Intracoronary adenosine compared with adrenaline and verapamil in the treatment of no-reflow phenomenon following primary PCI in STEMI patients.

BACKGROUND: no-reflow can complicate up to 25% of pPCI and is associated with significant morbidity and mortality. We aimed to compare the outcomes of intracoronary epinephrine and verapamil with intracoronary adenosine in the treatment of no-reflow after primary percutaneous coronary intervention (pPCI). METHODS: 108 STEMI patients had no-reflow during pPCI were assigned into four groups. Group 1, in which epinephrine and verapamil were injected through a well-cannulated guiding catheter. Group 2, in which same drugs were injected in the distal coronary bed through a microcatheter or perfusion catheter. Group 3, in which adenosine was injected through a guiding catheter. Group 4, in which adenosine was injected in distal coronary bed. Primary end point was the achievement of TIMI III flow and MBG II or III. Secondary end point was major adverse cardiovascular and cerebrovascular events (MACCEs) during hospital stay. RESULTS: The study groups did not differ in their baseline characteristics. Primary end point was achieved in 15 (27.8%) patients in the guide-delivery arm compared with 34 (63%) patients in the local-delivery arm, p < 0.01. However, the primary end point did not differ between the epinephrine/verapamil group and the adenosine group (27 (50%) vs 22 (40.7%), p = 0.334). The secondary end points were similar between the study groups. CONCLUSION: Local delivery of epinephrine, verapamil and adenosine in the distal coronary bed is more effective in achieving TIMI III flow with MBG II or III compared with their guide-delivery in patients who suffered no-reflow during pPCI. There was no difference between epinephrine/verapamil Vs. adenosine.

Efficacy and safety of intracoronary epinephrine for the management of the no-reflow phenomenon following percutaneous coronary interventions: a systematic-review study.

BACKGROUND: Currently, no pharmacological or device-based intervention has been fully proven to reverse the no-reflow phenomenon. OBJECTIVES: To assess the efficacy and safety of intracoronary (IC) epinephrine in the management of no-reflow phenomenon following percutaneous coronary intervention (PCI), either as first-line treatment or after the failure of conventional agents. DESIGN: Systematic review. DATA SOURCES AND METHODS: PubMed and Scopus databases were systematically searched up to 28 May 2022, with additional manual search on the Google Scholar and review of the reference lists of the relevant studies to identify all published studies. Cohort studies, case series, and interventional studies written in English which evaluated the efficacy and safety of IC epinephrine in patients with no-flow phenomenon were included in our review. RESULTS: Six of the 646 articles identified in the initial search met our inclusion criteria. IC epinephrine was used either as a first-line treatment [two randomized clinical trials (RCTs)] or after the failure of conventional agents (two cohort studies and two case series) for restoring the coronary flow, mainly after primary PCI. As first-line therapy, IC epinephrine successfully restored coronary flow in over 90% of patients in both RCTs, which significantly outperformed IC adenosine (78%) but lagged behind combination of verapamil and tirofiban (100%) in this regard. In the refractory no-flow phenomenon, successful reperfusion [thrombolysis in myocardial infarction (TIMI) flow grade = 3] was achieved in three out of four patients after the administration of IC epinephrine based on the results from both case series. Their findings were confirmed by a recent cohort study that further compared IC epinephrine with IC adenosine and found significant differences between them in terms of efficacy [% TIMI flow grade 3: (69.1% versus 52.7%, respectively; p value = 0.04)] and 1-year major adverse cardiac event (MACE) outcomes (11.3% versus 26.7%, respectively; p value ⩽ 0.01). Overall, malignant ventricular arrhythmias were reported in none of the patients treated with IC epinephrine. CONCLUSION: Results from available evidence suggest that IC epinephrine might be an effective and safe agent in managing the no-reflow phenomenon.

Intracoronary epinephrine versus adenosine in the management of refractory no-reflow phenomenon: a single-center retrospective cohort study.

