However, studies performed in the isolated perfused hearts subjected to ischemia/reperfusion (I/R) do not suggest the involvement of microembolization and microthrombi in this phenomenon. The intracoronary administration of alteplase has been found to have no effect on the occurrence of MVO in patients with acute myocardial infarction. Consequently, the major events preceding the appearance of MVO in coronary arteries are independent of microthrombi, platelets, and neutrophils. Endothelial cells appear to be the target where ischemia can disrupt the endothelium-dependent vasodilation of coronary arteries. However, reperfusion triggers more pronounced damage, possibly mediated by pyroptosis. MVO and intra-myocardial hemorrhage contribute to the adverse post-infarction myocardial remodeling. Therefore, pharmacological agents used to treat MVO should prevent endothelial injury and induce relaxation of smooth muscles. Ischemic conditioning protocols have been shown to prevent MVO, with L-type Ca In 1967, Majno et al reported the absence of the complete restoration of blood flow after rabbit brain ischemia (15 min). Investigators called this phenomenon "no-reflow". The no-reflow phenomenon has been demonstrated after both renal ischemia and reperfusion (I/R). More recently, Kloner et al found that microvascular damage was involved in the genesis of the "no-reflow" phenomenon in dogs. In the dogs underwent CAO for 40 min and followed by reperfusion for 90 min, complete CBF restoration occurred after a 40-min ischemia; however, CBF was not completely restored after CAO with a duration of 90 min, confirming that the formation of the no-reflow area was associated with microvascular injury. In 1985, Schofer et al discovered that the no-reflow phenomenon was observed in patients with ST-segment elevation myocardial infarction . It was found that thrombolysis did not result in the complete CBF restoration. The no-reflow area was documented by scintigraphy with thallium-201 and 99mTc-microalbumin aggregates. All patients had an acute myocardial infarction (AMI), and the onset of chest pain was less than 3 h before hospital admission.In 1966, Krug n = 5) with STEMI. It should be noted that both studies involved small samples of patients–6; therefore, these studies cannot be used to assess the incidence of the microvascular obstruction (MVO) phenomenon. It should also be noted that there is no generally accepted definition of the terms "the no-reflow phenomenon" and "MVO". Sometimes these terms are used as interchangeably, with some investigators believing that MVO is one manifestation of the no-reflow phenomenon or the slow flow phenomenon. Currently, investigators use the term "MVO" or the term "the slow flow phenomenon" more often, because the complete no-reflow phenomenon is observed angiographically only in 5% of patients after PCI, and in the remaining patients, there could be a non-complete restoration of CBF. Here, the terms "no-reflow" and "MVO" are used synonymously. We will use the term "MVO" more often than the term "no-reflow" in the description of clinical studies, because in our opinion "no-reflow" is a clinical situation where CBF has not been restored in the infarct-related coronary artery. Professor G. Heusch has made a great contribution to the study of MVO.In 1989, the vasoconstriction area after successful percutaneous coronary intervention (PCI) was observed in patients (. MVO has been diagnosed by the contrast-enhanced magnetic resonance imaging (MRI) in 25% of patients with STEMI, diagnosed angiographically in 29% of patients with both STEMI and PCI, but detected by MRI in 56% of patients with both STEMI and PCI and diagnosed with transthoracic echocardiography in 50% of patients with both STEMI and PCI. MVO also can be detected by the angiographic TIMI flow grade in 25% of patients with STEMI and PCI in one study but in 46% of patients with STEMI and PCI by the same method in another study. However, MRI data alone suggested that the incidence of MVO was 37% in patients with STEMI and PCI. These data suggest that the incidence of MVO may range between 25% and 56% in patients with STEMI and PCI.The persistent full no-reflow phenomenon  can be angiographically found in approximately 5% of patients with AMI and PCI, but MVO may be more common. The in-hospital mortality rate was approximately 14% in patients with MVO and 3% in those without MVO, with a total mortality of 6% as reported. Persistent no-reflow was associated with an increased all-cause mortality during a 3-year follow-up after AMI. Patients with STEMI and no-reflow had an increased risk of in-hospital mortality, compared with patients without no-reflow.Patients with MVO six months after AMI had a greater number of cardiovascular events than those without MVO. MVO measured by myocardial contrast echocardiography is the most powerful independent predictor of the adverse left ventricular remodeling after STEMI. In patients with STEMI undergoing PCI, the no-reflow is a strong independent predictor of 5-year mortality. MVO is associated with a larger myocardial infarction, a lower ejection fraction, and a high mortality during five years after AMI. MVO is also accompanied by the adverse cardiac remodeling eight months after AMI. Major adverse cardiac events during six months after STEMI often occur in patients with MVO detected by MRI.MVO predicts a more frequent development of cardiovascular complications in patients with AMI within two years. It appears that endothelial cells are more tolerant to ischemia than cardiomyocytes. According to Kloner et al, the no-reflow area was distinguished by ultrastructural microvascular damage, including swelling of endothelial cells and the obstruction of the lumen of small vessels. The presence of endothelial swelling and peri-capillary edema in animals with no-reflow is beyond doubt. However, there is no conclusive evidence of the important role of endothelial swelling in the pathogenesis of MVO, because decongestants have not been used for treatment of MVO. When an isolated rodent heart was subjected to global ischemia for 45 min and reperfusion for 15 min, I/R reduced the lumen of capillaries by approximately 50%, endothelial swelling was developed, and the endothelial cell size was increased by approximately 20%. It is unclear whether these alterations induce MVO, even though the antioxidant Trolox increased the lumen of capillaries but did not affect endothelial cell swelling.In dogs underwent CAO at 20, 40, 60, 90, or180 min intervals, ultrastructural injury of cardiomyocytes was found 20–40 min after the onset of ischemia, but microvascular injury was detected 60–90 min after the onset of ischemia. I/R injured the endothelial glycocalyx when isolated guinea pig hearts were subjected to global ischemia (15 min) and reperfusion (20 min). However, a correlation analysis between plasma concentration syndecan , thrombomodulin , and MVO size had not been performed before (Table 1).The glycocalyx is a pericellular matrix layer containing glycoproteins and glycolipids that covers the cell membranes of endothelial cells, epithelial cells, and other cells. I/R induced glycocalyx injury and, as a result, endothelial cell dysfunction. Therefore, thrombosis of coronary microvessels did not play a key role in the pathogenesis of the no-reflow phenomenon. In a later article, Kloner et al reported that the aggregation of blood elements could play a greater role in the development of no-reflow. Indeed, clinical studies have confirmed the important role of aggregation of platelets–29 and erythrocytes in the development of MVO in patients with AMI. Professor G. Heusch claimed that he could demonstrate an important role of microembolization and microthrombi in the appearance of no-reflow personal communication. However, his opinion is not shared by other investigators.In dogs undergoing CAO (3 h) and reperfusion(3 h), the infarct area of the left ventricle