Stig Eggen Hermansen

Vasopressin impairs brain, heart and kidney perfusion: an experimental study in pigs after transient myocardial ischemia.

IntroductionArginine vasopressin (AVP) is increasingly used to restore mean arterial pressure (MAP) in low-pressure shock states unresponsive to conventional inotropes. This is potentially deleterious since AVP is also known to reduce cardiac output by increasing vascular resistance. The effects of AVP on blood flow to vital organs and cardiac performance in a circulation altered by cardiac ischemia are still not sufficiently clarified. We hypothesised that restoring MAP by low dose, therapeutic level AVP would reduce vital organ blood flow in a setting of experimental acute left ventricular dysfunction.MethodsCardiac output (CO) and arterial blood flow to the brain, heart, kidney and liver were measured in nine pigs using transit-time flow probes. Left ventricular pressure-volume catheter and central arterial and venous catheters were used for haemodynamic recordings and blood sampling. Transient left ventricular ischemia was induced by intermittent left coronary occlusions resulting in a 17% reduction in cardiac output and a drop in MAP from 87 ± 3 to 67 ± 4 mmHg (p < 0.001). A low-dose therapeutic level of AVP (0.005 U/kg/min) was used to restore MAP to pre-ischemic values (93 ± 4 mmHg).ResultsAVP further impaired systemic perfusion (CO and brain, heart and kidney blood flow reduced by 29, 18, 23 and 34%, respectively) due to a 2.0-, 2.2-, 1.9- and 2.1-fold increase in systemic, brain, heart and kidney specific vascular resistances. The hypoperfusion induced by AVP was associated with an increased systemic oxygen extraction. Oxygen saturation in blood drawn from the great cardiac vein fell from 29 ± 1 to 21 ± 3% (p = 0.01). Finally, these effects were reversed 40 min after AVP was withdrawn.ConclusionLow dose AVP induced a pronounced reduction in vital organ blood flow in pigs after transient cardiac ischemia. This indicates a potentially deleterious effect of AVP in patients with heart failure or cardiogenic shock due to impaired coronary perfusion.

Shear stress regulates inflammatory and thrombogenic gene transcripts in cultured human endothelial progenitor cells

Shear stress has an established effect on mature endothelial cells, but less is known about how shear stress regulates endothelial progenitor cells (EPCs). In vitro expanded EPCs isolated from adult human blood represent a novel tool in regenerative vessel therapy. However, in vitro culturing may generate cells with unfavourable properties. The aim of the present study was therefore to assess whether shear stress may influence the inflammatory and thrombotic phenotype of in vitro expanded EPCs. In late outgrowth EPCs, 6 hours of shear stress (6.0 dynes/cm2) significantly reduced the mRNA levels of IL-8, COX2, and tissue factor (TF) compared to static controls. This was associated with a reduced TF activity. In contrast, mRNA expression of NOS3 was significantly increased following 6 and 24 hours of shear stress. In accordance with this, NOS3 protein expression was increased following 24 hours of shear stress. Overall stimulation with the proinflammatory mediator, TNFalpha, for the final 2 hours increased the mRNA expression of IL-6, IL-8, MCP-1, ICAM1, and TF. However exposure to 6 hours of shear stress significantly suppressed the inductory potential of TNFalpha to increase the mRNA levels of IL-6, IL-8, COX2, and TF. Additionally, TNFalpha increased TF activity approximately 10 times, an effect that was also significantly reduced by exposure to 6 and 24 hours of shear stress. The effect of shear on the gene levels of TF and NOS3 were not blocked by the NOS inhibitor L-NAME. These observations suggest that EPCs are capable of functionally responding to shear stress.

Dobutamine-norepinephrine, but not vasopressin, restores the ventriculoarterial matching in experimental cardiogenic shock.

We assessed the hemodynamic effects of guideline therapy in experimental cardiogenic shock and compared this treatment with a combination containing an alternative vasopressor (arginine vasopressin, AVP). Our hypothesis was that combined dobutamine-norepinephrine still is the superior inopressor therapy assessed by ventriculoarterial matching in both systole and diastole. Cardiogenic shock (CS) was induced by coronary microembolization in 16 pigs. Dobutamine (Dobu, 2ug/kg/min) alone and combined with either norepinephrine (NE, 100 ng/kg/min) or the pure vasopressor AVP (0.001 u/kg/min) were infused. In CS, Dobu increased cardiac output (CO) and central venous oxygen saturation (SVO₂) from 74 ± 3 mL/kg and 37 ± 2% to 103 ± 8 mL/kg and 49 ± 3%. Adding NE resulted in a further improvement of CO (125 ± 9 mL/kg) and SVO₂ (59 ± 4%) because of an increased heart rate and contractility with minimal change in systemic vascular resistance. Also, energy transfer from the ventricle to the arterial system was restored partly by Dobu and was normalized by supplementing NE. In contrast, supplemental AVP further worsened the shock state by decreasing CO (70 ± 6 mL/kg) and SVO₂ (45 ± 5%) compared with Dobu alone. Combined Dobu-NE has an efficient hemodynamic profile in CS. A pure afterload increasing substance used in acute ischemic CS aggravates the shock state by causing a ventriculoarterial mismatch despite its use in combination with an inotropic compound.

