Images in cardiovascular medicine. Contrast-enhanced magnetic resonance imaging of a patient with chloroquine-induced cardiomyopathy confirmed by endomyocardial biopsy.
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Adult↗
Biomedical subjects
Thorsten Reffelmann
Publications and source records attributed to Thorsten Reffelmann.
The no-reflow phenomenon: A basic mechanism of myocardial ischemia and reperfusion.
Both animal models of experimental myocardial infarction and clinical studies on reperfusion therapy for acute myocardial infarction have provided evidence of impaired tissue perfusion at the microvascular level after initiation of reperfusion despite adequate restoration of epicardial vessel patency. Characteristics of this "no-reflow" phenomenon found in basic science investigations, such as distinct perfusion defects, progressive decrease of resting myocardial flow with ongoing reperfusion and functional vascular alterations are paralleled by clinical observations demonstrating similar features during the course of reperfusion. In experimental animal investigations of coronary occlusion and reperfusion, this no-reflow phenomenon could be characterized as a fundamental mechanism of myocardial ischemia and reperfusion. Major determinants of the amount of no-reflow are the duration of occlusion, infarct size, but also the length of reperfusion, as rapid expansion of perfusion defects occurs during reperfusion. Moreover, no-reflow appears to persist over a period of at least four weeks, a period when major steps of infarct healing take place. The significant association of the degree of compromised tissue perfusion at four weeks and indices of infarct expansion, found in chronic animal models of reperfused myocardial infarction, might be the pathoanatomic correlate for the prognostic significance observed in the clinical setting.
Animals↗
Cardiovascular effects of phosphodiesterase 5 inhibitors.
Phosphodiesterase 5 inhibitors, such as sildenafil, vardenafil and tadalafil, are now approved for the treatment of erectile dysfunction. They inhibit the cGMP-specific isoform 5 of phosphodiesterase, resulting in cGMP accumulation, which, for example in smooth muscle cells, reduces muscular tone. In the cardiovascular system, they slightly reduce arterial systemic blood pressure. This moderate effect was also shown in combination with many antihypertensive drugs. But the important contraindication is the concomitant use of PDE 5 inhibitors with any drug serving as a nitric oxide donor, as this combination can lead to significant arterial hypotension. Caution is needed in patients on alpha-blocking agents. In general, this class of drugs was not shown to exhibit direct deleterious effects on the myocardium or promote arrhythmias. Furthermore, statistical evaluations did not demonstrate an increased risk for patients taking PDE 5 inhibitors in comparison with an adequate control population. Many patients suffering from erectile dysfunction may be characterized by multiple cardiovascular risk factors or even ischemic heart disease, suggesting an increased baseline risk. While in many forms of erectile dysfunction, these agents seem to be very effective, it becomes clear that endothelial dysfunction is an attractive target of PDE 5 inhibitors and may also be the underlying cause in many types of erectile dysfunction. In addition, these agents seem to be very effective in lowering pulmonary arterial pressure, which might provide the opportunity to treat primary and some forms of secondary pulmonary hypertension, perhaps in combination with inhaled nitric oxide or other pulmonary arterial vasodilators. Sildenafil was approved for treatment of primary arterial hypertension in the U.S. in June 2005. Recently, direct cardioprotective effects were described in animal research, resembling preconditioning-like effects, which may, under certain conditions, also be applicable in clinical research.
3',5'-Cyclic-GMP Phosphodiesterases↗
Pharmacotherapy of erectile dysfunction: focus on cardiovascular safety.
Therapy of erectile dysfunction has been revolutionised in recent years, as specific pharmacological inhibitors of phosphodiesterase 5 (PDE5), such as sildenafil, tadalafil, or vardenafil, were shown to be highly effective in the treatment of erectile dysfunction. They dilate arterial smooth muscle cells of the corpora cavernosa, which express PDE5 abundantly, by inhibiting the breakdown of 3'5'-cyclic guanosine monophosphate. Despite theoretical concerns of a reduced myocardial tolerance to ischaemia or promoting cardiac arrhythmias, randomised trials and retrospective analyses do not support an increased cardiac risk with oral treatment. Therapeutic doses of PDE 5 inhibitors exhibit slight blood pressure lowering effects, and do not appear to compromise coronary blood flow in coronary artery disease. However, the combination of PDE5 inhibitors with any nitric oxide donor is absolutely contraindicated because of potentially life-threatening hypotension. Before prescribing medication for erectile dysfunction, any patient with cardiovascular disease should be evaluated for a potential risk of a cardiovascular event during sexual activity according to the Princeton Consensus Panel. When a stable cardiac condition can be achieved (low risk group), oral treatment for erectile dysfunction may be appropriate.
