Early Gastrointestinal Complications From Ventricular Assist Devices is Increased by Non-Pulsatile Flow.

BACKGROUND: Measurements of organ flow and perfusion during cardiopulmonary bypass suggest that perfusion of the splanchnic bed can be impaired by non-pulsatile flow. We postulated that non-pulsatile flow from centrifugal ventricular assist devices might also compromise splanchnic blood flow and cause bowel ischaemia especially in the period of circulatory instability early post-implant. The aim of the present studies was to compare the incidence of gastrointestinal (GI) complications in patients having a non-pulsatile device with the incidence in those having a pulsatile device. METHODS: In a pilot study, the initial 12 patients who received the Ventrassist (Ventracor, Sydney, NSW, Australia) centrifugal, non-pulsatile device during the period from June 2003 to September 2005 at the Alfred Hospital, Melbourne were compared with 11 patients who received a Thoratec (Thoratec, Pleasanton, CA, USA), pulsatile, positive displacement device and the incidence was recorded of GI complications requiring an intervention either surgical, endoscopic or by interventional radiology. This was followed by a larger (full) study of a second cohort of similar ventricular assist device (VAD) patients from January 1992 until December 2012 comparing 53 patients having non-pulsatile devices and 110 having pulsatile devices. RESULTS: In the pilot study, the overall incidence of complications in the non-pulsatile group (67%) was almost double that in the pulsatile group (36%) but the difference was not statistically significant (p = 0.15) because of the small number (n = 23) of participants. In the full study, all GI complications with either device occurred within the first 3 weeks post-implant. In the non-pulsatile patients, there was a higher incidence of GI bleeding, 23% vs 4% (p = 0.002), endoscopies, 24% vs 12% (p = 0.049). More patients with a non-pulsatile flow device had delayed absorption of nasogastric feeds than their pulsatile counterparts, 35% vs 7% (p < 0.0001). Patients with a non-pulsatile flow device had a higher overall rate of gastrointestinal complications than patients had with a pulsatile flow device, 56% vs 20% (p < 0.0001). After correcting for the other predictors, the odds of developing a gastrointestinal complication in the pulsatile group was significantly lower (odds ratio 0.07) than in the non-pulsatile device group (p < 0.0001). CONCLUSIONS: We conclude that the use of non-pulsatile centrifugal VADs compared with pulsatile positive displacement VADs is associated with a higher incidence of both haemorrhagic and ischaemic complications in the gastro-intestinal system especially in the very early post-implant period. Whether these complications could be reduced in centrifugal devices by increasing their pulsatility is not clear and merits further research.

On-Pump Beating Heart Versus Conventional Coronary Artery Bypass Grafting Early After Myocardial Infarction: A Propensity-Score Matched Analysis From the ANZSCTS Database.

BACKGROUND: Coronary artery bypass grafting (CABG) performed early after acute myocardial infarction (AMI) carries a high risk of mortality. By avoiding cardioplegic arrest and aortic cross-clamping, on-pump beating heart CABG (ONBEAT) may benefit patients requiring urgent or emergency revascularisation in the setting of AMI. We evaluated the early and long-term outcomes of ONBEAT versus conventional CABG (ONSTOP) utilising the ANZSCTS National Cardiac Surgery Database. METHODS: Between 2001 and 2015, 5,851 patients underwent non-elective on-pump CABG within 7 days of AMI. Of these, 77 patients (1.3%) underwent ONBEAT and 5774 (98.7%) underwent ONSTOP surgery. Propensity-score matching (with a 1:2 matching ratio) was performed for risk adjustment. Survival data were obtained from the National Death Index. RESULTS: Before matching, the unadjusted 30-day mortality was ONBEAT: 9/77 (11.7%) vs. ONSTOP: 256/5,774 (4.4%), p<0.001. Preoperative factors independently associated with the ONBEAT were: septuagenarian age, peripheral vascular disease, redo surgery, cardiogenic shock, emergency surgery and single-vessel disease. After propensity-score matching, 30-day mortality was similar (ONBEAT: 9/77 (11.7%) vs. ONSTOP: 16/154 (10.4%), p=0.85), as was the rate of major adverse cardiac and cerebrovascular events (ONBEAT: 17/77 (22.1%) vs. ONSTOP: 38/154 (24.7%), p=0.84). ONBEAT patients received fewer distal anastomoses and were more likely to have incomplete revascularisation (ONBEAT: 15/77 (19.5%) vs. ONSTOP: 15/154, (9.7%), p=0.03). Despite this, 12-year survival was comparable (ONBEAT: 64.8% (95% CI 39.4-82.4%) vs. ONSTOP: 63.6% (95% CI 50.5, 74.3%), p=0.89). CONCLUSIONS: ONBEAT can be performed safely in high-risk patients requiring CABG early after AMI with similar short and long-term survival compared to ONSTOP.