BACKGROUND: The no-reflow phenomenon is associated with a considerable reduction in myocardial salvage in patients with ST elevation myocardial infarction (STEMI) treated by primary percutaneous intervention (PCI). There has been no head-to-head comparison of intra-coronary epinephrine to adenosine in the management of no-reflow phenomenon. OBJECTIVES: Evaluate the short- and long-term efficacy and safety of using intracoronary epinephrine versus adenosine for management of the catastrophic no-reflow phenomenon that may occur during primary PCI. DESIGN: Retrospective cohort. SETTING: Single center in Egypt. PATIENTS AND METHODS: The study included STEMI patients who developed refractory no-reflow phenomenon during primary PCI after failure of conventional treatments and received either intracoronary epinephrine or adenosine. MAIN OUTCOME MEASURES: No-reflow management measured through improvement of thrombolysis in myocardial infarction grade (TIMI flow), myocardial blush grade, TIMI frame count and major adverse cardiovascular events (MACE) at 1-year follow up. SAMPLE SIZE: 156 patients with refractory no-reflow phenomenon during primary PCI. RESULTS: Successful reperfusion was achieved in 74 of 81 (91.4%) of patients who received epinephrine and in 65 of 75 (86.7%) who received adenosine (P<.05). Fifty-six of 81 patients (69.1%) achieved TIMI III flow after epinephrine administration versus 39 of 75 patients (52.7%) in the adenosine group (P=.04). The incidence of heart failure after 1 year of follow up was lower in the epinephrine group compared to the adenosine group (6.3% vs. 19.2%, P<.017). MACE after 1 year of follow up was lower in patients who received epinephrine compared to those who received adenosine (11.3 % Vs. 26.7 %, P<.01). CONCLUSION: During primary PCI, intracoronary epinephrine is as effective as adenosine in successful management of refractory no-reflow phenomenon with a more favorable long-term prognosis compared to adenosine. LIMITATIONS: Retrospective design. CONFLICT OF INTEREST: None.

Slow Coronary Flow: Pathophysiology, Clinical Implications, and Therapeutic Management.

Coronary slow flow (CSF) is an angiographic phenomenon with specific epidemiologic characteristics, associated clinical presentation, and prognosis. Although patients with CSF are diagnosed as having "normal coronary arteries," it seems appropriate to consider CSF as a distinct disease entity requiring specific treatment. The patient with CSF is usually male, smoker, obese, with a constellation of risk factors suggestive of metabolic syndrome. Unstable angina is the most common clinical presentation, with recurrent episodes of chest pain at rest associated with electrocardiographic changes often requiring readmission and reevaluation. Regarding definition and diagnosis, interventionists should first exclude possible "secondary" causes of CSF, use objective means for definition and then differentiate from other similar conditions such as microvascular angina. Although the phenomenon is generally benign, patients with CSF are severely symptomatic with recurrent episodes of chest pain and poor quality of life. Furthermore, acute presentation of the phenomenon is commonly life-threatening with ventricular tachyarrhythmias, conduction abnormalities, or cardiogenic shock. Acute treatment of CSF includes, but is not restricted to, intracoronary infusion of dipyridamole, adenosine, or atropine. Chronic management of patients with CSF encompasses dipyridamole, diltiazem, nebivolol, telmisartan, and/or atorvastatin associated with amelioration of angina symptoms, improved quality of life, and good prognosis.

Tongmai Yangxin pill reduces myocardial No-reflow via endothelium-dependent NO-cGMP signaling by activation of the cAMP/PKA pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: The Tongmai Yangxin pill (TMYX) is derived from the Zhigancao decoction recorded in Shang han lun by Zhang Zhongjing during the Han dynasty. TMYX is used for the clinical treatment of chest pain, heartache, and qi-yin-deficiency coronary heart disease. Previous studies have confirmed that TMYX can improve vascular endothelial function in patients with coronary heart disease by upregulating nitric oxide activity and then regulating vascular tension. Whether TMYX can further improve myocardial NR by upregulating NO activity and then dilating blood vessels remains unclear. AIM OF THE STUDY: This study aimed to reveal whether TMYX can further improve myocardial NR by upregulating NO activity and then dilating blood vessels. The underlying cAMP/PKA and NO-cGMP signaling pathway-dependent mechanism is also explored. MATERIALS AND METHODS: The left anterior descending coronary arteries of healthy adult male SD rats were ligated to establish the NR model. TMYX (4.0 g/kg) was orally administered throughout the experiment. Cardiac function was measured through echocardiography. Thioflavin S, Evans Blue, and TTC staining were used to evaluate the NR and ischemic areas. Pathological changes in the myocardium were assessed by hematoxylin-eosin staining. An automated biochemical analyzer and kit were used to detect the activities of myocardial enzymes and myocardial oxidants, including CK, CK-MB, LDH, reactive oxygen species, superoxide dismutase, malonaldehyde, and NO. The expression levels of genes and proteins related to the cAMP/PKA and NO/cGMP signaling pathways were detected via real-time fluorescence quantitative PCR and Western blot analysis, respectively. A microvascular tension sensor was used to detect coronary artery diastolic function in vitro. RESULTS: TMYX elevated the EF, FS, LVOT peak, LVPWd and LVPWs values, decreased the LVIDd, LVIDs, LV-mass, IVSd, and LV Vols values, demonstrating cardio-protective effects, and reduced the NR and ischemic areas. Pathological staining showed that TMYX could significantly reduce inflammatory cell number and interstitial edema. The activities of CK, LDH, and MDA were reduced, NO activity was increased, and oxidative stress was suppressed after treatment with TMYX. TMYX not only enhanced the expression of Gs-α, AC, PKA, and eNOS but also increased the expression of sGC and PKG. Furthermore, TMYX treatment significantly decreased ROCK expression. We further showed that TMYX (25-200 mg/mL) relaxed isolated coronary microvessels. CONCLUSIONS: TMYX attenuates myocardial NR after ischemia and reperfusion by activating the cAMP/PKA and NO/cGMP signaling pathways, further upregulating NO activity and relaxing coronary microvessels.