Adrenomedullin augments the angiogenic potential of late outgrowth endothelial progenitor cells

The therapeutic utility of endothelial progenitor cells (EPCs) in cardiovascular disease is potentially hampered by their low numbers in the circulation, impaired functional activity, and inhibitory factors in the recipient. These obstacles can possibly be circumvented by the use of proangiogenic cytokines and peptides. We sought to examine the effect of the endogenous vasoactive peptide adrenomedullin (AM) on the angiogenic potential of late outgrowth EPCs and their release of proangiogenic and proinflammatory cytokines/chemokines. Human peripheral blood mononuclear cells were cultured until the appearance of typical late outgrowth EPC colonies. The effect of AM on EPC proliferation was assessed using a colorimetric MTS proliferation assay while differentiation and formation of tubular structures in an EPC/fibroblast coculture or matrigel assay was used to assess the angiogenic potential of the cells. Finally, the release and mRNA transcripts of cytokines/chemokines were quantified in stimulated vs. nonstimulated EPCs using real-time PCR and a bead-based multiplex assay. The cultured EPCs possessed an endothelial phenotype and expressed the AM receptor (calcitonin receptor-like receptor/receptor activity modifying protein-2). AM stimulation induced proliferation of EPCs compared with controls (P < 0.05). Furthermore, AM produced a 36% and 80% increase in the formation of tubular networks in the EPC/fibroblast coculture and matrigel assay, respectively (P < 0.05). These effects seemed to be mediated through the phosphatidylinositol 3-kinase/Akt signaling pathway. AM did not seem to significantly influence the release or production of IL-6, IL-8, VEGF, stromal cell-derived factor 1, or the expression of CXCR-4 or VEGF receptor 2. In conclusion, adrenomedullin augmented the growth and angiogenic properties of late outgrowth EPCs, but did not influence their paracrine properties.

Inflammation and reduced endothelial function in the course of severe acute heart failure.

Systemic inflammation and elevated circulating levels of the endogenous nitric oxide inhibitor asymmetrical dimethylarginine (ADMA) have been associated with increased risk in cardiogenic shock (CS). In this prospective study, we assessed, over 4 consecutive days, the changes and possible associations between vascular function, markers of inflammation, and circulating ADMA levels in patients with CS (n = 12) and postcardiotomy heart failure (n = 12, PC-HF). Vasodilator function was measured as a reactive hyperemia index (RH-index) using a finger plethysmograph. Blood samples were analyzed for plasma ADMA, interleukine-6, interleukine-8, intracellular adhesion molecule-1, and vascular adhesion molecule-1. Baseline RH-index was significantly attenuated compared with healthy controls (2.28) for both CS and PC-HF (1.35 and 1.45, respectively, P = 0.001). Although vasodilator function improved in PC-HF patients, it remained attenuated in CS. Inflammatory markers were markedly elevated followed by a significant fall during the observation period in both groups. ADMA levels increased significantly during the observation period for PC-HF, whereas no pattern of change was observed for CS. No association was found between the longitudinal changes in RH-index, markers of inflammation, or ADMA in CS. However, an improved RH-index was associated with decreasing inflammatory markers in PC-HF. ADMA correlated to arterial lactate levels and the degree of organ dysfunction in CS. In conclusion, CS and PC-HF were characterized by a marked inflammatory activation accompanied by an attenuated vasodilator function. ADMA was related to organ dysfunction and degree of hypoperfusion during CS but showed no correlations to inflammation or hampered vasodilator function. The pathogenic significance of these responses needs clarification.