Relationships Among Cognitive Function and Cerebral Blood Flow, Oxidative Stress, and Inflammation in Older Heart Failure Patients.

BACKGROUND: The mechanisms for cognitive impairment in heart failure (HF) are unclear. We investigated the relative contributions of cerebral blood flow velocity (BFV), oxidative stress, and inflammation to HF-associated cognitive impairment. METHODS AND RESULTS: Thirty-six HF patients (≥60 years) and 40 healthy controls (68 ± 7 vs 67 ± 5 years, P > .05; 69% vs 50% male, P > .05) completed the Cognitive Drug Research computerized assessment battery and Stroop tasks. Common carotid (CCA) and middle cerebral arterial BFV were obtained by transcranial Doppler. Blood samples were collected for oxidant (diacron-reactive oxygen metabolites; F2-isoprostanes), antioxidant (coenzyme Q10; CoQ10), and inflammatory markers (high-sensitivity C-reactive protein). Compared with controls, patients exhibited impaired attention (Cognitive Drug Research's Power of Attention domain, congruent Stroop) and executive function (incongruent Stroop). Multiple regression modeling showed that CCA-BFV and CoQ10 but not group predicted performance on attention and executive function. Additionally, in HF patients, CCA-BFV and CoQ10 (ß = -0.34 vs ß = -0.35) were significant predictors of attention, and CCA-BFV (ß = -0.34) was a predictor of executive function. CONCLUSIONS: Power of Attention and executive function is impaired in older HF patients, and reduced CCA-BFV and CoQ10 are associated with worse cognition. Interventions addressing these mechanisms may improve cognition in older HF patients.

Anatomy and Physiology of Left Ventricular Suction Induced by Rotary Blood Pumps.

This study in five large greyhound dogs implanted with a VentrAssist left ventricular assist device focused on identification of the precise site and physiological changes induced by or underlying the complication of left ventricular suction. Pressure sensors were placed in left and right atria, proximal and distal left ventricle, and proximal aorta while dual perivascular and tubing ultrasonic flow meters measured blood flow in the aortic root and pump outlet cannula. When suction occurred, end-systolic pressure gradients between proximal and distal regions of the left ventricle on the order of 40-160 mm Hg indicated an occlusive process of variable intensity in the distal ventricle. A variable negative flow difference between end systole and end diastole (0.5-3.4 L/min) was observed. This was presumably mediated by variable apposition of the free and septal walls of the ventricle at the pump inlet cannula orifice which lasted approximately 100 ms. This apposition, by inducing an end-systolic flow deficit, terminated the suction process by relieving the imbalance between pump requirement and delivery from the right ventricle. Immediately preceding this event, however, unnaturally low end-systolic pressures occurred in the left atrium and proximal left ventricle which in four dogs lasted for 80-120 ms. In one dog, however, this collapse progressed to a new level and remained at approximately -5 mm Hg across four heart beats at which point suction was relieved by manual reduction in pump speed. Because these pressures were associated with a pulmonary capillary wedge pressure of -5 mm Hg as well, they indicate total collapse of the entire pulmonary venous system, left atrium, and left ventricle which persisted until pump flow requirement was relieved by reducing pump speed. We suggest that this collapse caused the whole vascular region from pulmonary capillaries to distal left ventricle to behave as a Starling resistance which further reduced right ventricular output thus contributing to a major reduction in pump flow. We contend that similar complications of manual speed control also occur in the human subject and remain a major unsolved problem in the clinical management of patients implanted with rotary blood pumps.

Increased myocardial methionine-enkephalin with reduced arterial oxygenation in congenital heart disease.

