 4 (p = 0.05). Hippocampal neuronal loss was not significantly altered. In a subsequent study the area of cortical infarction was 12.1 +/- 3 mm2 in group 1 (n = 11) compared with 3.4 +/- 1.5 mm2 group 4 treated rats (n = 10) 21 d after the injury (p < 0.01). Thus hypothermia spanning both the first 6 h and from 6 to 72 h after injury was needed to improve outcome. Conversely exposure to the thermoneutral environment exacerbated the injury. These observations suggest that prolonged moderate cerebral hypothermia can be used to suppress the cytotoxic processes that occur after hypoxic-ischemic injury.

We sought to characterize UK-wide balloon aortic valvuloplasty (BAV) experience in the TAVI era.BAV for acquired calcific aortic stenosis is in a phase of renaissance, largely due to the development of transcatheter aortic valve implantation (TAVI).Data from 423 patients at 14 centers across the UK were analyzed.Patients were aged 80.9 ± 9.5 years; 52.5% were male. Mean logistic EuroScore was 27.3% ± 16.8%. Mean peak transaortic gradient fell from 62.0 ± 26.3 to 28.3 ± 16.2 mm Hg. Aortic valve area increased from 0.58 ± 0.19 to 0.80 ± 0.25 cm(2) echocardiographically. Procedural complication rate was 6.3%, comprising death (2.4%), blood transfusion ≥ 2 U (1.2%), cardiac tamponade (1.0%), stroke (1.0%), vascular surgical repair (1.0%), coronary embolism (0.5%), and permanent pacemaker (0.2%). Mortality was 13.8% at 30 days and 36.3% at 12 months. Subsequently, 18.3% of patients underwent TAVI and 7.0% sAVR, with improved survival compared to those who had no further intervention (logrank0.0001). Multivariate Cox proportional hazard analysis demonstrated that survival was adversely effected by the presence of coronary artery disease (HR 1.53, 95%CI 1.08-2.17, P = 0.018), poor LV function (HR 1.54, 95%CI 1.09-2.16, P = 0.014), and either urgent (HR 1.70, 95%CI 1.18-2.45; P = 0.004) or emergent presentation (HR 3.72, 95%CI 2.27-6.08; P0.0001).Balloon aortic valvuloplasty offers good immediate hemodynamic efficacy at an acceptable risk of major complications. Medium-term prognosis is poor in the absence of definitive therapy.

Temporary epicardial pacing wires (TEPWs) are commonly used during cardiac surgery to meet unforeseen complications like heart blocks or asystole. These are generally considered to be safe. The incidence of major complications with their use is low, but could be life threatening. Complications can be divided into those encountered during placement, removal, or retention of temporary epicardial pacing wires. We report a rare case of prosthetic mitral valve endocarditis caused by TEPWs that migrated into the pulmonary artery, presenting 5 months following mitral and aortic valve replacement surgery that required percutaneous removal of these temporary pacing wires via a right femoral vein approach. This case highlights the fact that delayed complications can rarely occur due to retained TEPWs and may have serious consequences. This fact should be taken into account when the strategy on dealing with such wires following cardiac surgery is determined. Routine retention of temporary epicardial pacing wires is not recommended.

Intraventricular injection of insulin-like growth factor 1 (IGF-1) 2 h after hypoxic–ischemic injury reduces neuronal loss. To clarify the mode of action, we compared histological outcome between treatment groups in the following three studies: 0, 0.5, 5, and 50 μg IGF-1 given 2 h after injury; 0 and 20 μg IGF-1 given 1 h before; and 20 μg IGF-1 and insulin or vehicle alone given 2 h after. Unilateral hypoxic-ischemic injury was induced in adult rats by ligation of the right carotid and exposure to 6% O2 for 10 min. Histological outcome was evaluated in the cortex, striatum, and hippocampus 5 days later. Five to 50 μg IGF-1 reduced the incidence of infarction and neuronal loss in a dose-dependent manner in all regions (p < 0.05), and 50 μg reduced the infarction rate from 87 to 26% (p < 0.01). Pretreatment did not alter outcome. IGF-1 improved outcome compared with equimolar doses of insulin (p < 0.05) and did not affect systemic glucose concentrations or cortical temperature. The results indicate that the neuronal protective effects of IGF-1 are specific and are not mediated via insulin receptors, hypothermia, or hypoglycemic mechanisms. Centrally administered IGF-1 appears to provide worthwhile trophic support to cells within most cerebral structures after transient hypoxic-ischemic injury.