was almost identical between the control (13.4%) and streptokinase-treated groups (13.0%); CBF was decreased by 90% in the subendocardial area at risk (I/R zone) during ischemia; CBF in the subendocardium was 0.33 mL/(min·g) in the control group and 0.38 mL/(min·g) in the streptokinase group during reperfusion; however, these differences were not statistically significant. In one study, isolated rabbit hearts were subjected to global ischemia (30 or60 min) and reperfusion (90 or 60 min), global ischemia without reperfusion induced edema of the myocardium; the reperfusion triggered an increase in perfusion pressure, indicating the presence of coronary vasospasm and MVO; and coronary artery permeability was measured by recording the passage of l25I-BSA  through the coronary vessels; in addition, vascular permeability increased as the duration of reperfusion increased. These findings indicate that MVO can exist without the involvement of thrombosis, platelets, and leukocytes.In a placebo-controlled trial, it was demonstrated that intracoronary administration of alteplase in patients with STEMI and PIC had no effect on the incidence of MVO, and this exposure triggered the formation of a no-reflow area. Therefore, erythrocyte plugging, platelet aggregation, and thrombosis could be excluded as the main causative factors in MVO. When isolated rat hearts were subjected to global ischemia  and reperfusion (5 min), the complete restoration of coronary flow (CF) was documented after a 15-min ischemia, and the complete no-reflow area was detected in the subendocardium after a 30-min ischemia with a reduction in CBF by 50% in the middle myocardium; in addition, a decrease in CBF in the subepicardium was detected after a 45-min ischemia. These investigators hypothesized that no-reflow could be a result of compressed myocardial contracture. When isolated rat hearts were subjected to global ischemia (30 min) and reperfusion , CBF in left ventricle outer layers before ischemia was 13.2 mL/(g·min) but decreased to 4.8 mL/(g·min) after a 1-min reperfusion, and further decreased to 2.5 mL/(g·min) after a 60-min reperfusion. These results suggest that the cause of no-reflow is an ischemic injury of coronary arteries, but reperfusion injury also plays a role in the no-reflow phenomenon. In isolated rat heart, global ischemia (30 min) and reperfusion (30 min) resulted in the appearance of no-reflow after I/R of the isolated heart, and that the no-reflow area was occupied 30% of the left ventricle.In another study, an isolated perfused rodent heart was subjected to global ischemia (60 min) and reperfusion (20 min)in vivo.Therefore, the role of microembolization and microthrombi in the pathogenesis of MVO remains a matter of debate. MVO could develop without the involvement of platelets, leukocytes, and erythrocytes. However, we cannot exclude the involvement of platelets, leukocytes, and erythrocytes in the pathogenesis of MVO . It was observed then that the labeled platelet accumulation in the myocardium of hypercholesterolemic rabbits was approximately 4-fold higher than in control animals; the infarct size was also approximately 2-fold higher than in the control group; and the no-reflow area was 4-fold higher than in the control rabbits–38. It was also observed that goat anti-rabbit platelet serum reduced the infarct size and the MVO area only in hypercholesterolemic rabbits. It appears that platelets are involved in the pathogenesis of MVO in animals with hypercholesterolemia.To study the role of platelet aggregation in MVO, rabbits underwent CAO (30 min) and reperfusion were used (5.5 h) in the development of MVO12 receptor antagonist clopidogrel or glycoprotein Ⅱb/Ⅲa inhibitor tirofiban for three days before CAO, both clopidogrel and tirofiban significantly reduced platelet aggregation rate; although only tirofiban reduced the MVO area by 71%, a combination of clopidogrel + aspirin had no effect on the MVO area. These investigators left this surprising difference between clopidogrel and tirofiban without an explanation.Aggregating platelets could disrupt the relaxation of isolated rings of canine coronary arteries. For example, when mini-pigs were subjected to CAO (3 h) and reperfusion (60 min) and also pretreated with the aspirin + P2Y.However, there is evidence that platelets can exhibit cardioprotective properties in I/R of the heart. For example, when isolated rat hearts were subjected to global ischemia (15 min) and reperfusion (10 min), I/R induced disturbances of contractile function and an increase in coronary perfusion pressure (CPP) that indirectly indicated the appearance of MVO; perfusion of hearts with a solution containing rat platelets prevented reperfusion-reduced contractile dysfunction and abolished an increase in CPP, while reperfusion creatine kinase release was also reducedet al. In his study, the isolated rat hearts were subjected to global ischemia (30 min) and reperfusion (60 min), and platelets of healthy volunteers were added to a perfusion solution prior to global ischemia. In this case, platelets resulted in a decrease in the infarct size by approximately 15%; although platelets of patients with diabetes mellitus did not limit the infarct size, platelets of healthy volunteers induced phosphorylation (activation) of extracellular signal-regulated kinase (ERK1/2); furthermore, platelets of patients with diabetes also had no effect on ERK1/2 phosphorylation, while inhibition of ERK1/2, protein kinase C (PKC), phosphatidylinositol -bisphosphate 3-kinase (PI3K) eliminated the cardioprotective effect of platelets. It should be noted that ERK1/2, PI3K, and PKC participate in the pre- and postconditioning-induced cardiac tolerance to I/R. It is possible that platelets could release a cardioprotective substance that increases cardiac tolerance to I/R and that platelets could be involved in MVO. It should be noted that the infarct-limiting effect of platelets was weak (−15%). These data were not confirmed by other investigators.The cardioprotective effect of platelets was experimentally confirmed by Russo 2+ channel blocker verapamil mitigated the I/R-induced disturbance in vascular relaxation. Therefore, it is likely that I/R disturbed endothelium-dependent vasodilation of coronary arteries through Ca2+ overload of endothelial cells. However, when dogs were subjected to CAO (2 h) and reperfusion (3 h), and acetylcholine was infused intracoronary in reperfusion, the reperfusion disturbed endothelium-dependent vasodilation of the infarcted coronary artery. In another study, cats underwent CAO(90 min) and reperfusion , and then vasodilation of coronary arterial rings isolated from the left anterior descending (LAD) coronary artery subjected to I/R was studied; in addition, the following compounds were used: acetylcholine, A23187 (an endothelium-dependent vasodilator), and NaNO2 (an endothelium-independent vasodilator); the results showed that acetylcholine-induced relaxation of LAD coronary artery rings was not impaired after ischemia without reperfusion, that the reperfusion (2.5 min) reduced acetylcholine-triggered vasodilation by 36%, and that A23187-induced vasodilation decreased after 20-min reperfusion. However, there was no decrease in response to NaNO2 in the LAD artery rings in reperfusion; although pretreatment with superoxide dismutase (SOD) improved acetylcholine-induced vascular relaxation in reperfusion, a free radical scavenger N-(2-mercapto propionyl)-glycine did not improve acetylcholine-triggered vasodilation. Furthermore, transmission electron microscopy revealed very little endothelial cell damage even after long-term CAO (4.5 and 6.0 h) without reperfusion. These results suggest that reperfusion, but not ischemia, is the main cause of I/R injury of coronary arteries in I/R in cats. Therefore, these investigators concluded that reperfusion injured endothelial cells and reduced endothelium-derived relaxing factor release