BACKGROUND: Cardiac opioid peptides have been identified to exert important adaptive metabolic signalling for cardioprotection against ischaemia or hypoxia-related injury. AIMS: To determine myocardial methionine-enkephalin content in children with hypoxemic congenital heart defects and to correlate myocardial content of methionine-enkephalin with the extent of arterial oxygen desaturation. METHODS: Children (n= 20, median age of 16 months), undergoing cardiac surgical repair (tetralogy of Fallot, 17/20), were included in this study. Arterial oxygen saturation was measured on admission. Myocardial samples obtained during surgery were assayed via radioimmunochemistry for methionine-enkephalin content. RESULTS: Greater methionine-enkephalin content was measured in the right ventricles of the patients suffering from recent cyanotic spells compared with those with no recent spells (cyanotic spells: 2418 ± 844 pg/g wet weight tissue, n= 6; no spells: 1175 ± 189 pg/g wet weight tissue, n= 14, P= 0.04). An inverse correlation was evident between the arterial oxygen saturation and myocardial methionine-enkephalin content. CONCLUSION: Myocardial methionine-enkephalin levels increase with the severity of hypoxic stress in congenital cardiac disease and may play an important adaptive role in countering adrenergic over-activity and related excess demand on myocardial metabolic capacity.

Bacteraemia in ventricular assist devices: a common complication that need not affect clinical outcomes.

BACKGROUND: Ventricular assist device (VAD) implantation has become an effective option for patients with severe heart failure. However, device-related infections remain a significant problem. The aim of this study was to describe the incidence and microbiological aetiology of bacteraemia in patients with VADs, and to assess the impact of bacteraemia on clinical outcomes. METHODS: A retrospective study was conducted of patients having VAD implantation at the Alfred Hospital (Melbourne, Australia) from October 1990 to July 2009. Medical records and microbiology databases were reviewed. Patients who were supported with a VAD for 72h or more were evaluated for demographic data, VAD type, the occurrence of bacteraemia and clinical outcomes. RESULTS: During the 19-year period, 135 VAD patients (89 Thoratec PVAD, 10 Novacor, and 36 Ventrassist) supported for a total duration of 17,304 (median 74) support days were included. Sixty-one patients (45%) developed VAD-associated bacteraemia, an incidence of 5.6 episodes per 1000 support days. The incidence of bacteraemia per 1000 days of support was similar for the three devices used: Thoratec PVAD, Novacor and Ventrassist VADs (7.8±0.8, 5.2±1.5 and 3.4±0.5, respectively, p=0.74). Staphylococcus aureus was the most common pathogen (25%). The rates of death on device, survival to transplant, recovery with explant and outcomes after transplantation, including 30-day mortality, median survival time and incidence of cerebrovascular accidents were not significantly impacted upon by bacteraemia. CONCLUSIONS: Bacteraemia is common in VAD patients. However, the incidence of VAD-associated bacteraemia is independent of device type and with aggressive antimicrobial therapy; clinical outcomes need not be affected by the bacteraemia.

Prophylaxis against atrial fibrillation after cardiac surgery: beneficial effect of perioperative metoprolol.

INTRODUCTION: Multiple agents have been investigated to prevent atrial fibrillation (AF) after cardiac surgery. Several studies have investigated the use of ß-blockers such as metoprolol or amiodarone with promising results. We aimed to investigate perioperative pharmacologic prophylaxis against AF using metoprolol, and amiodarone in combination with metoprolol. METHODS: We conducted a prospective, randomised, single-blind, controlled pilot study in patients undergoing elective cardiac surgery. Subjects were randomised pre-operatively to one of three treatment groups: standard therapy (control) or metoprolol (5 mg IV over 5 min on commencement of bypass then 5 mg IV qid for 24h then 25-50 mg tds orally until discharge) or amiodarone (300 mg over 1h starting shortly after the commencement of bypass, then 900 mg over 24h then 400 mg orally tds until discharge) plus metoprolol as above. Patients had ECG monitoring for the occurrence of AF for six days or until discharge. RESULTS: Two hundred and fifteen patients were enrolled. Between-group differences in AF in an intention-to-treat analysis were not significant: control 34% (23-45%), metoprolol 35% (24-46%), combined 22% (12-33%) (p = 0.21). However 87 patients (40%) did not receive the assigned treatment mainly due to side effects, especially bradycardia. The remaining 128 patients were analysed on a per-protocol basis with the overall difference between the three groups bordering on significance: control 34% (23-45%), metoprolol 26% (9-43%), combined 11% (0-23%) (p = 0.06). Logistic regression analysis, correcting for age and gender, was used to separate the individual effects of metoprolol and amiodarone in the presence of metoprolol which showed that compared to control there was a significant effect of metroprolol on AF incidence (O.R. 0.31 (0.10-0.99), p = 0.048) but not of amiodarone (O.R. 0.97 (0.19-5.02), p = 0.97). CONCLUSIONS: (1) Perioperative metoprolol but not amiodarone itself in combination with metoprolol is associated with a significant reduction in postoperative AF. (2) Perioperative administration of metoprolol and combination of metoprolol with amiodarone is associated with a high incidence of side effects, especially bradycardia. (3) Further studies are indicated to confirm these preliminary findings but in the meantime it would not be unreasonable to implement the use of perioperative metoprolol for routine prophylaxis of AF.