Aims To compare the performance of apolipoproteins (Apo) and oxidized LDL against routine clinical lipid profiles in the discrimination of atherosclerotic burden and cardiac function in stable coronary artery disease (CAD) patients. Methods and results Using a cross-sectional approach, we measured oxidized LDL, Apo AI and B in 199 patients (34–81 years) with stable symptomatic CAD. The discrimination of (i) atherosclerotic burden (coronary atheroma scores, the number of diseased coronary vessels), and (ii) cardiac function [NYHA classification, left-ventricular systolic dysfunction (LVSD)] were judged using receiver operating characteristic (ROC) curves. The ratio of Apo AI to B was correlated to oxidized LDL (Spearman, r = 0.37, P < 0.001); however, oxidized LDL was unrelated to measures of cardiac function or CAD severity. Concentrations of Apo AI decreased from 1.38 to 1.20 g/L with increasing atheroma scores (P = 0.02), while triglyceride levels increased from 1.50 to 2.23 mmol/L (P = 0.016). High-density lipoprotein (HDL) cholesterol and Apo AI levels were higher among those with heart failure (P = 0.002), and increased ordinally with NYHA class (P = 0.005). On ROC analysis, reduced levels of Apo AI and HDL cholesterol were discriminators for patients in the upper quartile for atheroma score (P < 0.004). Raised indices of HDL were associated with heart failure (P < 0.002). Conclusion Apo AI levels are a consistent discriminator of atherosclerotic burden among patients with stable CAD. However, heart failure presents an element of confounding in the diagnostic and prognostic utility of Apo monitoring among these patients.

Suppression of electroencephalogram (EEG) spectral edge (SE) is a suggested marker for preterm white matter (WM) injury; however, there are few specific data. We examined the relationship between SE and EEG intensity and white and grey matter injury after a severe ischemic insult, induced by 30 min carotid occlusion (n=10) compared with sham-control (n=7) in preterm fetal sheep at 95-96 days of gestation (term=147 days). Fetuses were instrumented with a microdialysis probe placed within the left periventricular region and with EEG probes over the parietal cortex bilaterally. Fetuses that showed only brief suppression of the EEG during bilateral carotid occlusion (Mild group, n=4) were compared with those who exhibited persistent suppression (Severe group, n=6). After 72 h recovery, the severe ischemia group showed parasagittal cortical neuronal loss accompanied by diffuse WM damage in the right hemisphere, whereas the mild group showed little or no neuronal loss, either with (n=2) or without diffuse (n=2) WM damage. Left sided focal periventricular WM infarction corresponding with probe placement was seen in all groups. EEG intensity and SE were profoundly suppressed in the severe group, with only partial recovery after 72 h (P

Background The transfemoral approach is the most widely used access route for transcatheter aortic valve implantation (TAVI). Early experience incorporated surgical cutdown and closure. As the equipment size has been reduced from 24 to 16F, many centres have adopted a true percutaneous approach to both cannulation and closure. However, vascular complications are frequent (4–34%) and are associated with significant morbidity and mortality. There are no direct comparisons reported between these two methods. We present data on all patients undergoing transfemoral TAVI in a single tertiary centre where surgical access and closure by a vascular surgeon remains the default approach. Methods Clinical details of all patients who underwent transfemoral-TAVI in a large tertiary centre between 2009 and 2013 were analysed. All patients underwent CT angiography of the aorta, iliac and femoral arteries in advance of treatment. During every transfemoral-TAVI procedure, a vascular surgeon performed surgical cutdown and identified most suitable site for femoral arterial cannulation. Access was then obtained under direct vision with Seldinger technique and sheath was deployed. At the end of procedure the arteriotomy site was closed surgically. In selected cases planned vascular intervention was performed pre-emptively to facilitate transfemoral-TAVI. Vascular complications were defined according to the Valve Academic Research Consortium criteria and divided into major and minor complications. Results During the study period, 92 patients (Mean Age 80.03 ± 6. 41, 73% Males) underwent TAVI procedure. In 80% (74/92) of cases a transfemoral TAVI was performed via surgical cutdown while 19% (18/92) underwent transapical TAVI. While the majority of transfemoral procedures 70/74(94%) were performed under general anaesthetic, 4 (6%) patients had only regional anaesthesia. Major vascular complication occurred in 1/74 (1.3%) patients. This involved rupture of the right common iliac induced by pre-dilatation with and 18F dilator. Emergency surgical repair was performed and the patient underwent successful transapical TAVI a month later. There was one (1.3%) minor vascular complication, a small femoral artery pseudoaneurysm which was managed conservatively. In 2/74 cases (3%), the femoral vessels were significantly stenosed and a Dacron conduit was anastomosed to the common iliac vessel via a retroperitoneal approach. The valve treatment was then successfully performed through that conduit. One patient (1.3%) with severe claudication underwent a femoral endarterectomy and reconstruction of that vessel electively as part of the TAVI procedure. Conclusions Published data suggests that vascular complications remain a major cause of morbidity in patients undergoing TAVI. Our experience demonstrates that retention of a vascular surgeon as an intrinsic member of the TAVI team both minimises vascular complication and also allows alternative access to be explored.