Coronary No-Reflow Phenomenon in Clinical Practice.

Timely delivered coronary revascularization with no residual anatomical stenosis does not always lead to prompt restoration of anterograde coronary flow and complete myocardial reperfusion. This condition is known as coronary no-reflow and is associated with major clinical adverse events and poor prognosis. The pathophysiology of no-reflow phenomenon is still poorly understood. Proposed mechanisms include distal microembolization of thrombus and plaque debris, ischemic injury, endothelial dysfunction and individual susceptibility to microvascular dysfunction/obstruction. Older age, diabetes, hypercholesterolemia, prolonged ischemic time, hemodynamic instability, high thrombus burden, complex angiographic lesions and multivessel disease are frequently reported to be associated with the no-reflow phenomenon. There is no general consensus on the correct prevention and management of no-reflow. Non-pharmacological measures such as distal embolic protection devices and manual thrombus aspiration did not result in improved flow or reduction of infarct size. Current preventive measures include reduction of time from symptoms onset to reperfusion therapy, and intracoronary administration of vasodilators such as adenosine, verapamil or nitroprusside.

Effect of intracoronary agents on the no-reflow phenomenon during primary percutaneous coronary intervention in patients with ST-elevation myocardial infarction: a network meta-analysis.

BACKGROUND: Despite the restoration of epicardial flow after primary percutaneous coronary intervention (PPCI), myocardial reperfusion remains impaired in a significant proportion of patients. We performed a network meta-analysis to assess the effect of 7 intracoronary agents (adenosine, anisodamine, diltiazem, nicorandil, nitroprusside, urapidil, and verapamil) on the no-reflow phenomenon in patients with ST-elevation myocardial infarction (STEMI) undergoing PPCI. METHODS: Database searches were conducted to identify randomized controlled trials (RCTs) comparing the 7 agents with each other or with standard PPCI. Outcome measures included thrombolysis in myocardial infarction flow grade (TFG), ST-segment resolution (STR), left ventricular ejection fraction (LVEF), major adverse cardiovascular events (MACEs), and adverse events. RESULTS: Forty-one RCTs involving 4069 patients were analyzed. The addition of anisodamine to standard PPCI for STEMI was associated with improved post-procedural TFG, more occurrences of STR, and improvement of LVEF. The cardioprotective effect of anisodamine conferred a MACE-free survival benefit. Additionally, nitroprusside was regarded as efficient in improving coronary flow and clinical outcomes. Compared with standard care, adenosine, nicorandil, and verapamil improved coronary flow but had no corresponding benefits regarding cardiac function and clinical outcomes. The ranking probability for the 7 treatment drugs showed that anisodamine consistently ranked the highest in efficacy outcomes (TFG < 3, STR, LVEF, and MACEs). No severe adverse events, such as hypotension and malignant arrhythmia, were observed in patients treated with anisodamine. Network meta-regression analysis showed that age, the time to reperfusion, and study follow-up did not affect the treatment effects. CONCLUSIONS: The intracoronary administration of anisodamine appears to improve myocardial reperfusion, cardiac function, and clinical outcomes in patients with STEMI undergoing PPCI. Given the limited quality and quantity of the included studies, more rigorous RCTs are needed to verify the role of this inexpensive and well-tolerated regimen.

Perforated balloon technique: A simple and handy technique to combat no-reflow phenomenon in coronary system.