Effect of parameter variations on the hemodynamic response under rotary blood pump assistance.

Numerical models, able to simulate the response of the human cardiovascular system (CVS) in the presence of an implantable rotary blood pump (IRBP), have been widely used as a predictive tool to investigate the interaction between the CVS and the IRBP under various operating conditions. The present study investigates the effect of alterations in the model parameter values, that is, cardiac contractility, systemic vascular resistance, and total blood volume on the efficiency of rotary pump assistance, using an optimized dynamic heart-pump interaction model previously developed in our laboratory based on animal experimental measurements obtained from five canines. The effect of mean pump speed and the circulatory perturbations on left and right ventricular pressure volume loops, mean aortic pressure, mean cardiac output, pump assistance ratio, and pump flow pulsatility from both the greyhound experiments and model simulations are demonstrated. Furthermore, the applicability of some of the previously proposed control parameters, that is, pulsatility index (PI), gradient of PI with respect to pump speed, pump differential pressure, and aortic pressure are discussed based on our observations from experimental and simulation results. It was found that previously proposed control strategies were not able to perform well under highly varying circulatory conditions. Among these, control algorithms which rely on the left ventricular filling pressure appear to be the most robust as they emulate the Frank-Starling mechanism of the heart.

Numerical optimization studies of cardiovascular-rotary blood pump interaction.

A heart-pump interaction model has been developed based on animal experimental measurements obtained with a rotary blood pump in situ. Five canine experiments were performed to investigate the interaction between the cardiovascular system and the implantable rotary blood pump over a wide range of operating conditions, including variations in cardiac contractility and heart rate, systemic vascular resistance (SVR), and total blood volume (V(total) ). It was observed in our experiments that SVR decreased with increasing mean pump speed under the healthy condition, but was relatively constant during the speed ramp study under reduced cardiac contractility conditions. Furthermore, we also found a significant increase in pulmonary vascular resistance with increasing mean pump speed and decreasing total blood volume, despite a relatively constant SVR. Least squares parameter estimation methods were utilized to fit a subset of model parameters in order to achieve better agreement with the experimental data and to evaluate the robustness and validity of the model under various operating conditions. The fitted model produced reasonable agreement with the experimental measurements, both in terms of mean values and steady-state waveforms. In addition, all the optimized parameters were within physiological limits.

Coronary artery bypass surgery provides long-term results superior to percutaneous coronary intervention.

Traditionally, patients presenting with symptoms of coronary artery disease (CAD) were managed medically. If medical treatment proved unsuccessful, patients were referred for coronary artery bypass surgery (CABG). However, in recent years, increasing numbers of patients have received percutaneous coronary intervention (PCI), usually a coronary stent, for primary treatment. PCI is attractive because it is minimally invasive, has proven success in the immediate treatment of acute myocardial infarction and is well-accepted for poor surgical candidates in selected cases. However, evidence from emerging and ongoing clinical trials and registries suggests that compared to PCI, CABG offers superior long-term prognostic benefits in many, if not most, patients with significant CAD. We present an analysis of recent evidence showing that patients with complex atherosclerotic lesions, multivessel disease, left main stem disease, left ventricular dysfunction and diabetes mellitus derive more benefit from surgical revascularisation than from PCI. We conclude that PCI should be restricted to patient groups where superiority or equivalence to CABG has been demonstrated and that the decision-making process in allocating treatment should be made by a multidisciplinary team to ensure that every patient receives balanced advice and therapy that is most effective in the long term.

Quantifying recirculation in extracorporeal membrane oxygenation: a new technique validated.