Administration, Oral↗
Effects of adenosine and verapamil on anatomic no-reflow in a rabbit model of coronary artery occlusion and reperfusion.
Adenosine and verapamil have successfully been used in the treatment of clinical no-reflow after direct angioplasty for acute myocardial infarction. However, their effects on anatomic perfusion defects in experimental myocardial ischemia/reperfusion are unknown. Thus the area of no-reflow (ANR), visualized after in-vivo staining of perfused tissue by thioflavin S (% of the risk area, RA, blue dye), and regional myocardial blood flow (radioactive microspheres) were determined in anesthetized open-chest rabbits after 30 minutes of occlusion and 120 minutes of reperfusion. Adenosine, administered intravenously during the entire reperfusion period, reduced vascular resistance in the RA at 120 minutes of reperfusion by 39% compared with controls (P < 0.053). However, in every animal, sizable perfusion defects developed and the ANR with adenosine treatment (29 +/- 3%) was not significantly different from saline controls (35 +/- 6%). Intravenous verapamil, given during the entire reperfusion period, reduced vascular resistance in the RA by 54% at 120 minutes of reperfusion (P < 0.03). But perfusion defects, visible in every animal, were similar in size between verapamil (38 +/- 5%) and saline (35 +/- 6%) groups. Therefore, neither treatment prevented or attenuated perfusion defects after ischemia/reperfusion despite reducing vascular resistance in the RA; hence vasospasm is not a major contributor to microvascular perfusion defects in this model.
Adenosine↗
A novel minimal-invasive model of chronic myocardial infarction in swine.
BACKGROUND: Most animal studies on myocardial infarction (MI) have used open-chest models with direct surgical coronary artery ligation, which imply local as well as generalized side effects of major surgery. Some closed-chest models of MI have been established, mainly using catheterization techniques with coronary artery embolization, balloon occlusion, and intracoronary injection of thrombogenic agents. The aim of this study was to develop a closed-chest technique of chronic coronary artery occlusion at a selected location with subsequent thrombus formation without use of balloon inflation or thrombotic chemical agents. METHODS AND RESULTS: A coronary angiography via the carotid artery was performed using a 7 F guiding catheter in 21 pigs. After insertion of a percutaneous transluminal coronary angioplasty (PTCA) guide wire into the distal coronary artery, a vessel-size adapted flexible foreign body comprising an open-cell sponge was advanced into the coronary artery via the guide wire by a non-inflated PTCA balloon. Five min after removal of the guide wire and the balloon catheter, total coronary artery occlusion was documented by angiography. Retrograde thrombosis of the coronary artery occurred in three animals. After one week, total vessel occlusion at the previously selected location was visualized by coronary angiography in animals that had survived. Macroscopic analysis demonstrated the foreign body with subsequent thrombus formation in the coronary artery and distal MI. Post-mortem histological analysis revealed myocardial necrosis and granulocyte infiltration at the margin of the infarction, without damage to remote myocardium. CONCLUSIONS: This new easy-to-perform closed-chest technique provides reproducible chronic coronary artery occlusion at a selected location with subsequent MI. It avoids major surgery and thoracotomy and does not require balloon inflation or intracoronary injection of thrombotic or chemical agents.
Animals↗
Microvascular alterations after temporary coronary artery occlusion: the no-reflow phenomenon.