OBJECTIVE: Examining the efficacy and outcomes of intracoronary (IC) instillation of adenosine using a novel perforated balloon technique (PBT) to combat no-reflow phenomenon during percutaneous coronary intervention (PCI) for acute coronary syndrome (ACS). BACKGROUND: Occurrence of no-reflow during PCI is a serious adverse prognostic event and inability to re-establish better flow is associated with poor outcomes. Several pharmacological and non-pharmacological interventions have been used to treat this situation. This series describes the use of PBT for IC adenosine administration and its effects on outcomes during real world interventional practice. METHODS: Subjects comprised of 24 patients with ACS (out of a total of 1,634 patients undergoing PCI between January 2016 and June 2017) in whom we used PBT for IC administration of adenosine to treat coronary no-reflow. RESULTS: PBT for IC adenosine instillation was used in 24 (1.5%) of 1,634 patients undergoing PCI. TIMI grade III flow was established in 21 patients (87.5%). In two patients (8.3%) TIMI grade II flow was established and in one patient (4.2%) we were unsuccessful. CONCLUSION: We demonstrate the safety and efficacy of a novel strategy for adenosine instillation in the distal coronary bed, the PBT. This technique enables rapid and cost-effective treatment of no-reflow phenomenon during PCI for ACS.

Effects of dabigatran regulates no­reflow phenomenon in acute myocardial infarction mice through anti­inflammatory and anti­oxidative activities and connective tissue growth factor expression.

Pradaxa is a novel oral anticoagulant, which was originally used to prevent thrombosis following joint replacement surgery. The aim of the current study was to investigate the effect dabigatran on acute myocardial infarction through regulating no­reflow phenomenon and oxidative stress, neutrophil intraplaque infiltration and apoptosis. In the present study, dabigatran significantly inhibited the infarct size, increased arterial pressure and reduced no­reflow phenomenon in acute myocardial infarction (AMI) vehicle rabbits. Treatment with dabigatran significantly inhibited the P65 of nuclear factor κB, tumor necrosis factor α, interleukin (IL)­1ß and IL­6 activities and significantly enhanced the catalase and superoxide dismutase activities in the AMI rabbits. In addition, dabigatran significantly suppressed inducible nitric oxide synthase (iNOS), collagen I, transforming growth factor ß1 (TGF­ß1), α­smooth muscle actin (α­SMA) and connective tissue growth factor (CTGF) protein expression in AMI rabbits. Taken together, these results suggest that the effects of dabigatran inhibit no­reflow phenomenon, infarct size and enhance arterial pressure in AMI through anti­inflammatory and anti­oxidative activity, and regulating iNOS, collagen I, TGF­ß1, α­SMA and CTGF protein expression in AMI rabbits.

Effects of tripterygium glycosides on restenosis following endovascular treatment.

The mechanism and associated factors of restenosis following intravascular stent implantation remain to be elucidated. The present two­part experimental and clinical study aimed to investigate the effects of tripterygium glycosides on in­stent restenosis subsequent to intra­arterial therapy. Following endovascular stent implantation in rabbit iliac arteries, post­stent outcomes were evaluated in cyclosporine groups, low­dose and high­dose tripterygium glycosides groups and controls. Post­operative angiography indicated that vessel diameters were similar between groups; however, at 28 days after receiving the therapeutic agents, vessels of the cyclosporine and tripterygium glycosides groups were significantly larger than those of the controls. Furthermore, three groups of patients had comparable baseline levels of interleukin (IL)­10, IL­18 and C­reactive protein, and intima­media thickness. However, 1 month after stent implantation, levels of IL­10 and IL­18 were markedly reduced in the high­ and low­dose tripterygium glycosides groups compared with controls. At 6 months after surgery, the stent patency rate in patients with bare stents was significantly lower than in patients receiving tripterygium glycosides (P≤0.009). In addition, the ankle­brachial index was also higher than in those without tripterygium glycosides (P<0.001). Results of the experimental and clinical studies suggest that tripterygium glycosides may inhibit and possibly aid in the prevention of in­stent restenosis formation following endovascular treatment of lower­extremity artery disease.

Sodium tanshinone IIA sulfonate ameliorates experimental coronary no-reflow phenomenon through down-regulation of FGL2.