through an increase in superoxide radical production.In dogs underwent CAO (60 min) and reperfusion (60 min), the responses of arterial rings to acetylcholine, an endothelium-dependent vasodilator, were studied; it was found that I/R of the heart reduced acetylcholine-induced vasodilation, whereas the response to nitroprusside, an endothelium-independent vasodilator, was not altered; furthermore, intravenous administration of the L-type Caet al used bradykinin to stimulate endothelium-dependent vasodilation and sodium nitroprusside, an NO donor, for endothelium-independent vasodilation. It was found that ischemia (60 min) disturbed vasodilation, that the vasodilator effect of bradykinin disappeared after90-min of ischemia, and that the vasodilator effect of sodium nitroprusside was not altered by ischemia. These results suggest that both reperfusion and ischemia can disrupt endothelium-dependent vasodilation of coronary arteries. It is unclear why the response of coronary arteries to ischemia is so different in cats and pigs.To study vascular relaxation of intramyocardial artery rings isolated from the ischemic porcine myocardium, Dignan , I/R blocked blood flow in 40% of capillaries in the area at risk; moreover, some evidence was obtained that pericytes could induce vasoconstriction of microvessels in the heart, but adenosine mitigated pericyte constriction and no-reflow. Another study showed that the GPR39 receptor was expressed in vascular smooth muscle cells and pericytes, and the activation of this receptor promoted the vasoconstriction of microvessels in myocardial tissue. When the wild-type mice and GPR39 knockout mice underwent CAO(45 min) and reperfusion (2 h), the no-reflow area was smaller in the GPR39 knockout mice, compared with the wild-type mice, while the administration of the GPR39, a VC43 receptor antagonist, 30 min before the onset of reperfusion also reduced MVO. These investigations suggest that pericytes may be involved in the I/R-induced vasoconstriction of microvessels.Pericytes are perivascular cells found in the heart, which are involved in angiogenesis, regulation of CBF, and vascular permeability. Dysfunction of pericytes is also involved in the pathogenesis of MVO. For example, when rats underwent CAO(45 min) and reperfusion (15 min). Another study performed in pigs subjected to CAO (90 min) and reperfusion also showed persistent MVO on days 7–9 after the onset of reperfusion. Thus, MVO may be a persistent pathological alteration in CBF, which could promote adverse post-infarction remodeling of the heart.In rats underwent CAO (60 min) and reperfusion, scar thickness and the infarct expansion index were assessed four weeks after myocardial infarction in one study, and the results showed that CBF was reduced in the infarcted myocardium, compared with the non-infarcted myocardium; then, a number of perfused capillaries in the infarcted area were found to be closely correlated with the infarct expansion index and significantly correlated with scar thickness, suggesting that MVO may persist for one month after reperfusion and predict adverse myocardial remodeling2+ overload or oxidative stress,42,44. In one study, the isolated perfused rat hearts were subjected to global low-flow ischemia (30 min) and reperfusion (30 min) and the coronary arteries were constricted by the addition of U46619, a stable analogue of thromboxane A2 and the vasodilation were induced by acetylcholine (an endothelium-dependent vasodilator) or an NO donor glyceryl trinitrate (an endothelium-independent vasodilator), and then the measurements were performed before ischemia, after ischemia, or pretreatment with the oxygen radical inducer tert-butyl hydroperoxide (tBHP); the results showed that the vasodilation induced by acetylcholine was reduced by 34% after reperfusion and by 48% after tBHP, while responses to an NO donor were not altered; moreover, tBHP-injured vasodilatation responses to acetylcholine were improved by pretreatment with the L-type Ca2+ channel blocker nisoldipine; by contrast, the vasodilator effect of acetylcholine was not improved when the hearts were perfused with L-type Ca2+ channel blockers diazepam or verapamil, suggesting that reperfusion or oxidative stress may disturb endothelium-dependent vasodilation; however, the investigators provided no explanation as to why nisoldipine could abolish reperfusion or free radical-induced disturbance of vasodilation, but verapamil or diazepam had no effect? In another study, rabbits underwent CAO (30 min) and reperfusion (5.5 h); at the same time, the L-type Ca2+ channel blocker gallopamil was administered in CA, and SOD was administered in reperfusion; the results showed that both gallopamil and SOD reduced the infarct size and decreased the no-reflow area by about 60%. These data demonstrate that Ca2+ overload and oxidative stress are involved in reperfusion injury of coronary arteries. Neutrophils could also be a source of oxygen radicals in injured coronary arteries in reperfusion; however, they cannot be a source of oxygen radicals as shown in a study with the isolated rat heart, in which dogs underwent CAO (90 min) and reperfusion (6 h), and CBF decreased by 82% in the subendocardium after a 80-min ischemia but completely restored after a 30-min reperfusion, while CBF was reduced by 32% in the subendocardial area at risk after a 3-h reperfusion, compared with the pre-ischemic value, and continued to decline with further reperfusion, but the L-type channel blocker clentiazem given at reperfusion mitigated no-reflow and reduced the infarct size.What is the trigger of microvascular dysfunction? The aforementioned data suggest that it could be Ca. However, our group found that the administration of verapamil at a dose of 0.2 mg/kg5 min before reperfusion reduced the infarct size by 30% in rats with CAO (45 min) and reperfusion(120 min). Therefore, the absence of the infarct-reducing effect of verapamil in Reffelman's study was surprising to us. In another study, when pigs underwent CAO (3 h) and reperfusion (1 h), and then diltiazem and verapamil were injected with intracoronary at a bolus of 2 mg 1 min before reperfusion; the results showed that both diltiazem and verapamil reduced the no-reflow area (P < 0.01) but had no effect on the infarct size, suggesting that the L-type channel blockade did not affect the infarct size, if the duration of ischemia was 3 h, but could reduce the no-reflow area within 3 h.In one study, rabbits underwent CAO (30 min) and reperfusion (120 min), and verapamil was administered intravenously (5 min prior to reflow) as a bolus of 50 μg/kg and infused at 150 μg/(kg·h) until the end of reperfusion to make the total dose of verapamil 0.35 mg/kg; the results showed that verapamil did not affect the no-reflow area and the infarct size2+ overload was also involved in the I/R injury of the heart, and histidine triad nucleotide-binding 2 (HINT2) further regulated the Ca2+ level in mitochondria as reported, in which HINT2 overexpressed mice and wild-type mice underwent CAO (45 min) and reperfusion; the results showed that HINT2 overexpression promoted a decrease in the no-reflow area, and the same effect was exhibited by Ru360, an inhibitor of Ca2+ transport into mitochondria. These findings indicate that mitochondrial Ca2+ overload is also involved in MVO. Therefore, it appears that reactive oxygen species (ROS) and Ca2+ overload may be involved in the pathogenesis of MVO, but surprisingly, some antioxidants and the L-type Ca2+ channel blockers cannot prevent the development of MVO.Mitochondrial calcium Ca. The investogators suggested that endothelins did not play a key role in MVO.One study showed that when the isolated rabbit hearts were subjected to global ischemia (60 min) and reperfusion (60 min), I/R reduced the left ventricular-developed pressure and CPP; but the endothelin receptor antagonist BQ-123 had no effect on reperfusion recovery of contractility