In experimental models of temporary coronary artery occlusion, tissue perfusion at the microvascular level remains incomplete even after patency of the infarct-related epicardial coronary artery is established, and distinct perfusion defects develop within the risk zone. This no-reflow phenomenon can be regarded as a basic cardiac response to ischemia-reperfusion. Perfusion defects observed in the clinical realm after reperfusion therapy for myocardial infarction may substantially be related to this mechanism in addition to microembolization and activation of platelets, as suggested in several recent studies. A major determinant of the amount of no-reflow seems to be infarct size itself. Reperfusion-related expansion of no-reflow zones occurs within the first hours after the reopening of the coronary artery with a parallel reduction of regional myocardial flow, resulting in a potential therapeutic window. With various cardioprotective interventions, a close correlation between the size of the anatomic no-reflow and necrosis is a reproducible feature, which suggests a causal link between both entities of ischemic cardiac damage. Although vasodilating interventions failed to uncouple no-reflow zones from necrosis, the steps in the causal chain between microvascular and myocardial damage remain to be identified. On a long-term basis, tissue perfusion after ischemia-reperfusion remains markedly compromised for at least 4 weeks. Recent morphometric cardiac analyses suggested that the level of tissue perfusion after 4 weeks is a significant predictor of various indices of infarct healing, such as scar thickness, and infarct expansion index. As a consequence, improving tissue perfusion might concomitantly improve the healing process, which may provide the pathoanatomic basis for prognostic implications of no-reflow.
Animals↗
No-reflow phenomenon persists long-term after ischemia/reperfusion in the rat and predicts infarct expansion.
BACKGROUND: No-reflow after reperfusion therapy for myocardial infarction is a strong predictor of clinical outcome. But its fate on a long-term basis and potential significance for infarct healing are not yet known. METHODS AND RESULTS: Twenty-nine female Fisher rats were subjected to 60 minutes of coronary occlusion followed by reperfusion. At 4 weeks, 15 survivors were euthanized after measurement of regional myocardial blood flow (radioactive microspheres) and in vivo staining of perfused tissue (0.5 mL 50% Uniperse blue IV). Infarct size (34.3+/-3.4%), scar thickness (1.19+/-0.10 mm), and infarct expansion index (0.51+/-0.04) were assessed from histological sections (2 additional exclusions because of failed occlusion). Regional myocardial blood flow in the reperfused infarct was reduced significantly compared with noninfarcted tissue (1.98+/-0.47 versus 4.55+/-0.86 mL x min(-1) x g(-1), P<0.003, apical slice, and 1.77+/-0.44 versus 5.34+/-0.38 mL x min(-1) x g(-1), P<0.0001, second slice), accompanied by a striking reduction of perfused capillaries within the infarct (n=23+/-4 versus 163+/-8 in the noninfarcted tissue, P<0.0001, microscopically assessed as capillaries containing blue particles per high-power field). Macroscopically, no-reflow areas were visible in 9 of 13 hearts. The number of perfused capillaries within the infarct correlated significantly with infarct expansion index (r=-0.76, P<0.003), infarct thickness (r=0.60, P<0.03), and the ratio of infarct to septum thickness (r=0.74, P<0.004). CONCLUSIONS: The no-reflow phenomenon persists for 1 month after reperfusion and predicts worse scar thinning and infarct expansion. Thus, one might shift the "open-artery" hypothesis downstream to an "open-microvessel" hypothesis, relating infarct healing, infarct expansion, and outcome to the completeness of microvascular reperfusion above and beyond epicardial artery patency.
Animals↗
Effects of sildenafil on myocardial infarct size, microvascular function, and acute ischemic left ventricular dilation.