Insulin-like growth factor (IGF-1) is induced in damaged brain tissue after hypoxia—ischemia, and exogenous administration of IGF-1 shortly after injury has been shown to be neuroprotective. However, it is unknown whether treatment with IGF-1 delayed by more than a few hours after injury may be protective. Hypothermia after brain injury has been reported to delay the development of ischemic neuronal death. The authors therefore hypothesize that a reduction in the environmental temperature during recovery from hypoxia—ischemia could prolong the window of opportunity for IGF-1 treatment. Unilateral brain damage was induced in adult rats using a modified Levine model of right carotid artery ligation followed by brief hypoxia (6% O2 for 10 minutes). The rats were maintained in either a warm (31°C) or cool (23°C) environment for the first 2 hours after hypoxia. All rats were subsequently transferred to the 23°C environment until the end of the experiment. A single dose of IGF-1 (50 μg) or its vehicle was given intracerebroventricularly at either 2 or 6 hours after hypoxia. Histologic outcome in the lateral cortex was quantified 5 days after hypoxia. Finally, cortical temperature was recorded from 1 hour before and 2 hours after hypoxia in separate groups of rats exposed to the “warm” and “cool” protocols. In rats exposed to the warm recovery environment, IGF-1 reduced cortical damage ( P < 0.05) when given 2 hours but not 6 hours after insult. In contrast, with early recovery in the cool environment, a significant protective effect of IGF-1 in the lateral cortex ( P < 0.05) was found with administration 6 hours after insult. In conclusion, a reduction in cerebral temperature during the early recovery phase after severe hypoxia—ischemia did not significantly reduce the severity of injury after 5 days' recovery; however, it markedly shifted and extended the window of opportunity for delayed treatment with IGF-1.

Prolonged cerebral hypothermia is neuroprotective if started within a few hours of hypoxia-ischemia. However, delayed seizure activity is one of the major clinical indicators of an adverse prognosis after perinatal asphyxia. The aim of this study was to determine whether head cooling delayed until after the onset of postasphyxial seizures may still be neuroprotective. Unanesthetized near-term fetal sheep in utero received 30 min of cerebral ischemia induced by bilateral carotid artery occlusion. Eight and one-half hours later, they received either cooling (n = 5) or sham cooling (n = 13) until 72 h after the insult. Intrauterine cooling, induced by circulating cold water through a coil around the fetal head, was titrated to reduce fetal extradural temperature from 39.4+/-0.1 degrees C to between 30 and 33 degrees C. Cerebral ischemia led to the delayed development of intense epileptiform activity from 6 to 8 h postinsult, followed by a marked secondary rise in cortical impedance (a measure of cytotoxic edema) and in carotid blood flow. Cerebral cooling markedly attenuated the secondary rise in impedance and reduced carotid blood flow (p < 0.001). After 5 d recovery, there was no significant difference in loss of parietal EEG activity relative to baseline in the hypothermia compared with the control group (-12.5+/-1.4 versus -15.2+/-1.2 dB, mean +/- SEM, NS) or in parasagittal cortical neuronal loss (82+/-9 versus 90+/-5%, NS). In conclusion, delayed prolonged head cooling begun after the onset of postischemic seizures was not neuroprotective. These data highlight the importance of intervention in the latent phase, after reperfusion but before the onset of secondary injury.

