DHA Supplementation Attenuates MI-Induced LV Matrix Remodeling and Dysfunction in Mice.

OBJECTIVE: Myocardial ischemia and reperfusion (I/R) injury is associated with oxidative stress and inflammation, leading to scar development and malfunction. The marine omega-3 fatty acids (ω-3 FA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) are mediating cardioprotection and improving clinical outcomes in patients with heart disease. Therefore, we tested the hypothesis that docosahexaenoic acid (DHA) supplementation prior to LAD occlusion-induced myocardial injury (MI) confers cardioprotection in mice. METHODS: C57BL/6N mice were placed on DHA or control diets (CD) beginning 7 d prior to 60 min LAD occlusion-induced MI or sham surgery. The expression of inflammatory mediators was measured via RT-qPCR. Besides FACS analysis for macrophage quantification and subtype evaluation, macrophage accumulation as well as collagen deposition was quantified in histological sections. Cardiac function was assessed using a pressure-volume catheter for up to 14 d. RESULTS: DHA supplementation significantly attenuated the induction of peroxisome proliferator-activated receptor-α (PPAR-α) (2.3 ± 0.4 CD vs. 1.4 ± 0.3 DHA) after LAD occlusion. Furthermore, TNF-α (4.0 ± 0.6 CD vs. 1.5 ± 0.2 DHA), IL-1ß (60.7 ± 7.0 CD vs. 11.6 ± 1.9 DHA), and IL-10 (223.8 ± 62.1 CD vs. 135.5 ± 38.5 DHA) mRNA expression increase was diminished in DHA-supplemented mice after 72 h reperfusion. These changes were accompanied by a less prominent switch in α/ß myosin heavy chain isoforms. Chemokine mRNA expression was stronger initiated (CCL2 6 h: 32.8 ± 11.5 CD vs. 78.8 ± 13.6 DHA) but terminated earlier (CCL2 72 h: 39.5 ± 7.8 CD vs. 8.2 ± 1.9 DHA; CCL3 72 h: 794.3 ± 270.9 CD vs. 258.2 ± 57.8 DHA) in DHA supplementation compared to CD mice after LAD occlusion. Correspondingly, DHA supplementation was associated with a stronger increase of predominantly alternatively activated Ly6C-positive macrophage phenotype, being associated with less collagen deposition and better LV function (EF 14 d: 17.6 ± 2.6 CD vs. 31.4 ± 1.5 DHA). CONCLUSION: Our data indicate that DHA supplementation mediates cardioprotection from MI via modulation of the inflammatory response with timely and attenuated remodeling. DHA seems to attenuate MI-induced cardiomyocyte injury partly by transient PPAR-α downregulation, diminishing the need for antioxidant mechanisms including mitochondrial function, or α- to ß-MHC isoform switch.

3D motion adapted gating (3D MAG): a new navigator technique for accelerated acquisition of free breathing navigator gated 3D coronary MR-angiography.

This study aimed to evaluate the influence of a new navigator technique (3D MAG) on navigator efficiency, total acquisition time, image quality and diagnostic accuracy. Fifty-six patients with suspected coronary artery disease underwent free breathing navigator gated coronary MRA (Intera, Philips Medical Systems, 1.5 T, spatial resolution 0.9x0.9x3 mm3) with and without 3D MAG. Evaluation of both sequences included: 1) navigator scan efficiency, 2) total acquisition time, 3) assessment of image quality and 4) detection of stenoses >50%. Average navigator efficiencies of the LCA and RCA were 43+/-12% and 42+/-12% with and 36+/-16% and 35+/-16% without 3D MAG (P<0.01). Scan time was reduced from 12 min 7 s without to 8 min 55 s with 3D MAG for the LCA and from 12 min 19 s to 9 min 7 s with 3D MAG for the RCA (P<0.01). The average scores of image quality of the coronary MRAs with and without 3D MAG were 3.5+/-0.79 and 3.46+/-0.84 (P>0.05). There was no significant difference in the sensitivity and specificity in the detection of coronary artery stenoses between coronary MRAs with and without 3D MAG (P>0.05). 3D MAG provides accelerated acquisition of navigator gated coronary MRA by about 19% while maintaining image quality and diagnostic accuracy.

A murine model of ischemic cardiomyopathy induced by repetitive ischemia and reperfusion.