OBJECTIVE: Adverse cardiac events in patients treated with the phosphodiesterase-5 inhibitor sildenafil for erectile dysfunction raised concerns about its safety in ischemic heart disease. METHODS: In anesthetized open-chest rabbits, receiving 1.45 mg/kg sildenafil intravenously or saline 30 min prior to ischemia (n=12, each), infarct size (IS, triphenyltetrazolium), the area of no-reflow (ANR, thioflavin S) (% of the risk area, RA, blue dye), and regional myocardial blood flow (RMBF, radioactive microspheres) were measured after 30 min of coronary occlusion and 180 min of reperfusion. Left ventricular hemodynamics and dimensions (echocardiography) were determined in a separate series of animals (n=5, each). RESULTS: Sildenafil significantly lowered arterial blood pressure before occlusion (-17 to -19 mmHg over 30 min), but during ischemia and reperfusion hemodynamics were comparable to controls. IS in treated animals (51+/-4%) did not significantly differ from control animals (47+/-4%). No major arrhythmias or lengthening of QT/QTc occurred. While sildenafil slightly increased RMBF and significantly reduced specific vascular resistance in the RA during reperfusion (51+/-7 versus 73+/-10 mmHg g min/ml, P<0.05), the ANR (46+/-3%) was similar to control animals (44+/-4%). Sildenafil reduced left ventricular dP/dt(max) (P<0.05) and dP/dt(min) (P<0.01) in non-ischemic conditions, and slightly during ischemia, along with a pronounced decrease in ischemic left ventricular end-diastolic pressure (9+/-2 versus 15+/-2 mmHg after saline, P<0.05), but did not attenuate acute ischemic left ventricular dilation. CONCLUSIONS: Sildenafil reduced cardiac pre- and afterload, and parameters of left ventricular contractility. Myocardial necrosis and microvascular dysfunction were neither exacerbated nor attenuated.
Animals↗
Therapeutic potential of phosphodiesterase 5 inhibition for cardiovascular disease.
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3',5'-Cyclic-GMP Phosphodiesterases↗
Transthoracic echocardiography in rats. Evalution of commonly used indices of left ventricular dimensions, contractile performance, and hypertrophy in a genetic model of hypertrophic heart failure (SHHF-Mcc-facp-Rats) in comparison with Wistar rats during aging.
Two-weekly echocardiographic examinations were conducted in nine SHHF-Mc-fa(cp) rats in comparison with eight age-matched Wistar rats. In the SHHF-rats, characterized by progressive LV-dilation and decreasing contractile function between 77-87 weeks of age, left ventricular (LV) hypertrophy was most sensitively demonstrated by increased LV-mass-index (p < 0.001). LV-areas and area-ejection fraction (EF) (2D-images) discriminated more sensitively in the early stages than M-mode-derived diameters and fractional shortening (FS); midwall shortening was the most sensitive parameter of reduced systolic function. Post-mortem measurements showed an excellent correlation with calculated LV-mass (r = 0.91). Post-mortem LV-volumes correlated significantly with diastolic LV-diameters, LV-areas, and calculated LV-volumes (r = 0.56-0.59). Mean within-subject standard deviations in controls were 0.5-0.6 mm (LV-diameters), 3.1-4.6 mm(2) (LV-areas), approximately 10% of the mean for FS, area-EF and midwall shortening, and approximately 20% for wall thickness and LV-mass. The data might be used to choose the most sensitive parameters, and to estimate sample size for echocardiographic investigations in rats.
Aging↗
Cellular cardiomyoplasty--cardiomyocytes, skeletal myoblasts, or stem cells for regenerating myocardium and treatment of heart failure?
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Animals↗
Transplantation of neonatal cardiomyocytes after permanent coronary artery occlusion increases regional blood flow of infarcted myocardium.
BACKGROUND: Cellular cardiomyoplasty is a promising approach for rebuilding scar tissue after acute myocardial infarction. However, the angiogenic potential of transplanted immature cardiomyocytes and their effect on regional myocardial blood flow (RMBF) after coronary artery occlusion remain to be evaluated. METHODS AND RESULTS: Intramyocardial injection of cultured neonatal cardiomyocytes (4 x 10(6) cells/50-70 microliter) into the scar 1 week after permanent coronary occlusion in rats resulted in improved RMBF in the infarct 4 weeks after transplantation (radioactive microspheres, 0.97 +/- 0.18 ml/min/g) in comparison to medium-injected hearts (0.61 +/- 0.11 ml/min/g, P < 0.047). The macroscopic perfusion defect after in vivo staining with the blue dye 50% Uniperse blue was significantly smaller in the cell transplantation group (1.5 +/- 0.3% of the heart) compared to the medium group (3.0 +/- 0.6%, P < 0.017). Clusters of engrafted cells within the scar demonstrated a high capillary density (1217 +/- 114 perfused (blue) capillaries/mm(2)); however, in the scar tissue itself capillary density in the cell group (156 +/- 62/mm(2)) did not significantly differ from the medium group (125 +/- 10/mm(2)), suggesting that neo-angiogenesis was confined to regions of successful engraftment (non-infarcted tissue: 1924 +/- 114 perfused capillaries/mm(2)). The transplantation group was characterized by smaller diastolic and systolic left ventricular volumes, as assessed by intravenous ventriculography, along with thickened infarcts (0.93 +/- 0.07 vs. 0.75 +/- 0.04 mm, P < 0.020) and lower infarct expansion indices (0.64 +/- 0.07 vs. 0.83 +/- 0.06, P < 0.023), as determined by post-mortem morphometry of histologic slides. CONCLUSIONS: Transplantation of neonatal cardiomyocytes induced neo-angiogenesis in zones of successful cell engraftment within the scar, which effectively enhanced tissue perfusion.