In recent years improvements in obstetric and paediatric management have resulted in increased survival of infants from 24 weeks of gestation. However, these infants have continued to have a significantly increased risk of cerebral palsy, neurological morbidity and mortality (Volpe, 1997). There is increasing evidence to show that the neurological sequelae in many of these infants are the consequence of asphyxia during fetal life (Nelson & Leviton, 1991). Further it has been strongly suggested that haemodynamic factors both during asphyxia and during the post-asphyxial reperfusion phase contribute considerably to the pathogenesis of neurological disorders in the preterm fetus (Volpe, 1997). Currently, however, our understanding of the cerebrovascular and cardiovascular response of the preterm fetus to asphyxia is very limited. The cardiovascular and cerebrovascular responses of the near-term fetus to episodes of reduced oxygen supply have been well described (Jensen & Berger, 1991; Hanson, 1997; Volpe, 1997). These responses, particularly the redistribution of combined ventricular output (CVO) away from the periphery, contribute significantly to protecting essential organs such as the heart and brain. It has been suggested that immaturity of cardiovascular development may leave the preterm fetus more vulnerable to asphyxia (Jensen & Berger, 1991; Volpe, 1997). However, the current evidence regarding this hypothesis is both limited and contradictory. Several studies in the 0.6 gestation sheep fetus, an age broadly equivalent in neuronal development to a human fetus of 27-28 weeks gestation (McIntosh et al. 1979), have shown that unlike the near-term fetus redistribution of blood flow and bradycardia does not occur during hypoxia and that there is no rise in blood pressure (Boddy et al. 1974; Iwamoto et al. 1989). Similar observations were made during partial umbilical cord occlusion, although in this study there was evidence of redistribution of CVO (Iwamoto et al. 1991). Further, the ability of the fetal cerebrovasculature to vasodilate during hypoxia appears to be blunted and cerebral oxygen consumption is sustained in part by an increase in fractional oxygen extraction (Gleason et al. 1990). It has been suggested that these preterm fetal responses reflect relative immaturity of chemoreceptor function and neurohormonal modulators as well as an incomplete development of the autonomic nervous system (Walker et al. 1979; Iwamoto et al. 1991; Jensen & Berger, 1991). In contrast to these studies others have demonstrated that the 0.6 gestation sheep fetus appears to have a qualitatively similar cardiovascular response to complete occlusion of the umbilical cord to that of the near-term fetus, with an initial significant rise in blood pressure and a pronounced bradycardia (Mallard et al. 1994; Keunen et al. 1997). However, neither study evaluated the redistribution of blood flow. The study by Keunen et al. demonstrated the capacity of the immature animal to survive at least 20 min of complete umbilical cord occlusion, compared with a terminal duration for survival in the near-term sheep fetus of 10-12 min (Mallard et al. 1992). This capacity of the preterm fetus to survive longer periods of reduced oxygen supply is well described by others and is due to such factors as greater glycogen stores, greater anaerobic capacity in many tissues and lower basal metabolic activity (Dawes et al. 1959; Duffy et al. 1975). Speculatively, these data suggest that the very premature fetus may preferentially utilize this metabolic reserve during moderate hypoxia, and would only mount a full cardiovascular response to profound, near-terminal episodes of asphyxia. In pilot experiments we have determined that the preterm fetus is capable of surviving 30-33 min of complete umbilical cord occlusion. The cardiovascular response of the preterm fetus to such a near-terminal duration of asphyxia and the degree of haemodynamic compromise, including hypotension and cerebral hypoperfusion, that may occur is unknown. Furthermore the effects of such a profound insult on the post-asphyxial cardiovascular and cerebrovascular recovery of the preterm fetus have not been evaluated. There is considerable data from the more mature brain to suggest that the early post-asphyxial period is an important time during which further cerebral injury may occur. Ischaemia-reperfusion is associated with vascular dysfunction leading to post-insult impairment of blood flow and its regulation in many organs (Conger & Weil, 1995). A delayed, secondary fall in cerebral blood flow has been reported in both adult and neonatal preparations following asphyxia or ischaemia and is suggested to contribute to further injury (Rosenberg, 1988; Rosenberg et al. 1989; Gunn et al. 1997; Pourcyrous et al. 1997; Dorrepaal et al. 1997). Therapeutic intervention during this phase can significantly improve recovery of cerebral function (Gunn et al. 1997). It was the purpose of this study, therefore, to examine the cardiovascular, cerebrovascular and electroencephalographic (EEG) response of the 0.6 gestation fetal sheep to 30 min of asphyxia induced by complete umbilical cord occlusion and to evaluate the haemodynamic changes during the first 3 days after asphyxia.

The aim of this study was to determine whether there is a relationship between changes in PR-RR correlation of the fetal ECG and progressive changes in fetal acid-base status and blood pressure (BP) during repeated umbilical occlusion. Chronically instrumented fetal sheep at 126.8 ± 0.6 d (mean± SEM) were randomized to receive 1 min of total umbilical cord occlusion either every 5 min for 4 h (1:5 group; n = 8), or every 2.5 min until BP fell