and CPP+/H+ exchanger inhibitor cariporide (0.3 mg/kg) was also injected intravenously before ischemia, cariporide reduced the infarct size by 62% and promoted a reduction in the no-reflow area by 53%, compared with a decrease in the no-reflow area by 37% with ischemic preconditioning (Table 2). Thus, both the inhibition of the Na+/H+ exchanger and ischemic preconditioning could prevent the appearance of no-reflow, but cariporide exhibited a more pronounced effect, suggesting that the Na+/H+ exchanger plays an important role in MVO.One study showed that when rabbits were subjected to CAO (30 min) and reperfusion (180 min) and the Na2, could induce vasodilation of the coronary arteries even after I/R injury of the heart,44,46, which may suggest that vascular muscle cells are more tolerant to I/R than endothelial cells. Besides, in pigs that underwent CAO (50 min) and reperfusion (4 h), the inhalation with NO resulted in a decrease in the infarct size by about 50%, but intravenous administration of an NO donor, nitroglycerin, had no effect; moreover, NO inhalation increased CBF in the area at risk 4 h after the onset of reperfusion, but nitroglycerine did not abolish MVO (Table 2). Therefore, a dose of nitroglycerin was not enough for an increase in cardiac tolerance to I/R and prevention of MVO. It appears that NO inhalation only increased the NO level in the myocardial tissue.We have discussed above that NO donors, sodium nitroprusside and NaNO. In another study, mini-pigs were pretreated for three days with non-selective α1- and β-AR blocker carvedilol [1 mg/(kg·day)] or the β1- and β2-AR antagonist propranolol subjected to CAO (3 h) and reperfusion (1 h); carvedilol was found to reduce the no-reflow area by 70%, but propranolol had no effect. It should be noted that carvedilol can not only block the adrenergic receptor but also exhibit antioxidant properties as well as inhibit pyroptosis and stimulate autophagy. Thus, it appears that its protective effect against MVO may be independent of β-AR blockade. Additionally, carvedilol-induced protection of the coronary arteries in I/R was mediated via the ATP-sensitive K+ channel (KATP channel) opening and possibly a decrease in the endothelin-1 level in the plasma and myocardial tissue. These data suggest that β-adrenergic receptors do not play an important role in MVO.In one study, rabbits underwent CAO (30 min) and reperfusion (5.5 h), and the β-adrenergic receptor (β-AR) agonist isoproterenol was then infused [0.1 µg/(kg·min)] during ischemia and reperfusion, the unexplained results showed that isoproterenol increased the infarct size by about 2-fold but had no effect on the no-reflow area. Similarly, when mini-pigs underwent CAO (3 h) and reperfusion (2 h), pretreatment with fosinopril (an angiotensin-converting enzyme inhibitor) and valsartan (an angiotensin Ⅱ receptor antagonist) 3 days before CAO could both reduce the MVO area by approximately 30%. These findings suggest that angiotensin Ⅱ may be involved in the development of MVO.In one study, when the isolated perfused rat hearts were subjected to global ischemia (30 min) and reperfusion (30 min), pretreatment with the angiotensin Ⅱ AT1-receptor antagonist candesartan improved contractility of the heart and reduced the no-reflow area by about 70%. It also protected the isolated cardiomyocytes against hypoxia/reoxygenation, protected endothelial cells and coronary arteries against I/R, and prevented adhesion between isolated endothelial cells and neutrophils.Adenosine decreased the infarct size in CAO and reperfusion by reducing endothelin release from the heart in I/R in dogs. When dogs were subjected to CAO (90 min) and reperfusion(210 min), adenosine infusion in reperfusion(150 min) reduced the infarct size by increasing CBF in the non-ischemic myocardium by about 4-fold, but triggered a small increase in CBF in the subendocardium of the area at risk without alterations in the midmyocardium and epicardium; moreover, adenosine reduced the plasma endothelin-1 level in the blood from the coronary sinus. But when rabbits were subjected to CAO (30 min) and reperfusion(120 min) and adenosine was infused intravenously during the reperfusion period, adenosine had no effect on MVO. However, when mini-pigs underwent CAO (3 h) and reperfusion (1 h), adenosine infused 30 min before reperfusion and continued to administer during reperfusion could reduce the no-reflow area by 75%. Another study also used rabbits that were subjected to CAO (30 min) and reperfusion (3 h), and then GP531  was infused before, during, and after ischemia; the results showed that GP531 had no effect on CBF in the area at risk in reperfusion (Table 2). While, if pigs underwent CAO (45 min) and reperfusion (2 h) with adenosine infused intracoronary at a dose of50 μg/(kg·min) beginning 5 min prior to reperfusion and continued infusion throughout the 2-h reperfusion period, adenosine reduced the no-reflow area by 47%.In dogs that underwent CAO (2 h) and reperfusion (3 h), intracoronary infusion of adenosine during the first hour of reperfusion mitigated MVO, preventing reperfusion injury of coronary arteries,57,68, while others have demonstrated that adenosine has no effect on the no-reflow area,65. It should be noted that adenosine could increase CBF 4-fold in the non-infarcted myocardium but had virtually no effect on CBF in the area at risk at reperfusion. Therefore, it cannot be ruled out that adenosine may induce the appearance of coronary steal, which would exacerbate the course of AMI.Therefore, investigations related to the role of adenosine in the prevention of MVO are contradictory. Some investigators have reported that adenosine mitigates MVOTable 2). In mechanism, the inhibitor protein kinase A (PKA) H-89 was demonstrated to be partially abolished, but the NO-synthase (NOS) inhibitor L-NNA completely reversed the reduction in the no-reflow area; also, Tongxinluo could promote phosphorylation of endothelial NOS (eNOS) and increase PKA activity; thus, eNOS and PKA may be involved in the protective effect of Tongxinluo. Another study demonstrated that ischemic preconditioning reduced the MVO area by 78% in mini-pigs with I/R of the heart, and that both PKA and eNOS were involved in this protective effect. However, when min-pigs underwent a 1.5-h CAO and a 3-h reperfusion, simvastatin (2 mg/kg) that was administered intragastrically 1 h prior to ischemia reduced the no-reflow area by 28%, in which eNOS was involved in the effect of simvastatin. Thus, it could be hypothesized that these kinases might be involved in the protection of endothelial cells in I/R of the heart. Besides, it was reported that Tongmai Yangxin, a traditional Chinese medicine, could prevent the appearance of the no-reflow phenomenon in rats through PI3K/Akt/eNOS, cAMP/PKA, and NO/cGMP pathways –73.In one study, when rats underwent CAO (90 min) and reperfusion (3 h), Tongxinluo  that was administered intragastrically 1 h before coronary artery occlusion reduced the no-reflow area by 80% , Janus kinase (JAK), epidermal growth factor receptor  and Src-kinase (tyrosine kinase) in the protection of coronary arteries against I/R remains unknown, although these kinases are involved in the cardioprotective effect of pre- and post-conditioning.ATP channels have been reported to be involved in fosinopril- and valsartan-induced protection against MVO in mini-pigs with CAO and reperfusion; similarly, simvastatin has also demonstrated a protective effect against MVO in mini-pigs, but this effect can be abolished by 5-hydroxydecanoate, a blocker of mitochondrial KATP channels (mitoKATP channels); furthermore, nicorandil, acting as an opener of KATP channels and an NO donor, has been shown to reduce both the infarct size and the no-reflow area in mini-pigs with I/R, but this effect can be abolished by the NOS inhibitor L-NMMA and the KATP channel blocker glibenclamide–75. Additionally, nicorandil was found