Animals↗
Cardiomyocyte transplantation into the failing heart-new therapeutic approach for heart failure?
Heart failure, frequently the consequence of irreversible myocardial damage with subsequent formation of akinetic scar tissue, is a highly prevalent disease, and in its advanced stages associated with high mortality. The transplantation of exogenous cells with the inherent ability to contract has been put forward as one potential treatment strategy to increase contractility and cardiac performance. Besides skeletal myoblasts or stem cells from various sources, immature cardiomyocytes, such as fetal or neonatal cardiomyocytes, have been transplanted into normal, cryoinjured, infarcted myocardium, as well as into models of global heart failure. Survival of transplanted immature cardiomyocytes has been demonstrated up to 6-7 months, accompanied by vascularization of the grafted tissue. Transplants developed sarcomeric structures and other morphological features of differentiation. The principal possibility of cell-to-cell coupling between graft and host cells was demonstrated after cardiomyocyte transplantation into normal hearts and in some studies in damaged myocardium. But most long-term follow-up investigations in models of myocardial infarction reported that optimal integration of the engrafted cells appeared to be hindered by scar tissue, separating the transplant from the host. Nonetheless, in several studies, improved parameters of cardiac performance were demonstrated ex-vivo and in vivo. Potential mechanisms might involve beneficial effects on the remodeling process. In this review, we critically evaluate the potential value of cardiomyocyte transplantation as a new approach in the treatment of the syndrome of "heart failure".
Animals↗
Cardioprotection by Carvedilol: antiapoptosis is independent of beta-adrenoceptor blockage in the rat heart.
BACKGROUND: Carvedilol, a beta-blocking agent with beta-blocking properties is now widely used for the treatment of congestive heart failure. In addition to its beta-adrenergic receptor blockage, antiapoptotic effects have been demonstrated in experimental animals. OBJECTIVE: The cardioprotective effects of carvedilol and its hydroxylated analogue BM-91.0228 were tested with regard to their infarct-limiting and antiapoptotic properties in an experimental infarct model in the rat heart. METHODS: Anesthetized rats were subjected to either 30 (groups 1 to 3) or 60 minutes (groups 4 to 6) of coronary artery occlusion followed by 30 minutes of reperfusion. Groups 1 and 4 served as the control; groups 2 and 5 received intravenous Carvedilol (1 mg/kg) and groups 3 and 6 received intravenous administration of BM-91.0228 (1 mg/kg), respectively, 5 minutes prior to coronary occlusion. Infarct sizes were measured by triphenyltetrazolium chloride staining. In situ visualization of apoptosis was measured by nick end labeling. RESULTS: Carvedilol reduced infarct size after 30 minutes of coronary occlusion compared to controls (8.7% +/- 2.7% versus 27.3% +/- 3.4%, P <.001), while BM-91.0228 showed no significant infarct size reduction (23.7% +/- 5.9%, NS). Neither Carvedilol (36.9% +/- 3.9%) nor BM-91.0228 (42.4% +/- 3.6%) reduced infarct size after 60 minutes of coronary occlusion compared to controls (47.7% +/- 3.9%, NS). Carvedilol reduced apoptosis after 30 minutes (4.9% +/- 1.3% versus 16.7% +/- 3.2%, P <.01) and after 60 minutes (11.7% +/- 1.8% versus 25.5% +/- 0.5%, P <.001) of coronary occlusion compared to controls. BM-91.0228 reduced apoptosis after 30 minutes (7.3% +/- 1.4% versus 16.7% +/- 3.2%, P <.01) and after 60 minutes (13.4% +/- 1.8% versus 25.5% +/- 0.5%, P <.001) of coronary occlusion compared to controls. CONCLUSION: Carvedilol is cardioprotective by preventing ischemia-perfusion-induced necrosis and apoptosis of cardiomyocytes. The antiapoptotic effects of Carvedilol are independent of its beta-adrenoceptor blocking effects, but its effects might be caused by antioxidant properties and by modulation of the signalling pathway.