RATIONALE: The efficacy of veno-venous extracorporeal membrane oxygenation is limited by the phenomenon of recirculation, which is difficult to quantify. Existing measurement techniques using readily available equipment are unsatisfactory. OBJECTIVES: 1) To compare the accuracy of measurements of recirculation made using equations comparing blood oxygen content or saturation alone at different points in an ex vivo circuit; 2) to validate a new step-change technique for quantifying recirculation in vivo. METHODS: anesthetized greyhound dogs cannulated for veno-arterial support were connected to a circuit that allowed the creation of a known level of recirculation ex vivo and blood oxygen content/saturation monitoring. In two dogs, the accuracy of measurements derived from oxygen content and oxygen saturation were compared. The potential of a new technique for measuring recirculation in vivo by comparing the oxygen content of blood sampled during oxygenator bypass to that following a step-change in circuit oxygenation was demonstrated in a veno-venous pilot study and validated in a three-dog veno-arterial study. RESULTS: Measurements made using oxygen content versus oxygen saturation showed superior correlation with true recirculation (r(2)=0.87 vs. 0.64, p<0.0001) and less proportional measurement bias (10.3% vs. 49.8%, p=0.0045). Measurements of recirculation made using a step-change in circuit oxygenation and comparing oxygen content as is required for measuring in vivo recirculation overestimated by only 18.6% (95% Cl: 3.9-33.2%) and had excellent correlation with true values (r(2)=0.89). CONCLUSIONS: 1) Measurement of recirculation using oxygen content is superior to that using oxygen saturation alone, which demonstrates significant measurement bias; 2) the novel step-change technique is a sufficiently accurate technique for the measurement of recirculation in animal models.

p38 Mitogen-activated protein kinase inhibition reduces inflammatory cytokines in a brain-dead transplant donor animal model.

UNLABELLED: The aim of this study was to determine the degree of p38 mitogen-activated protein kinase (p38 MAPK) activation in rat heart and lungs after experimentally induced brain death and to test whether SD-282, a synthetic and selective small molecule inhibitor of p38 MAPK, abrogates p38 MAPK activation invoked by this brain death model. METHODS: Adult male Sprague Dawley rats were treated with vehicle (control, n=7) or SD-282 (40mg/kg, n=6), for 15min prior to the induction of brain death and maintained with ventilatory support for 3h. IL-6 and TNFalpha were measured in plasma, heart and lungs using ELISA, and p38 MAPK via Western blot assay. RESULTS: p38 MAPK inhibition was demonstrated by lower p38 MAPK activity in lungs from SD-282-treated donors compared to control (Median [inter-quartile range]: 13.6[4.0-19.0]% vs 20.2[14.7-31.5]% activity, p=0.06). Although levels varied, significant inhibition of p38 MAPK by SD-282 was not observed in the heart. SD-282 significantly lowered IL-6 and TNFalpha values compared to control in plasma (64[51-81]pg/ml vs 352[200-755]pg/ml, p=0.003 and 4.3[1.5-9.0]pg/ml vs 21.1[10.5-31.5]pg/ml, p=0.015, respectively) and lungs (0.14[0.12-0.62] vs 5.8[3.6-6.0]pg/mg protein, p=0.03 and 0.41[0.33-0.45] vs 2.1[1.4-2.7]pg/mg protein, p=0.0027, respectively), however SD-282 did not significantly affect cardiac cytokine levels. CONCLUSIONS: p38 MAPK inhibition with SD-282 decreases the pro-inflammatory response as represented by lower IL-6 and TNFalpha in plasma and lungs following brain death. However, although in heart this response was variable, no significant effect could be demonstrated under the present conditions.

Targeting oxidative stress in surgery: effects of ageing and therapy.

In the current era cardiac surgeons are being called upon to operate upon older, sicker patients. The effect is to augment oxidative stress and increase the rate of post-operative complications and ultimately mortality. We have developed antioxidant-based pre-treatment regimes initially based on coenzyme Q(10). A randomised trial of coenzyme Q(10) in elective cardiac surgery patients demonstrated augmented plasma and cardiac mitochondrial membrane coenzyme Q(10) content, improved mitochondrial respiration and increased myocardial tolerance of oxidative stress. The addition of omega-3 polyunsaturated fatty acids, alpha-lipoic acid, selenium and magnesium orotate in a second clinical trial, improved post-operative recovery with demonstrable reductions in myocardial damage, rate of atrial fibrillation and length of hospital stay. Finally we performed a pilot study of this combined metabolic therapy regimen to which we added preoperative physical exercise and mental stress reduction with indications of further improvements in post-operative recovery. We conclude that simultaneously targeting a number of key deficiencies with a metabolic formulation prior to surgery results in peri- and post-operative clinical and economic benefits.