AIMS: The effects of sodium tanshinone IIA sulfonate (STS) on coronary no-reflow (CNR) relevant to microvascular obstruction (MVO) remain unknown. Studies had shown that fibrinogen-like protein 2 (FGL2) expressed in microvascular endothelial cells (MECs) is a key mediator in MVO. Thus, we aimed to elucidate the roles of STS in CNR and relations between STS and FGL2. MAIN METHODS: Myocardial ischemia/reperfusion was selected to represent CNR model. The no-reflow zone and infarct area were assessed using Thioflavin S and TTC staining, and cardiac functional parameters were detected using echocardiography. Western blot was used to detected FGL2 level, fibrin level, protease-activated receptor-1 (PAR-1) activation and inflammation cells infiltration. FGL2 and inflammation cells were also identified by IHC. Microthrombus was detected by Carstairs' and MSB staining. We also detected the roles of STS on FGL2 expression, thrombin generation, phospho-Akt and NF-κB levels in MECs. KEY FINDINGS: Upon treatment with STS in CNR model, the no-reflow and infarct areas decreased significantly and cardiac function improved. The FGL2 expression was inhibited by STS in vivo as well as in vitro with thrombin generation inhibition. In addition, STS up-regulates Akt phosphorylation and suppressed NF-κB expression in activated MECs. Furthermore, fibrin deposition, PAR-1 activation and inflammatory response were inhibited with STS administration in CNR model. SIGNIFICANCE: Our results displayed a novel pharmacological action of STS on CNR. STS is able to ameliorate CNR through inhibition of FGL2 expression mediated by Akt and NF-κB pathways as well as prevention of MVO by suppressing fibrin deposition and inflammation.

Adenosine and verapamil for no-reflow during primary percutaneous coronary intervention in people with acute myocardial infarction.

BACKGROUND: Primary percutaneous coronary intervention (PPCI) is the preferred treatment for ST-segment elevation myocardial infarction. Although coronary flow is restored after PPCI, impaired myocardial perfusion (known as no-reflow) related to poor clinical outcomes is frequently observed. To overcome this phenomenon, drugs, such as atorvastatin, abciximab and others, have been tried as adjunctive treatment to PPCI. Among these drugs, verapamil and adenosine are among the most promising. No other systematic reviews have examined use of these two drugs in people with acute myocardial infarction (AMI) undergoing PPCI. This is an update of the version previously published (2013, Issue 6), for which the people of interest in the review were those treated with PPCI - not those given fibrinolytic therapy. OBJECTIVES: To study the impact of adenosine and verapamil on no-reflow during PPCI in people with AMI. SEARCH METHODS: We updated searches of the following databases in June 2014 without language restriction: the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, Web of Science and BIOSIS, China National Knowledge Infrastructure and clinical trials registers (ClinicalTrials.gov, Current Controlled Trials, Australian and New Zealand Clinical Trials Registry, the World Health Organization (WHO) International Clinical Trials Registry Platform). We also handsearched The American Journal of Cardiology. SELECTION CRITERIA: We selected randomised controlled trials (RCTs) in which adenosine or verapamil was the primary intervention. Participants were individuals diagnosed with AMI who were undergoing PPCI. DATA COLLECTION AND ANALYSIS: Two review authors collected studies and extracted data. When necessary, we contacted trial authors to obtain relevant information. We calculated risk ratios (RRs), P values and 95% confidence intervals (CIs) of dichotomous data. MAIN RESULTS: We included in our review 11 RCTs (one new study with 59 participants) involving 1027 participants. Ten RCTs were associated with adenosine and one with verapamil. We considered the overall risk of bias of included studies to be moderate. We found no evidence that adenosine reduced short-term all-cause mortality (RR 0.61, 95% CI 0.25 to 1.48, P value = 0.27), long-term all-cause mortality (RR 0.78, 95% CI 0.22 to 2.74, P value = 0.70), short-term non-fatal myocardial infarction (RR 1.32, 95% 0.33 to 5.29, P value = 0.69) or myocardial blush grade (MBG) 0 to 1 after PPCI (RR 0.96, 95% CI 0.76 to 1.22, P value = 0.75). The incidence of thrombolysis in myocardial infarction (TIMI) flow grade < 3 after PPCI (RR 0.62, 95% CI 0.42 to 0.91, P value = 0.01) was decreased. Conversely, adverse events with adenosine, such as bradycardia (RR 6.32, 95% CI 2.98 to 13.41, P value < 0.00001), hypotension (RR 11.43, 95% CI 2.75 to 47.57, P value = 0.0008) and atrioventricular (AV) block (RR 6.78, 95% CI 2.15 to 21.38, P value = 0.001), were significantly increased.Meta-analysis of verapamil as treatment for no-reflow during PPCI was not performed because data were insufficient. AUTHORS' CONCLUSIONS: It is difficult to draw conclusions because of the insufficient quality and quantity of current research studies. We considered the overall risk of bias of included studies to be moderate. Adenosine as treatment for no-reflow during PPCI could reduce angiographic no-reflow (TIMI flow grade < 3) but was found to increase adverse events. What's more, no evidence could be found to suggest that adenosine reduced all-cause mortality, non-fatal myocardial infarction or the incidence of myocardial blush grade 0 to 1. Additionally, the efficacy of verapamil for no-reflow during PPCI could not be analysed because data were insufficient. Further clinical research into adenosine and verapamil is needed because of the limited numbers of available trials and participants.