to decrease plasma endothelin-1 levels and endothelin-1 content in myocardial tissues, while simvastatin also decreased the area of no-reflow in mini-pigs with I/R, but this effect can be abrogated by glibenclamide. Therefore, it is likely that KATP channels are involved in the vasoprotective effects of carvedilol and adenosine. These data suggest that the opening of KATP channel may prevent MVO. However, the specific mechanism by which KATP channel opening protects coronary arteries against I/R, whether through the mitoKATP channel or the sarcolemmal KATP channel, remains unclear.K. Additionally, ischemic preconditioning reduced the MVO area by 78% in mini-pigs with I/R of the heart in another study. The protective effect of preconditioning is mediated thought PKA and eNOS. In mini-pigs underwent CAO (3 h) and reperfusion (2 h), and remote preconditioning was performed with four cycles of ischemia (5 min) and reperfusion (5 min) of lower limb ischemia beginning at 40 min before reperfusion of the heart; the results showed that remote preconditioning reduced the infarct size by 24% and the no-reflow area by 45%, but glibenclamide abrogated both effects of remote preconditioning. In rabbits underwent CAO (30 min) and reperfusion (3 h), however, post-conditioning had no effect on the infarct size and the no-flow area. Additionally, ischemic post-conditioning in pigs (n = 6) also showed no effect on the infarct size or the MVO area. Apparently, these findings suggest a potential error in the experimental protocol as a typical manifestation of post-conditioning is a decrease in the infarct size.Ischemic preconditioning decreased the no-reflow area by 37% in rabbits with CAO and reperfusion in one study. In another study involving pigs subjected to CAO(90 min) and reperfusion (3 h), ischemic preconditioning, ischemic postconditioning, and remote perconditioning all decreased myocardial edema and the MVO area, but only ischemic preconditioning reduced the infarct size.In one study involving pigs underwent CAO (40 min) and reperfusion, ischemic preconditioning was found to reduce the infarct size by 50% and the MVO area by 80%; however, post-conditioning had no effect on the infarct size and the MVO area. Still, it is currently unclear whether remote postconditioning can mitigate the no-reflow phenomenon. Further investigations focusing on the molecular mechanisms of the vasoprotective effect of preconditioning, postconditioning, remote perconditioning, and remote postconditioning will promote the creation of new drugs for treatment of MVO in patients with AMI.These data indicate that preconditioning and remote perconditioning can decrease the MVO area; however, the molecular mechanism of vasoprotection is unknown. Notably, there is a report suggesting that PKA and eNOS may could a role in the vasoprotective effect of preconditioning. The results showed that hearts perfused with a solution containing erythrocytes before ischemia demonstrated a decrease in perfused capillaries (approximately 25%) after 25 min of reperfusion; similarly, hearts perfused with leukocyte-free DWB before ischemia also exhibited a decrease in perfused capillaries (approximately 33%) after reperfusion; furthermore, hearts perfused with DWB containing leukocytes demonstrated a reduction in perfused capillaries (approximately 62%) after reperfusion, and coronary vascular resistance was increased by 76%. These findings suggest that both leukocytes and platelets could be involved in reperfusion MVO. However, it should be noted that the no-reflow phenomenon can occur without the involvement of leukocytes and platelets.In one study using the isolated rat hearts, global ischemia (30 min) and reperfusion (15 and 25 min) were induced, followed by three types of Krebs buffer solutions for heart perfusion: (1) a solution containing erythrocytes, (2) a solution containing diluted whole blood (DWB), and (3) a solution containing leukocyte-free DWB111In-neutrophils and 125I-BSA were used to measure neutrophil accumulation and microvascular plasma permeability. The results showed that I/R resulted in an increase in 111In-neutrophils and 125I-BSA in the area at risk, that anti-neutrophil serum abolished neutrophil accumulation in myocardial tissue but had no effect on microvascular plasma permeability and that the platelet-activating factor antagonist WEB 2086  had no effect on neutrophil invasion and microvascular permeability. These data indicate that neither neutrophils nor platelets are involved in I/R-induced microvascular permeability.I/R induces microvascular injury and triggers the appearance of MVO without leukocytes. For example, in rabbits underwent CAO (30 min) and reperfusion(3 h), in vivo I/R of the dog's heart induced leukocyte plugging in microvessels and no-reflow. Additionally, leukocyte depletion decreased manifestations of no-reflow in the dog's heart; furthermore, when dogs underwent CAO (90 min) and reperfusion (2 h), leukocyte depletion promoted a reduction in the infarct size and the no-reflow area.In dogs underwent CAO (3 h) and reperfusion (2.5 h), I/R induced neutrophil invasion into the walls of large epicardial coronary arteries; similarly, when dogs subjected to CAO (60 min) and reperfusion (120 min), reperfusion triggered leukocyte invasion in myocardial tissues, and . These results cast some doubt on a key role of leukocyte invasion in the pathogenesis of MVO.In contrast to the previous findings, one study in rabbits (subjected to CAO for 30 min and reperfusion for 4 h) using CY1503, an inhibitor of selectin adhesion molecules (administered 10 and 25 min after the onset of ischemia), found no significant effect on the infarct size or no-reflow. Based on these findings, it was concluded that platelets and neutrophils injured coronary arteries synergistically in reperfusion through enhancement of platelets' and neutrophils' adhesion in arteries mediated by P-selectin .Furthermore, an isolated rat heart model of I/R injury demonstrated that the addition of neutrophils or platelets individually to the perfusion solution resulted in a minor reduction in CF, approximately 5% each; however, when neutrophils and platelets were added to a perfusion solution together, they reduced CF by approximately 50%; furthermore, the selectin-mediated cell adhesion inhibitor sialyl LewisX-oligosaccharide completely abolished the negative effect of co-administration of neutrophils and platelets on CF, an exposure to CAO for 90 min followed by reperfusion was performed; it showed that in the control group, regional CBF before ischemia was 80 mL/(100 g·min) and decreased to17 mL/(100 g·min) at the end of ischemia, but, after 10 min of reperfusion, regional CBF was increased to 103 mL/(100 g·min) but then decreased to 60 mL/(100 g·min) after 180 min of reperfusion; in the group treated with the monoclonal antibody R15.7 against the neutrophil CD18 adhesion molecule that was injected 10 min before reperfusion, regional CBF before ischemia was 85 mL/(100 g·min) and decreased to 15 mL/(100 g·min) at the end of ischemia, but, after 10 min of reperfusion, regional CBF was 112 mL/(100 g·min) and decreased to 99 mL/(100 g·min) after 180 min reperfusion. In addition, R15.7 antibody decreased the infarct size by approximately 69% and reduced the no-reflow area by approximately 60%. These data indicate that neutrophils are involved in late no-reflow.In a dog study. Hypoxia/reoxygenation (H/R) induced adhesion of neutrophils with endothelial cells; however, the adenosine A2A receptor antagonist ZM-241385 abolished adhesion. Moreover, in rats underwent CAO (60 min) and reperfusion , a marker of neutrophils' myeloperoxidase activity was correlated with the no-reflow area. These data indicate that neutrophils are involved in the pathogenesis of MVO in animals with myocardial infarction.In a study using human umbilical vein endothelial cells, the cells were subjected to hypoxia (2 h) and reoxygenation (30 min), and subsequently, human neutrophils were added to the culture medium. There is evidence that pyroptosis is involved in the pathogenesis of MVO as shown in a study, in which mice underwent CAO (30 min) and reperfusion (3 or 24 h), reperfusion (3 h) increased NLRP3 expression in myocardial tissue by approximately 2.5-fold, caspase-1 activity increased by 2-fold, the interleukin-1β (IL-1β) level increased by approximately 10-fold, IL-18 content increased by 10-fold; moreover, intraperitoneal administration of inflammasome inhibitor BAY 11-7028 reduced macrophage and neutrophil invasion in myocardial tissue and decreased the infarct size. H/R might induce NLRP3 inflammasome and caspase-1 expression in cardiac microvascular endothelial cells (CMECs), increase IL-1β and IL-18 levels in CMECs, and trigger lactate dehydrogenase release, while H/R had no effect on NLRP3 inflammasome expression and IL-1β content in isolated cardiomyocytes. It appeared that H/R induced pyroptosis of CMECs and that CMECs were more sensitive to the H/R-induced pyroptosis than cardiomyocytes.Pyroptosis is a regulated cell death process that plays an important role in I/R injury of the heart, and nucleotide-binding oligomerization domain (NOD)-like receptor with a pyrin domain 3 (NLRP3) inflammasome plays a key role in pyroptosis,23. In one study including 78 patients with STEMI and PCI, blood samples were drawn from the aorta and the coronary artery for microparticle detection; it was observed then that microparticle content in the coronary artery was associated with MVO, as evaluated by myocardial blush grade (MBG) (Table 3). Based on these findings, the investigators suggested that microparticles could be involved in MVO. However, these data have not been consistently confirmed by other investigators; therefore, the key role of microembolization and microthrombi in MVO is questionable.According to Kloner and Heusch, the therapy for no-reflow may be an important approach to improving the outcome for patients with AMI and PCI. The results showed that MVO scores for no-reflow were lower in patients who received aspirin than in patients who did not receive aspirin; when MVO was evaluated by MRI in patients with STEMI and PCI, the incidence of MVO was significantly correlated with ADP-induced platelet aggregation, platelet-neutrophil aggregation, and platelet-monocyte aggregation, suggesting that platelets may play an important role in MVO. Thromboxane A2, synthesized and released by platelets, can induce vasoconstriction, while aspirin may inhibit platelet cyclooxygenase-1 activity that is required for thromboxane A2 synthesis; however, chronic administration of aspirin can trigger a reduction in the serum level of thromboxane B2, a stable metabolite of thromboxane A2. These data indirectly suggest that thromboxane A2 could be involved in MVO. Moreover, in another study including patients with STEMI and PCI, MVO was more frequently observed in the high platelet reactivity group than in the low platelet reactivity group, also indicating an important role of platelets in MVO. However, convincing data on the involvement of thromboxane in no-reflow are not yet available.In a study involving patients with STEMI and PCI, MVO was detected using MRI2+ channel blockers, NO donors, and nicorandil) or both endothelium independent and dependent relaxation of coronary arteries (β-AR agonists and adenosine).Currently, there is no clarity about the role of disturbance of endothelial dependent vasodilation in MVO, because acetylcholine, an endothelial-dependent vasodilator, has not been used for the treatment of MVO in patients with AMI. Other pharmacological agents used for treatment of MVO in patients with AMI can induce either endothelium-independent vasodilation . Therefore, whole blood viscosity could be involved in no-reflow in patients with AMI, although further research is required.It has been reported that acute coronary syndrome is accompanied by an increase in whole blood viscosity. In addition, there was a positive correlation among severe MVO, infarct size, and adverse myocardial remodeling six months after AMI. Similar findings have been reported by other investigators, supporting that MVO can predict adverse post-infarction myocardial remodeling. However, it should be noted that some investigators could not find the association between MVO and post-infarction remodeling of the heart.It was reported that patients with AMI + MVO showed a progressively increase in left ventricular volumes, compared with patients without MVO six months after AMI+CD16− monocyte level was higher in STEMI patients with MVO than in STEMI patients without MVO. Both CRP and interleukin-6 levels were reported to be predictors of MVO in STEMI patients underwent PCI. STEMI patients with MVO had a higher serum level of interleukin-18 than those without MVO. Therefore, CRP and interleukins may be involved in MVO formation.The MOV score was positively correlated with both plasma C-reactive protein (CRP) levels and leukocytes in STEMI patients treated by PCI, while the peak CD142+ channel blockers induced endothelium-independent vasodilation of coronary arteries, while verapamil could alleviate MVO in patients with STEMI. Thus, it could be hypothesized that the Ca2+ overload of vascular smooth muscles might be involved in MVO.The role of ROS in the pathogenesis of no-reflow has not been studied before in AMI patients. However, the L-type Can = 128) underwent PCI, the plasma endothelin-1 level on admission was associated with both MVO (assessed by MRI) and an increased long-term mortality, which suggests that an increase in the endothelin-1 level may promote MVO. Neuropeptide Y (NPY) is another potent vasoconstrictor released from sympathetic endings together with norepinephrine, and intracoronary infusion of NPY induced coronary vasospasm in humans. For example, STEMI patients with angiographic no-reflow had a higher plasma NPY level than those without angiographic no-reflow. Other investigators found no differences in the TIMI flow scores between STEMI patients with a low or high NPY level in coronary sinus, although the index of microcirculatory resistance was higher in patients with a high NPY concentration in coronary sinus. Arginine vasopressin could induce coronary microvessel spasm and ST elevation in rats as well as contractile response of coronary arterioles in humans; however, its role in MVO was not studied before. These findings indicate that endothelin-1 and NPY may participate in MVO. It is too early to draw a final conclusion about the role of NPY and endothelin-1, because correlation analysis between endothelin-1 and NPY levels and the no-reflow area has not been performed.Endothelin-1 is a potent vasoconstrictor peptide. In STEMI patients  and reperfusion (24 h), while the maximum MVO area was observed in these pigs after 120 min reperfusion. Additionally, the maximum IMH area was detected in rats with a 90-min CAO after 48-h reperfusion.MVO is often associated with intra-myocardial hemorrhage (IMH). For example, a combination of MVO and IMH was observed in 41%–54% of STEMI patients underwent PCI, and the hemorrhage area was approximately 3% of the left ventricular mass. IMH was developed after CAO lasting 40–120 min and reperfusion in pigs; however IMH did not occur in the infarcted myocardium unless successful reperfusion, and the IMH area was correlated with the MVO area and the infarct size. IMH often develops in STEMI patients who have deeper and wider Q waves, while antiplatelet and anticoagulant therapy could promote the appearance of IMH in AMI patients who received PCI.MVO preceded microvascular destruction and IMH, and the appearance of IMH was correlated with the adverse ventricular remodelling and worse outcome in AMI patients, while the large IMH area was associated with a late reperfusion and the duration of ischemia.The pathogenesis of IMH remains poorly understood. Classic