Correction of posteromedial papillary muscle displacement in repair of ischemic mitral regurgitation.

BACKGROUND AND AIM OF THE STUDY: Ischemic mitral regurgitation is present in a substantial proportion of patients presenting for coronary revascularization. Although patients with even mild to moderate ischemic mitral regurgitation (IMR) have a poorer long-term outcome, mitral valve repair in these cases can be unreliable due to the posterior leaflet tethering that commonly occurs. The aim of this animal-based study was to evaluate a novel technique to effect such a repair. METHODS: IMR was produced in six greyhound dogs by tying off the circumflex coronary artery; a mitral valve repair was then performed on cardiopulmonary bypass (CPB). Two hitching sutures from the posteromedial papillary muscle (PPM) to the annulus were individually assessed using epicardial echocardiography when the dogs had been weaned off CPB. RESULTS: Acute dilatation of the heart with PPM displacement and mitral regurgitation were produced in this acute infarct model. Both hitching sutures shortened the distance from the free edge of the posterior leaflet to the PPM tip and reduced its displacement, with a resultant reduction in mitral regurgitation. CONCLUSION: This simple repair technique may be a useful adjunct to annuloplasty in the treatment of ischemic mitral regurgitation.

The publication rate and impact of abstracts presented at the Cardiac Society of Australia and New Zealand (1999-2005).

AIMS: As there is no current information regarding the fate of abstracts presented at annual scientific meetings of the Cardiac Society of Australia and New Zealand (CSANZ), we examined the publication rate and indexed impact of original articles arising from these abstracts. METHODS: Conference abstracts from 1999 to 2005 were evaluated as these were accessible in electronic file form. Searches were conducted for abstract authors and keywords were searched for in journal publication citations (to November 30, 2007) in the National Library of Medicine (NIH, USA) PubMed database. A match of abstract to retrieve full article was identified on the basis of authorship, similarities in titles and study design. The ISI Web of Knowledge citation database (Philadelphia, USA) was accessed for Journal Citation Reports impact factors (IF). RESULTS: A total of 2172 abstract presentations resulted in 648 original publications (30%, mean IF = 4.4). Most publications were published within 1 (61%) or 2 years (84%), with a mean lag of 1.5 years. The proportions of abstract presentations represented by Clinical, Basic Science and Surgical categories were 70.6%, 26.9%, and 2.5%, respectively. Subsequent publication rates (and IF) arising from within these categories were 25.8% (IF = 4.8), 34.4% (IF = 5.1) and 97.9% (IF = 3.1), respectively. CONCLUSIONS: (1) Almost a third of CSANZ abstract presentations result in publication of an original article. (2) Most are published within 1-2 years. (3) The average IF is mid-range, with 32% of publications having an IF above 4.4. Despite the limitations to publication faced by CSANZ members, a high quality and timely publication rate is nonetheless evident.

Coenzyme Q10 in cardiovascular disease.

In this review we summarise the current state of knowledge of the therapeutic efficacy and mechanisms of action of CoQ(10) in cardiovascular disease. Our conclusions are: 1. There is promising evidence of a beneficial effect of CoQ(10) when given alone or in addition to standard therapies in hypertension and in heart failure, but less extensive evidence in ischemic heart disease. 2. Large scale multi-centre prospective randomised trials are indicated in all these areas but there are difficulties in funding such trials. 3. Presently, due to the notable absence of clinically significant side effects and likely therapeutic benefit, CoQ(10) can be considered a safe adjunct to standard therapies in cardiovascular disease.

Augmented myocardial methionine-enkephalin in a murine model of cardiac angiotensin II-overexpression.