Effect of inflammatory factor-induced cyclo-oxygenase expression on the development of reperfusion-related no-reflow phenomenon in acute myocardial infarction.

No reflow after reperfusion therapy for myocardial infarction is a strong predictor of clinical outcome. Increased levels of inflammatory factors, including C-reactive protein (CRP), in patients with acute myocardial infarction (AMI) undergoing primary percutaneous coronary intervention (PCI) may affect myocardial perfusion. However, why the no-reflow phenomenon increases in inflammation stress after PCI is not clear. The aim of the present study was to determine the effects and molecular mechanisms underlying the effects of CRP on the expression of cyclo-oxygenase (COX) on the development of the no-reflow phenomenon. There was a significant increase in plasma levels of CRP and interleukin (IL)-6 in no-reflow patients, suggesting that inflammatory factors play an important role in the development of the no-reflow phenomenon. The mechanisms involved were further evaluated after reperfusion in a rat model mimicking the no-reflow phenomenon. Compared with normal reflow rats, there were significant increases in both COX-1 and COX-2 in cardiac tissue from no-reflow rats. The COX inhibitor indomethacin (5 mg/kg, i.p.) significantly reduced the no-reflow area. In another series of experiments, human coronary artery endothelial cells (HCAEC) were treated with CRP at clinically relevant concentrations (5-25 µg/mL). C-Reactive protein significantly increased COX-1 and COX-2 levels in a time- and concentration-dependent manner. In addition, extracellular signal-regulated kinase (ERK) and Jun N-terminal kinase (JNK) were activated in CRP (5, 10, 25 µg/mL)-treated HCAEC cultures. Furthermore, the ERK inhibitor pd98059 (30 µmol/L) and the JNK inhibitor sp600125 (10 µmol/L) blocked CRP-induced COX-1 and COX-2 expression for 12 h. Together, the findings of the present study suggest that CRP can promote the development of the no-reflow phenomenon by increasing COX-1 and COX-2 expression, which is regulated, in part, via ERK and JNK activity.

Effects of verapamil and adenosine in an adjunct to tirofiban on resolution and prognosis of noreflow phenomenon in patients with acute myocardial infarction.

AIM: We aimed to investigate the effects of verapamil and adenosine in an adjunct to intravenous tirofiban on management and prognosis of no-reflow phenomenon during primary percutaneous coronary intervention (PPCI) and to compare their efficacies on reversing of no-reflow phenomenon and short and midterm survival. METHODS: We included 46 patients with acute ST-segment elevation myocardial infarction (STEMI) and occurrence of no-reflow phenomenon after PPCI. All patients received intravenous tirofiban and then randomized into one of the following 3 groups: intracoronary adenosine (N.=16), intracoronary verapamil (N.=15) or placebo (N.=15). RESULTS: Intracoronary verapamil therapy had significant effect in restoring impaired coronary blood flow by decreasing thrombolysis in myocardial infarction (TIMI) frame count from 73±44 to 52±48 (P=0.024). However, adenosine and serum physiologic administration were not found to be so effective in decreasing TIMI frame count (from 81±35 to 71±46, P=0.084; from 74±32 to 71±37, P=0.612, respectively). In-hospital and 6-month survival rates were similar among groups. CONCLUSION: In conclusion, intracoronary verapamil restored the impaired coronary blood flow more effectively than adenosine or placebo. However, none of them has changed the clinical course in the first 6 months.

Effects of single-dose atorvastatin on interleukin-6, interferon gamma, and myocardial no-reflow in a rabbit model of acute myocardial infarction and reperfusion