BACKGROUND: Repetitive brief myocardial ischemia has been implicated in the pathogenesis of the ventricular dysfunction associated with ischemic cardiomyopathy and myocardial hibernation. In this study we examine the effects of repetitive ischemia and reperfusion (I/R) on murine myocardium. METHODS: C57/BL6 mice underwent daily 15 min left anterior descending coronary occlusions followed by reperfusion. After 3, 5, 7, 14, 21 and 28 days, echocardiographic studies were performed, and hearts of I/R and sham-operated animals were processed for histological examination. RESULTS: Histological studies showed no evidence of myocardial necrosis in the ischemic region. Quantitative assessment of collagen revealed a marked persistent interstitial deposition of collagen after seven days I/R in the anterior left ventricular wall (sham 4.6 +/- 2.0 %, I/R 21.5 +/- 6.5 %, p < 0.05). Echocardiographic studies showed persistent regional anterior wall dysfunction in I/R animals. Histological evaluation showed absence of neovessel formation. After discontinuation of the I/R protocol, fibrosis and regional ventricular dysfunction decreased within 60 days. CONCLUSIONS: Repetitive brief murine myocardial I/R induces reversible fibrotic remodeling and ventricular dysfunction, without myocardial infarction and necrosis, and may play a role in the pathogenesis of ischemic cardiomyopathy and myocardial hibernation.

Brief murine myocardial I/R induces chemokines in a TNF-alpha-independent manner: role of oxygen radicals.

Early chemokine induction in the area at risk of an ischemic-reperfused (I/R) myocardium is first seen in the venular endothelium. Reperfusion is associated with several induction mechanisms including increased extracellular tumor necrosis factor (TNF)-alpha, reactive oxygen intermediate (ROI) species formation, and adhesion of leukocytes to the venular endothelium. To test the hypothesis that chemokine induction in cardiac venules can occur by ROIs in a TNF-alpha-independent manner, and in the absence of leukocyte accumulation, we utilized wild-type (WT) and TNF-alpha double-receptor knockout mice (DKO) in a closed-chest mouse model of myocardial ischemia (15 min) and reperfusion (3 h), in which there is no infarction. We demonstrate that a single brief period of I/R induces significant upregulation of the chemokines macrophage inflammatory protein (MIP) -1 alpha, -1 beta, and -2 at both the mRNA and protein levels. This induction was independent of TNF-alpha, whereas levels of these chemokines were increased in both WT and DKO mice. Chemokine induction was seen predominantly in the endothelium of small veins and was accompanied by nuclear translocation of nuclear factor-kappa B and c-Jun (AP-1) in venular endothelium. Intravenous infusion of the oxygen radical scavenger N-2-mercaptopropionyl glycine (MPG) initiated 15 min before ischemia and maintained throughout reperfusion obviated chemokine induction, but MPG administration after reperfusion had begun had no effect. The results suggest that ROI generation in the reperfused myocardium rapidly induces C-C and C-X-C chemokines in the venular endothelium in the absence of infarction or irreversible cellular injury.

Switch from a BIVAD to a LVAD in a boy with Kawasaki disease.

A 9-year-old boy with Kawasaki disease survived after two severe myocardial infarctions. Thereafter pharmacologically untreatable ventricular arrhythmia and rapidly deteriorating heart failure developed in the patient. After 19 days of biventricular and a further 27 days of left univentricular mechanical circulatory support with the Berlin Heart (Cardiotechnica, Berlin, Germany) assist device the boy successfully underwent heart transplantation. At a follow-up of 54 months, the boy is leading an active and unrestricted life.

Replacement of the valves of a Novacor LVAS without cardiopulmonary bypass.

We report the case of a 54-year old man with end-stage heart disease in whom the malfunctioning valves of a Novacor LVAS needed to be replaced after 490 days of circulatory support. This procedure could be performed without cardiopulmonary bypass.

Reproducibility of double indicator dilution measurements of intrathoracic blood volume compartments, extravascular lung water, and liver function.

STUDY OBJECTIVE: Arterial thermal dye dilution (TDDart) with the COLD system (Munich, Germany) allows measurement of cardiac index (CI), partial blood volumes, lung water, and liver function. The aim of the study was to determine agreement of TDDart measurements with pulmonary artery thermal dilution measurements (TDpa) and to assess the reproducibility of TDDart parameters. DESIGN: Prospective study. SETTING: ICU of a university hospital department of cardiac surgery. PATIENTS: Thirty consecutive patients after coronary artery bypass grafting. MEASUREMENTS AND RESULTS: Triplicate measurements of TDDart parameters were performed 1, 3, 6, 12, and 24 h postoperatively and coefficients of variation (CVs) were computed. At the 3-h point, additional fivefold TDDart measurements were done and compared with TDpa measurements. The coefficient of correlation for CI from TDDart vs TDpa was 0.96 (p<0.001), and the mean difference was 0.16 L/min/m2 (2.4%). The CVs of the TDDart and TDpa CI measurement were 7.2% and 5.9%; the CVs of other TDDart parameters were 4.6% (cardiac function index), 8.3% (global end-diastolic volume), 7.0% (intrathoracic blood volume), 7.6% (total blood volume), 7.4% (right ventricular end-diastolic volume), 7.4% (right heart end-diastolic volume), 11.3% (left heart end-diastolic volume [LHEDV]), 12.0% (right to left heart volume proportion [R/LHV]), 8.8% (pulmonary blood volume), 10.8% (extravascular lung water), 16.4% (plasma disappearance rate of dye), and 19.8% (dye clearance). The CV did not depend on Glasgow coma scale or on body temperature. CONCLUSION: The CVs of LHEDV and R/LHV are influenced by asynchronous TDDart and TDpa variation. The CVs of plasma disappearance and dye clearance are increased as the half-life of the dye is longer than the measurement sequence. All other parameters derived from TDDart and TDpa show a clinically sufficient reproducibility.