INTRODUCTION: The endogenous opioid system has been reported to interact with both the cardiac sympathetic and renin-angiotensin systems in exerting a local regulatory action on the heart. The goal of this investigation was to examine how cardiac levels of enkephalin production are altered in the development of normotensive primary hypertrophy due to elevated intra-cardiac angiotensin II (Ang II) production. METHODS: Atrial and ventricular methionine-enkephalin (ME) levels were measured by quantitative radioimmunoassay in 14 and 28-week-old male transgenic mice (TG1306/1R) and control mice. The TG1306/1R exhibit cardiac specific Ang II overexpression and cardiac hypertrophy, but not hypertension. RESULTS: TG1306/1R mice had significantly higher heart/body weight ratios (15-20%) than control littermates at both 14 (p=0.02) and 28 weeks (p=0.04). Relative to controls, ME content was significantly elevated (approximately two-fold) in atria and ventricles in the older 28-week TG1306/1R mice only. A significant inverse correlation between heart size and ME level was observed for 28-week TG1306/1R only. CONCLUSIONS: We have provided evidence that a marked elevation of myocardial enkephalin level is observed in the established (but not early) phase of cardiac hypertrophy associated with cardiac-specific Ang II-overexpression. This study identifies a potentially important relationship between two endogenous peptidergic signalling systems involved in the regulation of growth and function of the hypertrophic heart.

Precise determination of mitochondrial DNA copy number in human skeletal and cardiac muscle by a PCR-based assay: lack of change of copy number with age.

Deletions in mitochondrial DNA (mtDNA) accumulate with age in humans without overt mitochondriopathies, but relatively limited attention has been devoted to the measurement of the total number of mtDNA molecules per cell during ageing. We have developed a precise assay that determines mtDNA levels relative to nuclear DNA using a PCR-based procedure. Quantification was performed by reference to a single recombinant plasmid standard containing a copy of each target DNA sequence (mitochondrial and nuclear). Copy number of mtDNA was determined by amplifying a short region of the cytochrome b gene (although other regions of mtDNA were demonstrably useful). Nuclear DNA content was determined by amplification of a segment of the single copy beta-globin gene. The copy number of mtDNA per diploid nuclear genome in myocardium was 6970 +/- 920, significantly higher than that in skeletal muscle, 3650 +/- 620 (P = 0.006). In both human skeletal muscle and myocardium, there was no significant change in mtDNA copy number with age (from neonates to subjects older than 80 years). This PCR-based assay not only enables accurate determination of mtDNA relative to nuclear DNA but also has the potential to quantify accurately any DNA sequence in relation to any other.

Cold Crystalloid Perfusion Provides Cardiac Preservation Superior to Cold Storage for Donation After Circulatory Death.

BACKGROUND: We previously showed that donation after circulatory death (DCD) canine hearts can be resuscitated if perfused with warm blood. However, clinical application of this technique is complex and difficult. We have developed a simplified system of cold crystalloid perfusion and compared it with standard cold storage for DCD heart preservation. METHODS: Anesthetized greyhounds underwent 30 minutes DCD by withdrawal of ventilation followed by assignment to either 4 hours of perfusion (n = 6) or cold storage (n = 7). Nonpreserved hearts (n = 5) served as a normal reference group. Perfusion hearts were reperfused with a protective solution then perfused for 4 hours with a novel oxygenated, nutrient-containing solution at 20 mL/min at 4°C to 10°C. Cold storage hearts were flushed with St Thomas' cardioplegic solution and stored in ice. After preservation, the recovery of the hearts was assessed on a blood-perfused working heart rig. RESULTS: During preservation, perfusion hearts consumed oxygen (0.09 ± 0.01 mL/100 g per minute) and showed decreasing lactate production in the perfusate (initial: 0.031 ± 0.004 vs final: 0.007 ± 0.002 mmol/min; P = 0.001). After preservation, compared to cold storage hearts, perfusion hearts had higher cardiac output (P = 0.004), LV dP/dt max (P = 0.003) and myocardial oxygen efficiency (P = 0.01), with lower blood perfusate lactate (P = 0.007). Hemodynamic values of perfused hearts reached 60% or more those in the normal reference group. CONCLUSIONS: Continuous cold crystalloid perfusion in a canine model of DCD: (1) facilitates aerobic metabolism and resuscitates the DCD heart, (2) provides functional and metabolic recovery superior to cold storage, (3) shows promise for improved clinical preservation of DCD and marginal donor hearts.

First clinical implant of the VentrAssist left ventricular assist system as destination therapy for end-stage heart failure.

The VentrAssist device left ventricular assist system, designed for permanent implantation, is a novel centrifugal pump with a hydrodynamically suspended rotor. The first human implant was into a 72-year-old man with New York Heart Association (NYHA) class IV heart failure due to idiopathic dilated cardiomyopathy. The implant and recovery were uneventful, and the patient survives at 17 months, is NYHA class II, and lives at home. This device shows promise in end-stage heart failure for permanent implantation and bridge to transplantation.