The mechanisms of statins relieving the no-reflow phenomenon and the effects of single-dose statins on it are not well known. This study sought to investigate the effects of inflammation on the no-reflow phenomenon in a rabbit model of acute myocardial infarction and reperfusion (AMI/R) and to evaluate the effects of single-dose atorvastatin on inflammation and myocardial no-reflow. Twenty-four New Zealand white male rabbits (5-6 months old) were randomized to three groups of eight: a sham-operated group, an AMI/R group, and an atorvastatin-treated group (10 mg/kg). Animals in the latter two groups were subjected to 4 h of coronary occlusion followed by 2 h of reperfusion. Serum levels of interleukin (IL)-6 were measured by enzyme-linked immunosorbent assay. The expression of interferon gamma (IFN-γ) in normal and infarcted (reflow and no-reflow) myocardial tissue was determined by immunohistochemical methods. The area of no-reflow and necrosis was evaluated pathologically. Levels of serum IL-6 were significantly lower in the atorvastatin group than in the AMI/R group (P<0.01). Expression of IFN-γ in infarcted reflow and no-reflow myocardial tissue was also significantly lower in the atorvastatin group than in the AMI/R group. The mean area of no-reflow [47.01% of ligation area (LA)] was significantly smaller in the atorvastatin group than in the AMI/R group (85.67% of LA; P<0.01). The necrosis area was also significantly smaller in the atorvastatin group (85.94% of LA) than in the AMI/R group (96.56% of LA; P<0.01). In a secondary analysis, rabbits in the atorvastatin and AMI/R groups were divided into two groups based on necrosis area (90% of LA): a small group (<90% of LA) and a large group (>90% of LA). There was no significant difference in the area of no-reflow between the small (61.40% of LA) and large groups (69.87% of LA; P>0.05). Single-dose atorvastatin protected against inflammation and myocardial no-reflow and reduced infarct size during AMI/R in rabbits. No-reflow was not dependent on the reduction of infarct size.

Effects of single-dose atorvastatin on interleukin-6, interferon gamma, and myocardial no-reflow in a rabbit model of acute myocardial infarction and reperfusion.

The mechanisms of statins relieving the no-reflow phenomenon and the effects of single-dose statins on it are not well known. This study sought to investigate the effects of inflammation on the no-reflow phenomenon in a rabbit model of acute myocardial infarction and reperfusion (AMI/R) and to evaluate the effects of single-dose atorvastatin on inflammation and myocardial no-reflow. Twenty-four New Zealand white male rabbits (5-6 months old) were randomized to three groups of eight: a sham-operated group, an AMI/R group, and an atorvastatin-treated group (10 mg/kg). Animals in the latter two groups were subjected to 4 h of coronary occlusion followed by 2 h of reperfusion. Serum levels of interleukin (IL)-6 were measured by enzyme-linked immunosorbent assay. The expression of interferon gamma (IFN-γ) in normal and infarcted (reflow and no-reflow) myocardial tissue was determined by immunohistochemical methods. The area of no-reflow and necrosis was evaluated pathologically. Levels of serum IL-6 were significantly lower in the atorvastatin group than in the AMI/R group (P<0.01). Expression of IFN-γ in infarcted reflow and no-reflow myocardial tissue was also significantly lower in the atorvastatin group than in the AMI/R group. The mean area of no-reflow [47.01% of ligation area (LA)] was significantly smaller in the atorvastatin group than in the AMI/R group (85.67% of LA; P<0.01). The necrosis area was also significantly smaller in the atorvastatin group (85.94% of LA) than in the AMI/R group (96.56% of LA; P<0.01). In a secondary analysis, rabbits in the atorvastatin and AMI/R groups were divided into two groups based on necrosis area (90% of LA): a small group (<90% of LA) and a large group (>90% of LA). There was no significant difference in the area of no-reflow between the small (61.40% of LA) and large groups (69.87% of LA; P>0.05). Single-dose atorvastatin protected against inflammation and myocardial no-reflow and reduced infarct size during AMI/R in rabbits. No-reflow was not dependent on the reduction of infarct size.

Intracoronary adenosine administered during aortocoronary vein graft interventions may reduce the incidence of no-reflow phenomenon. A pilot randomised trial.

BACKGROUND: The results of percutaneous coronary intervention (PCI) for saphenous vein graft (SVG) disease are limited by distal embolisation and no-reflow which occurs in 10-43% of cases. AIM: To examine the role of a new protocol of adenosine administration during PCI in SVG on immediate angiographic results and clinical course. METHODS: A prospective, single-centre, randomised placebo-controlled pilot trial in 32 consecutive patients after coronary artery bypass graft (aged 71 ± 12 years, 22 male) with stable and unstable angina (CCS II-IV), who were admitted to our hospital for SVG PCI, was conducted. Patients were randomised to two groups. Group A (16 patients) received two times adenosine (2 mg + 2 mg) to the SVG during PCI procedure, and Group B (16 patients) received a placebo. RESULTS: No reflow was observed in one (6.25%) patient in the adenosine group and six (37.5%) patients in the placebo group (p = 0.0325). TIMI 3 flow (94% vs. 63%; p = 0.0322) and corrected TIMI frame count < 28 (94% vs. 63%; p = 0.0322) at the end of the procedure were better in patients who received adenosine. Myocardial blush grade 2 and 3 at the end of th eprocedure was observed in 15 patients in the adenosine group and ten patients in the placebo group (p = 0.083). A trend toward a lower rate of myocardial infarctions in the adenosine group was observed (6% vs. 25%; p = 0.144). CONCLUSIONS: Adenosine injections may be effective in preventing no-reflow in the setting of PCI of SVG. Adenosine administration seems to be associated with a more favourable clinical course.