Platelet morphology in patients with mechanical circulatory support.

OBJECTIVE: Mechanical circulatory support is a therapy for patients with end stage cardiac insufficiency. The thromboembolic events are feared complications during support, due to the surface thrombogenicity of the implanted device. Activated blood platelets play a major role in this context. Consequently the platelet morphology of patients was investigated. METHODS: Platelets of eight patients were observed by means of scanning electron microscopy during the period of support with the Novacor left ventricular assist system N100. Blood was collected preoperatively and daily during the first week as well as weekly during the first 3 months. Samples were fixed with cacodylic-acid buffered glutaraldehyde. Platelet alterations were classified as non-activated, activated and aggregated, based on the so-called 'shape change' morphology. In addition, blood coagulation parameters were evaluated (e.g. activated partial thromboplastin time, prothrombin time, antithrombin III). RESULTS: Preoperatively, 15.0 +/- 4.6% (overall mean values) of activated platelets were found. Within the first postoperative week, the mean level of activated platelets increased to 32.8 +/- 8.0% (P < 0.05). Comparing short- (< 30 days; n = 4) vs. long-period (> 30 days; n = 4) support, a significant difference of activated platelets was evaluated (24.3 +/- 3.3% vs. 34.8 +/- 3.4%, P = 0.004). A correlation was found between the values of activated clotting time and activated platelets. Specific platelet deformations and damages appeared during support, which could not be found preoperatively. CONCLUSIONS: The platelet morphology showed alterations in all patients probably most strongly induced by the surface activation of the implanted device. These observations should be taken into consideration in management of postoperative anticoagulation therapy.

Long-term results of total repair of tetralogy of Fallot in adulthood: 35 years follow-up in 104 patients corrected at the age of 18 or older.

Long-term survival after surgical repair of tetralogy of Fallot (TOF) is reported to be excellent if the patients are corrected in childhood. However, age at operation has been demonstrated as an important risk-factor. The aim of our study was to investigate whether adult patients also benefit from surgery. From December 1958 to May 1977, 739 patients underwent a correction of their TOF with pulmonary stenosis at our institution. Foreigners (n = 52) and those who moved to a foreign country (n = 13) were excluded from further analysis. Sixteen patients were lost during follow-up (98% complete). Of the remaining patient population (n = 658; mean age: 12.2 +/- 8.6 years; range 2-67 years), 104 patients were 18 years or older at the time of correction. Operative (n = 25) and one-year (n = 8) deaths were excluded for long-term calculations, resulting in a study group of 71 patients. Actuarial 10, 20, 30, and 35-year survival rates were 94%, 93%, 83%, and 72% respectively, and not different from normal life expectancy. The most common cause of death was congestive heart failure (n = 3), followed by myocardial infarction (n = 2) and sudden death (n = 2). Parameters influencing longterm survival could not be detected. At follow-up (mean 27.7 years), more than 80% (n = 48) of the 58 survivors reported themselves to be in NYHA functional class I or II and 95% (n = 55) were in a better condition than before the operation. Repair of tetralogy of Fallot in adulthood shows excellent results with normal life expectancy for the patients.

Improvement of heart-, lung-, and liver-performance during mechanical circulatory support by the Novacor-system.

OBJECTIVE: Since its clinical introduction, the Novacor left ventricular assist system (LVAS) has proved to be a reliable and safe method for bridging to cardiac transplantation. To find out whether univentricular assistance is sufficient in patients with severe global heart failure, multi organ monitoring using the COLD system was performed. METHODS: In seven patients (mean age 38.8 years), the wearable Novacor system N100 was implanted. Preoperatively, during the first 72 h thereafter and before heart transplantation right and left ventricular cardiac output, right ventricular ejection fraction, pulmonary-, intrathoracic-and total blood volume, extravascular lung water and excretory liver function were monitored by means of double indicator dilution technique with the COLD system. Conventional hemodynamic parameters have also been documented. RESULTS: During left ventricular assistance, both pulmonary and systemic arterial cardiac outputs increased significantly (Student's t-test, P < 0.05). Right ventricular ejection fraction rose from 17 to 26%, preoperatively elevated pulmonary and intrathoracic blood volumes and extravascular lung water fell significantly to normal ranges. Total blood volume remained constant, excretory liver function improved markedly. CONCLUSIONS: Pulmonary cardiac output improves due to the reduced right ventricular afterload by unloading the impaired left ventricle with the Novacor pump. The drop in pulmonary blood volume, intrathoracic blood volume and extravascular lung water also indicates a decrease of pulmonary congestion. Since total blood volume remains unchanged, a volume shift to the systemic circulation is suggested, resulting in an improved splanchnic perfusion as demonstrated by a better excretory liver function. In the absence of primary pulmonary hypertension, treatment of global heart failure with a left ventricular assist device is possible. The COLD system is a useful tool for managing this patient group during the postoperative period.