postconditioning did not prevent IMH or decreased the infarct size in pigs with CAO (40 min) and reperfusion (24 h), while classic preconditioning could reduce the IMH area and the infarct size in these pigs12 antagonists (prasugrel or ticagrelor) or the second-generation P2Y12 antagonist clopidogrel in addition to aspirin, the incidence of MVO as assessed by MRI was 66% in patients who received clopidogrel, and 49% in patients who received prasugrel or ticagrelor. In another study of STEMI patients who received aspirin and clopidogrel orally before PCI as well as received glycoprotein Ⅱb/Ⅲa inhibitor tirofiban intravenously or intracoronary, the incidence of MVO as evaluated by MRI was reduced in patients with intracoronary tirofiban administration, compared with those patients with intravenous administration of tirofiban.In a study of STEMI patients underwent PCI, who received aspirin incombination with third-generation P2Yet al reported, intracoronary administration of adenosinehave could reduce the incidence of MVO in AMI patients and PCI. However, Niccoli et al found that intracoronary administration of adenosine had no effect on the incidence of MVO in STEMI patients (n = 160) underwent PCI. Similar data were also obtained by Nazir et al in another study that included patients (n = 168) with STEMI and PCI. The last two studies are more credible, because they included a larger number of patients. However, it should be noted that adenosine could induce coronary steal and aggravate ischemic/reperfusion injury of the heart in patients with AMI. Thus, the use of adenosine for the treatment of AMI and MVO is not recommended.Can adenosine reduce the incidence of MVO? As Naghshtabrizi ATP channel openers prevent MVO? As mentioned above, sodium nitroprusside had no effect on the MVO area, while nicorandil could reduce the incidence of MVO by 50% in AMI patients (n = 81) with coronary angioplasty. Other studies found that an combined intracoronary administration of nicorandil and adenosine could decrease the incidence of no-reflow by 40%, and intracoronary infusion of nicorandil alone could also reduce the incidence of MVO in STEMI patients (n = 170) underwent PCI.Can NO donors and K. However, intracoronary norepinephrine infusion increased myocardial O2 consumption and induced myocardial hypoxia in the presence of coronary stenosis, and intravenous infusion of a non-toxic dose of isoproterenol induced an increase in the infarct size in rabbits. Therefore, the use of β-AR agonists in AMI patients could aggravate I/R injury of the heart. However, these data did not preclude a clinical study of the efficacy of intracoronary administration of epinephrine for treatment of no-reflow  in PCI in patients with AMI, which found that epinephrine could significantly improve CBF after PCI in these patients, compared with patients who did not receive epinephrine.Non-toxic doses of β-AR agonists could increase CBF without hypoxia in dogs with intact coronary arteries2+ channel blockers could induce vasodilation of coronary arteries. Intracoronary injection of verapamil reduced the MVO area in AMI patients with PCI. Intracoronary infusion of nicardipine could also alleviated no-reflow in 71 of 72 AMI patients underwent PCI. Moreover, co-administration of nicardipine, adenosine, and nitroglycerine was reported to reverse the no-reflow in AMI patients with PCI. Thus, L-type Ca2+ channel blockers may be used to prevent and reverse MVO. Data on treatment are presented in Table 4.L-type Ca. Therefore, it could be hypothesized that I/R-induced injury of coronary arteries may play a key role in the pathogenesis of MVO.There is no convincing animal evidence that microembolization and microthrombi are involved in no-reflow with CAO and reperfusion. Neutrophils and platelets are suggested to be involved in the pathogenesis of MVO in animals with CAO. No-reflow was observed in studies performed with isolated perfused hearts subjected to I/R-44. There is also evidence that pericytes could be involved in I/R-induced vasoconstriction of microvessels, and angiotensin Ⅱ could be involved in the appearance of MVO, while MVO may participate in the adverse post-infarction myocardial remodeling. Pyroptosis may participate in reperfusion microvascular endothelial injury, while eNOS, PKA, PI3K, Akt, mTOR, and GSK-3β are probably involved in the protection of coronary arteries against I/R. The KATP channel opening may prevent MVO, and ischemic preconditioning and remote perconditioning may also reduce the MVO area.No-reflow was found to be associated with disturbances of coronary artery vasodilation in animals with MI2+ overload of vascular smooth muscle cells was involved in no-reflow in AMI patients. There is also an indirect evidence that inflammation could participate in no-reflow. It is possible that an increased blood viscosity promotes MVO. Adenosine and sodium nitroprusside may not be able to prevent the appearance of MVO, but nicorandil can be used for therapy of MVO. P2Y12 antagonists and glycoprotein Ⅱb/Ⅲa inhibitor tirofiban were low effective in treatment for no-reflow, and L-type Ca2+ channel blockers remain the most effective drugs for treatment of no-reflow. Although epinephrine can mitigate MVO in patients with AMI and PCI, questions remain.There is clinical evidence that platelets could be involved in no-reflow in AMI patients. There is an indirect evidence that CaThere is no direct evidence that MVO is associated with injury of endothelial cells in patients with AMI and in animals with CAO, or some indisputable evidence of the involvement of inflammation in MVO in animals with CAO and in patients with AMI. The role of necroptosis, apoptosis, autophagy, and ferroptosis in reperfusion microvascular endothelial injury has also not been studied. It is unclear whether remote postconditioning or adaptation to hypoxia could prevent MVO. The role of PKCε, ERK1/2, AMPK, JAK, EGFR, and Src-kinase in the protection of coronary arteries against I/R remains unknown. The role of thromboxane A, vasopressin, NPY, and ROS in MVO was also not studied before.Finally, the possibility of antagonists of thromboxane A2 receptor, angiotensin Ⅱ receptors, and NPY antagonists to prevent MVO in patients with AMI and animals with CAO has not been studied, and the efficacy of cardioprotective peptides  for treatment of no-reflow has not been studied before.


In this study, we evaluated the clinical and radiological manifestations of teenagers presenting with chest pain after coronavirus disease 2019 (COVID-19) messenger RNA (mRNA) vaccination. We retrospectively enrolled 61 teenage patients, aged 13 to 19 years, who underwent echocardiography and cardiac magnetic resonance imaging (CMR) for chest pain after COVID-19 mRNA vaccination, from November 2021 to April 2022. Medical records, laboratory results, echocardiographic, and CMR findings were analyzed. The mean age of the participants was 14.4 ± 1.9 years, with a male:female ratio of 28:33. Among the sixty-one patients with chest pain after COVID-19 vaccination, only two (3.3%) were diagnosed as confirmed myocarditis, and almost all of them recovered with conservative treatments. However, on CMR, 24 (39.3%) presented with mild myocardial abnormalities; 22 (36.1%) showed myocardial edema, and 19 (31.1%) were found to have a myocardial injury. Multivariate logistic analyses revealed that older age and female sex were significantly associated with myocardial abnormalities. In teenagers who present with chest pain after COVID-19 mRNA vaccination, confirmed myocarditis is uncommon. However, myocardial abnormalities on CMR might occur frequently, and females in their late teens might be more vulnerable to myocardial abnormalities. During the coronavirus disease 2019 (COVID-19) pandemic, expedited efforts to develop safe and effective vaccines led to the development of novel messenger RNA (mRNA)-based vaccines