Oxygen Wasting Effect of inotropy—Is There a Need for a New Evaluation? An Experimental Large Animal Study Using Dobutamine and Levosimendan

Background— We addressed the hypothesis that the inotropic drugs dobutamine and levosimendan both induce surplus oxygen consumption (oxygen wasting) relative to their contractile effect in equipotent therapeutic doses, with levosimendan being energetically more efficient. Methods and Results— Postischemically reduced left ventricular function (stunning) was created by repetitive left coronary occlusions in 22 pigs. This contractile dysfunction was reversed by infusion of either levosimendan (24 μg/kg loading and 0.04 μg · kg−1 · min−1 infusion) or an equipotent dose of dobutamine (1.25 μg · kg−1 · min−1). Contractility and cardiac output were normalized by both drug regimens. The energy cost of drug-induced contractility enhancement was assessed by myocardial oxygen consumption related to the mechanical indexes tension-time index, pressure-volume area, and total mechanical energy. ANCOVA did not reveal any increased oxygen cost of contractility for either drug in these doses. However, both dobutamine and levosimendan at supratherapeutic levels (10 μg · kg−1 · min−1 and 48 μg/kg loading with 0.2 μg · kg−1 · min−1 infusion, respectively) induced a highly significant increase in oxygen consumption related to mechanical work, compatible with the established oxygen-wasting effect of inotropy ( P <0.001 for all mechanical indexes with dobutamine; P =0.007 for levosimendan as assessed by pressure-volume area). Conclusion— Therapeutic levels of neither dobutamine nor levosimendan showed inotropic oxygen wasting in this in vivo pig model. Thus, relevant hemodynamic responses can be achieved with an adrenergic inotrope without surplus oxygen consumption. Received March 17, 2009; accepted November 16, 2009.Background—We addressed the hypothesis that the inotropic drugs dobutamine and levosimendan both induce surplus oxygen consumption (oxygen wasting) relative to their contractile effect in equipotent therapeutic doses, with levosimendan being energetically more efficient. Methods and Results—Postischemically reduced left ventricular function (stunning) was created by repetitive left coronary occlusions in 22 pigs. This contractile dysfunction was reversed by infusion of either levosimendan (24 &mgr;g/kg loading and 0.04 &mgr;g·kg−1·min−1 infusion) or an equipotent dose of dobutamine (1.25 &mgr;g·kg−1·min−1). Contractility and cardiac output were normalized by both drug regimens. The energy cost of drug-induced contractility enhancement was assessed by myocardial oxygen consumption related to the mechanical indexes tension-time index, pressure-volume area, and total mechanical energy. ANCOVA did not reveal any increased oxygen cost of contractility for either drug in these doses. However, both dobutamine and levosimendan at supratherapeutic levels (10 &mgr;g·kg−1·min−1 and 48 &mgr;g/kg loading with 0.2 &mgr;g·kg−1·min−1 infusion, respectively) induced a highly significant increase in oxygen consumption related to mechanical work, compatible with the established oxygen-wasting effect of inotropy (P<0.001 for all mechanical indexes with dobutamine; P=0.007 for levosimendan as assessed by pressure-volume area). Conclusion—Therapeutic levels of neither dobutamine nor levosimendan showed inotropic oxygen wasting in this in vivo pig model. Thus, relevant hemodynamic responses can be achieved with an adrenergic inotrope without surplus oxygen consumption.