[On-site laboratory monitoring on the intensive care unit. Blood gas, electrolyte, glucose, hemoglobin and lactate determination with the CIBA Corning 865 Analysis System]. / Stationsbezogenes Labor-Monitoring auf der Intensivstation. Blutgas-, Elektrolyt-, Glucose-, Hämoglobin- und Lactat-Bestimmungen mit dem CIBA-Corning 865 Analyse-System.

INTRODUCTION: For decision-making in the ICU, rapid and accurate analysis of vital laboratory parameters is essential. The industry provides devices which analyse these parameters on a decentralised setting and which are designed for use by non-laboratory personnel. We investigated whether accuracy and handling of a new analyser (Ciba-Corning 865, Chiron Diagnostics, Medfield, USA) are good enough for basing clinical decisions on the measured parameters. MATERIALS AND METHODS: The Ciba-Corning 865 allows measurement of blood gases, electrolytes, haemoglobin, glucose and lactate by use of photometric, ion-selective, enzymatic and electrochemical sensors in less than 18 microliters of whole blood. In a cardiac surgical intensive-care unit the accuracy of the device was tested by comparison to 61 measurements of quality control reagents, 48 tonometered blood samples and 536 parallel measurements in the clinical laboratory. Besides a 10-minute instruction, the participating personnel had no formal training with the device. RESULTS: The differences between measurements in quality control reagents and tonometered blood and the expected value were lower than 5%. The comparison with clinical laboratory measurements showed correlation coefficients from 0.94 (sodium) to 0.99 (glucose, lactate). The biases in Bland-Altman analyses were below 5%, the limits of agreement were found to be in a clinically acceptable range for all parameters. During the test period no technical problems occurred with the analyser and good acceptance by the personnel was found. CONCLUSIONS: The measured parameters were accurate enough to be used for therapeutic decisions in acute care medicine. Although it should not be a complete alternative to the clinical laboratory, because of rapid analyses, small sample volumes and easy handling the use of the Ciba-Corning 865 is advantageous for patients and users.

Experience with the Novacor left ventricular assist system as a bridge to cardiac transplantation, including the new wearable system.

The three components of the Novacor left ventricular assist system, compact controller, battery, and back-up battery, have been miniaturized in the development of the wearable system. Therefore patients can be fully mobilized receiving mechanical circulatory support while awaiting heart transplantation. Between February 1992 and April 1994 a total of eight patients with decompensated heart failure (6 dilated cardiomyopathy, 1 acute myocarditis, 1 ischemic cardiomyopathy) were treated with the Novacor left ventricular assist systems. In the most recent four cases the wearable system (N100P) was used. Patients' ages ranged from 17 to 49 years. In five patients severe failure of the right side of the heart was present at the time of implantation. Hemodynamic stabilization was achieved in all patients during the 2 to 122 days (mean 30.8 +/- 42.5 days) of support. The following parameters were measured on average before and 24 hours after implantation of the left ventricular assist system: mean arterial pressure 70 +/- 11 versus 87 +/- 13 mm Hg (p < 0.05), cardiac index 1.71 +/- 0.42 versus 3.23 +/- 0.74 L/min/m2 (p < 0.05), pulmonary capillary wedge pressure 27.1 +/- 4.4 versus 9.9 +/- 5.2 mm Hg (p < 0.01), mean pulmonary pressure 41 +/- 9 versus 27 +/- 6 mm Hg (p < 0.05), and right ventricular ejection fraction 16.7% +/- 10.3% versus 22.0% +/- 11.6% (not significant). Patients who received the wearable system were capable of managing their own power supply during the bridging period and were able to walk to the hospital park and shopping area. One patient had a serious pulmonary infection, which was treated successfully, and two patients had a cerebrovascular accident, which resolved in one and resulted in a minor residual deficit in the other. All eight patients received a heart transplant. One patient died early after transplantation and seven patients are alive and well. In summary, the wearable Novacor left ventricular assist system provides major advantages regarding quality of life of patients during mechanical circulatory support. However, there is a remaining risk of thromboembolism despite anticoagulation therapy.