Adenosine and verapamil for no-reflow during primary percutaneous coronary intervention in people with acute myocardial infarction.

BACKGROUND: Primary percutaneous coronary intervention (PPCI) is the preferred treatment for ST segment elevation myocardial infarction. Although there is restoration of coronary flow after PPCI, impaired myocardial perfusion (known as no-reflow) is frequently observed, and is related to poor clinical outcomes. In order to overcome this phenomenon, drugs have been tried as adjunctive treatments to PPCI. Among them, verapamil and adenosine are two of the most promising drugs. There are no systematic reviews of these two drugs in people with acute myocardial infarction (AMI) undergoing PPCI. OBJECTIVES: To study the impact of adenosine and verapamil on people with AMI who are undergoing PPCI. SEARCH METHODS: We searched the following databases in February 2012: the Cochrane Central Register of Controlled Trials (CENTRAL) on The Cochrane Library, MEDLINE, EMBASE, Web of Science and BIOSIS, China National Knowledge Infrastructure, Clinical Trials registers (Clinical Trials.gov, Current Controlled Trials, Australian & New Zealand Clinical Trials Registry, the WHO International Clinical Trials Registry Platform). We also handsearched the American Journal of Cardiology. SELECTION CRITERIA: We selected randomised controlled trials (RCTs) where adenosine or verapamil was the primary intervention. Participants were individuals diagnosed with AMI who were undergoing PPCI. DATA COLLECTION AND ANALYSIS: Two review authors collected studies and extracted data. Where necessary, we contacted the trial authors to obtain the relevant information. We calculated risk ratios (RRs), P values, and 95% confidence intervals (CIs) of dichotomous data. MAIN RESULTS: We included 10 RCTs involving 939 participants in our review. Nine RCTs were associated with adenosine and one with verapamil. We considered the overall risk of bias of included studies to be moderate. There was no evidence that adenosine reduced short-term all-cause mortality (RR 0.61, 95% CI 0.23 to 1.61, P = 0.32), long-term all-cause mortality (RR 1.20, 95% CI 0.27 to 5.22, P = 0.81), short-term non-fatal myocardial infarction (RR 1.38, 95% 0.28 to 6.96, P = 0.69) or the incidence of angiographic no-reflow (TIMI flow grade < 3 after PPCI: RR 0.72, 95% CI 0.49 to 1.07, P = 0.11, and myocardial blush grade (MBG) 0 to 1 after PPCI: RR 0.96, 95% CI 0.76 to 1.22, P=0.75). But the incidence of adverse events with adenosine, such as bradycardia (RR 6.57, 95% CI 2.94 to 14.67, P<0.00001), hypotension (RR 11.43, 95% CI 2.75 to 47.57, P=0.0008) and atrioventricular (AV) block (RR 6.67, 95% CI 1.52 to 29.21, P=0.01) was significantly increased.Meta-analysis of verapamil as treatment for no-reflow during PPCI was not calculated due to lack of data. AUTHORS' CONCLUSIONS: We found no evidence that adenosine and verapamil as treatments for no-reflow during PPCI can reduce all-cause mortality, non-fatal myocardial infarction or the incidence of angiographic no-reflow (TIMI flow grade < 3 and MBG 0 to1), but there was some evidence of increased adverse events. Further clinical research into adenosine and verapamil is needed because of the limited numbers of included trials and participants.

Intracoronary injection of drugs to treat no--reflow phenomenon and microcirculatory dysfunction.

In a variant proportion of patients presenting with chest pain and electrocardiographic changes characteristic for ST - elevation myocardial infarction, percutaneous coronary intervention achieves epicardial coronary artery reperfusion but not the myocardial reperfusion (ranging from 5% to 50%). Furthermore, prolonged myocardial ischemia often breaks down the coronary microvasculature and the flow to the infarct myocardium may seem to be markedly reduced. This condition is known as no reflow - phenomenon. The no reflow - phenomenon is associated with an increased incidence of malignant ventricular arrhythmias, heart failure and 30-days mortality. In the recent years in literature, several articles (subsequently discussed in the present review) have been published and made relevant to the study of the pathophysiology regarding no reflow - phenomenon. This knowledge has assisted in the development of new treatment strategies, such as prophylactic use of vasodilators, mechanical devices and drugs inhibiting platelet. The review has focused on the current literature about intra - coronary injection of drugs to treat no - reflow and microvascular dysfunction.