Oxygen-Wasting Effect of InotropyCLINICAL PERSPECTIVE

Background— We addressed the hypothesis that the inotropic drugs dobutamine and levosimendan both induce surplus oxygen consumption (oxygen wasting) relative to their contractile effect in equipotent therapeutic doses, with levosimendan being energetically more efficient. Methods and Results— Postischemically reduced left ventricular function (stunning) was created by repetitive left coronary occlusions in 22 pigs. This contractile dysfunction was reversed by infusion of either levosimendan (24 μg/kg loading and 0.04 μg · kg−1 · min−1 infusion) or an equipotent dose of dobutamine (1.25 μg · kg−1 · min−1). Contractility and cardiac output were normalized by both drug regimens. The energy cost of drug-induced contractility enhancement was assessed by myocardial oxygen consumption related to the mechanical indexes tension-time index, pressure-volume area, and total mechanical energy. ANCOVA did not reveal any increased oxygen cost of contractility for either drug in these doses. However, both dobutamine and levosimendan at supratherapeutic levels (10 μg · kg−1 · min−1 and 48 μg/kg loading with 0.2 μg · kg−1 · min−1 infusion, respectively) induced a highly significant increase in oxygen consumption related to mechanical work, compatible with the established oxygen-wasting effect of inotropy ( P <0.001 for all mechanical indexes with dobutamine; P =0.007 for levosimendan as assessed by pressure-volume area). Conclusion— Therapeutic levels of neither dobutamine nor levosimendan showed inotropic oxygen wasting in this in vivo pig model. Thus, relevant hemodynamic responses can be achieved with an adrenergic inotrope without surplus oxygen consumption. Received March 17, 2009; accepted November 16, 2009.Background—We addressed the hypothesis that the inotropic drugs dobutamine and levosimendan both induce surplus oxygen consumption (oxygen wasting) relative to their contractile effect in equipotent therapeutic doses, with levosimendan being energetically more efficient. Methods and Results—Postischemically reduced left ventricular function (stunning) was created by repetitive left coronary occlusions in 22 pigs. This contractile dysfunction was reversed by infusion of either levosimendan (24 &mgr;g/kg loading and 0.04 &mgr;g·kg−1·min−1 infusion) or an equipotent dose of dobutamine (1.25 &mgr;g·kg−1·min−1). Contractility and cardiac output were normalized by both drug regimens. The energy cost of drug-induced contractility enhancement was assessed by myocardial oxygen consumption related to the mechanical indexes tension-time index, pressure-volume area, and total mechanical energy. ANCOVA did not reveal any increased oxygen cost of contractility for either drug in these doses. However, both dobutamine and levosimendan at supratherapeutic levels (10 &mgr;g·kg−1·min−1 and 48 &mgr;g/kg loading with 0.2 &mgr;g·kg−1·min−1 infusion, respectively) induced a highly significant increase in oxygen consumption related to mechanical work, compatible with the established oxygen-wasting effect of inotropy (P<0.001 for all mechanical indexes with dobutamine; P=0.007 for levosimendan as assessed by pressure-volume area). Conclusion—Therapeutic levels of neither dobutamine nor levosimendan showed inotropic oxygen wasting in this in vivo pig model. Thus, relevant hemodynamic responses can be achieved with an adrenergic inotrope without surplus oxygen consumption.

Radial artery graft patency relates to gender, diabetes mellitus and angiotensin inhibition

Abstract The radial artery is resistant to atherosclerotic degeneration and therefore appears more attractive for coronary artery bypass grafting than the saphenous vein. However, the patency of radial artery grafts varies widely among studies. Therefore, before deciding whether to adopt this as the conduit of choice second to internal mammary artery grafts, we have prospectively monitored our first cohort of patients with radial-to-coronary bypasses. Design. Angiographic and clinical outcome parameters were registered for the 119 patients receiving radial artery grafts at our institution during April 4, 2001 to October 7, 2003. Results. Reangiography of 102 patients (86%) showed that after two to three years, 79% of the radial artery and 87% of the saphenous vein grafts remained patent. Radial artery harvesting was well tolerated. Patency of radial artery grafts was correlated to diabetes mellitus (detrimental), gender (women had higher occlusion rates), and use of angiotensin inhibiting medication (beneficial). Conclusions. The pre-study assumption that radial artery grafts would out-perform those of saphenous vein at mid-term is not borne out. The propensity of radial artery graft failure in diabetics and the higher patency associated with angiotensin inhibition might both relate to endothelial modulation of the muscular tone of the graft.

Circulatory assistance in acute heart failure--where do we go from here?

The comment concerns two short-term assist systems, namely the Impella axial-flow recovery system and extra-corporeal membrane oxygenation (ECMO) used for circulatory assistance in patients with acute heart failure. The results, particularly for patients in cardiogenic shock not related to cardiac surgery, calls for cautious optimism.

How many acute heart failure patients need a ventricular assist device

Objectives. The most severe forms of acute heart failure have a dismal prognosis despite modern invasive treatment. For some of these patients, improved outcome must relay on early institution of ventricular assist devices (VAD). We aimed to estimate the potential VAD need in acute heart failure. Design. All patients admitted to the ICU or CCU for acute heart failure (AHF) in 2003/04 (n=302) were reviewed. Non-survivors with severe acute heart failure, i.e. cardiogenic shock and postcardiotomy HF, were individually reviewed to assess eligibility for VAD-treatment. Results. Cardiogenic shock and postcardiotomy HF was present in 23% (n=69) and 19% (n=57) of the AHF patients. Overall in hospital mortality in these groups was 38% (n=48). Of these, 15 were less than 75 years of age, without serious comorbidities and thus deemed to be potential candidates for VAD-treatment. Conclusion. This survey indicates that 12% of patients with severe acute heart failure are potential candidates for VAD-treatment. Extending these figures to a national level, indicate that approximately 70 patients per year could be candidates for short-term VAD-treatment in Norway.