Adrenergic beta-Antagonists↗
Is microvascular protection by cariporide and ischemic preconditioning causally linked to myocardial salvage?
Two independent cardioprotective interventions, Na(+)/H(+) exchange inhibition and ischemic preconditioning (PC), were investigated with respect to differential effects on microvascular and myocardial salvage in anesthetized rabbits (30 min of ischemia, 180 min of reperfusion). Cariporide (Car, 300 microg/kg) administered before occlusion and PC reduced infarct size (IS) as measured by triphenyltetrazolium staining [control, 46.0 +/- 4.2% of risk area (RA); Car, 17.6 +/- 3.7% (P < 0.01); PC, 27.5 +/- 4.1% (P < 0.01)] and concomitantly decreased the area of anatomic no reflow (ANR) as measured by thioflavin S staining [control, 40.4 +/- 3.7%; Car, 19.0 +/- 2.9% (P < 0.01); PC, 26.9 +/- 3.4% (P < 0.05)]. Regional myocardial blood flow (RMBF, measured by radioactive microspheres) in the RA, which deteriorated between 30 and 180 min of reperfusion (control, from 79 +/- 6 to 26 +/- 2% of nonischemic flow), was shifted to higher values with both treatments [Car, from 110 +/- 12 to 49 +/- 7% (P < 0.05); PC, from 109 +/- 8 to 38 +/- 6% (P < 0.05)]. However, neither intervention uncoupled the close relationship between IS and ANR (r = 0.92-0.95) or RMBF. Car given at reperfusion did not alter IS, ANR, RMBF, or the close interrelationships. Because size and spatial distribution of no reflow and myocardial necrosis remained closely coupled with independent cardioprotective interventions, a potential causal connection between microvascular and myocardial salvage is discussed.
Animals↗
The "no-reflow" phenomenon: basic science and clinical correlates.
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Aged↗
Microvascular reperfusion injury: rapid expansion of anatomic no reflow during reperfusion in the rabbit.
The aim was to define the degree and time course of reperfusion-related expansion of no reflow. In five groups of anesthetized, open-chest rabbits (30-min coronary occlusion and different durations of reperfusion), anatomic no reflow was determined by injection of thioflavin S at the end of reperfusion and compared with regional myocardial blood flow (RMBF; radioactive microspheres) and infarct size (triphenyltetrazolium). The area of no reflow progressively increased from 12.2 +/- 4.2% of the risk area after 2 min of reperfusion to 30.8 +/- 3.1% after 2 h and 34.9 +/- 3.3% after 8 h and significantly correlated with infarct size after 1 h of reperfusion (r = 0.88-0.97). This rapid expansion of no reflow predominantly occurred during the first 2 h, finally encompassing approximately 80% of the infarct size, and was accompanied by a decrease of RMBF within the risk area, being hyperemic after 2 min of reperfusion (3.78 +/- 0.75 ml x min(-1) x g(-1)) and plateauing at a level of approximately 0.9 ml x min(-1) x g(-1) by 2 and 8 h of reperfusion (preischemic RMBF: 2.06 +/- 0.01 ml x min(-1) x g(-1)). The development of macroscopic hemorrhage lagged behind no reflow, was closely correlated with it, and may be the consequence of microvascular damage.
Animals↗