for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) . FrequenAmong the various adverse symptoms, chest pain is a major symptom of acute myocarditis ,12 and aIn this retrospective study, we aimed to evaluate the clinical and radiological manifestations of teenagers presenting with chest pain after COVID-19 mRNA vaccination.This was a retrospective observational study. Records of patients who underwent CMR at our institution between November 2021 and April 2022 were retrospectively reviewed. The inclusion criteria were as follows: (1) patients referred to our hospital because of chest pain after COVID-19 mRNA vaccination, (2) teenagers aged between 13 and 19 years, and (3) patients who underwent echocardiography and CMR within a 1-week interval. The exclusion criteria included the following: (1) a previous history of myocarditis or SARS-CoV-2 infection and (2) incomplete medical records. This study was approved by the institutional review board of Gangnam Severance Hospital . The requirement for written informed consent was waived owing to the retrospective nature of this study.Venous blood samples were collected from all patients. The lower detection limits for troponin I and troponin T assays were 0.012 and 0.003 mcg/L, respectively. In addition, basic, routine laboratory tests were performed, including complete blood cell count, routine chemistry, electrolyte levels, and iron profiles.All patients underwent transthoracic echocardiography in the left lateral decubitus or supine position using commercially available echocardiography systems with the help of a 1.7–3.4 MHz transducer , including two-dimensional, M-mode, color flow, conventional spectral Doppler, and tissue Doppler imaging (TDI). All data were acquired from parasternal, apical, and subcostal views. Three consecutive beats were stored in the cine-loop format, and the images were analyzed offline using dedicated software .All examinations were performed in accordance with the American Society of Echocardiography. The measurements included in the analysis were as follows: left ventricular ejection fraction , left ventricular end-diastolic dimension (mm), left ventricular end-systolic dimension (mm), interventricular septal thickness at diastole (mm), interventricular septal thickness at systole (mm), left ventricular posterior wall thickness at diastole (mm), left ventricular posterior wall thickness at systole (mm), mitral E (m/s), mitral A (m/s), E/A ratio, lateral E’ (m/s), lateral A’ (m/s), lateral S’ (m/s), lateral E/E’, septal E’ (m/s), septal A’ (m/s), septal S’ (m/s), septal E/E’, tricuspid E’ (m/s), tricuspid A’ (m/s), tricuspid S’ (m/s), tricuspid annular plane systolic excursion , pulmonary artery velocity (m/s), and inferior vena cava diameter (mm). The mean value of more than three measurements obtained using echocardiography was used in the analysis.Measurements were performed to determine whether they were within a reasonable range. This study defined myocardial injury or myocarditis as LVEF < 45%, noticeable segmental wall motion abnormality, abnormal findings on conventional Doppler spectral velocities, and advanced tissue Doppler velocities.All CMR examinations were performed using a 3.0-Tesla scanner  with a 32-element phased-array coil. After cardiac localization, cine imaging with a steady-state free precession sequence, native T1 mapping using a modified look-locker inversion recovery (MOLLI) sequence with a 5(3)3 protocol, and T2 mapping using a T2-prepared balanced steady-state free precession sequence were performed. Ten minutes after intravenous injection of 0.2 mmol/kg of gadoterate dimeglumine , T1-weighted inversion recovery segmented breath–hold late gadolinium enhancement (LGE) imaging was performed with magnitude- and phase-sensitive inversion recovery reconstruction. The optimal inversion time was selected using an inversion time scout. Subsequently, post-contrast T1 mapping was performed using the MOLLI sequence with a 4(1)3(1)2 scheme. All CMR images were transferred to a picture archiving and communication system station  and commercially available CMR-dedicated software  for image analysis. Extracellular volume (ECV) maps were generated semi-automatically with native T1 map images and post-contrast T1 map images.Two radiologists (with more than ten years of experience in cardiothoracic radiology) who were blinded to the clinical information, including the patient’s symptoms and laboratory data, independently reviewed the CMR images. The radiologists evaluated the CMR findings using the 2018 Lake–Louise criteria (LLC) . FunctioMyocardial edema was evaluated using T2-based images (T2 maps), and a prolonged T2-relaxation time was defined as T2 values > 40 ms. Myocardial injury was assessed using T1-based imaging, including native T1 maps, ECV maps, and LGE imaging. Prolonged T1-relaxation time and ECV fraction were defined as T1 values > 1230 ms and ECV fractions higher than 28%, respectively .t-test or Mann–Whitney U test was used to compare demographic, echocardiographic, or CMR parameters between the groups. Interobserver agreements measuring T2 values, T1 values, and ECV fractions were evaluated using the intraclass correlation coefficient (ICC). Univariate logistic regression analysis was used to assess the association between myocardial changes and patient demographics, laboratory examinations, and echocardiographic parameters. Multivariable logistic regression was used to identify independent factors, including demographics, laboratory test results, and echocardiographic parameters for myocardial changes in the MR parameters. For this analysis, variables from the univariable analysis with p < 0.1 were entered. If there was a significant correlation between the independent variables, only one variable was entered into the model to avoid multicollinearity. Statistical significance was set at p < 0.05. All statistical analyses were performed using SAS .The distribution of data was evaluated using the Shapiro–Wilk test. Continuous variables are expressed as means ± standard deviations or medians (interquartile ranges), according to the results of the normality test. Categorical variables are expressed as frequencies (percentages). An independent two-sample 2; and BSA, 1.64 ± 0.23 m2. None of the patients were presented with baseline comorbidities, including asthma, diabetes mellitus, or autoimmune diseases. Detailed baseline characteristics of the enrolled patients are summarized in In total, 61 patients were enrolled in this study. The mean age of the participants was 14.4 ± 1.9 years, with a male:female ratio of 28:33. The mean physical characteristics included the following: height, 164.1 ± 9.4 cm; weight, 59.0 ± 14.7 kg; body mass index (BMI), 21.7 ± 3.9 kg/mp > 0.05) ; 26 (42.6%) and 35 (57.4%) patients developed chest pain after the first and second vaccinations, respectively. Other symptoms included fatigue (100%), palpitations (78%), dyspnea (70%), dizziness (57%), headache (45%), and epigastric pain (8%). Electrocardiography (ECG) revealed a normal sinus rhythm in 47 patients (77%), whereas 14 patients (23%) presented with various abnormal features, including incomplete right bundle branch block, incomplete left bundle branch block, premature ventricular contraction, sinus bradycardia, T-wave inversion, and borderline QT prolongation. However, none of the patients showed ST elevation, a typical sign of myocarditis. The mean hemoglobin (Hb) level was 13.5 ± 1.1 g/dL, and the hematocrit level was 41.7 ± 3.4%. Of the sixty-one patients, three (4.9%) had elevated serum troponin T (ref: 0.003–0.014 mcg/L) and troponin I (0.012–0.034 mcg/L) levels, above the upper limit of the reference level. The levels of C-reactive protein, creatine kinase MB fraction, and N-terminal pro-B-type natriuretic peptide were not statistically different between groups  .We used conventional Doppler echocardiography to evaluate LV mitral inflow, as well as TDI to quantitatively assess LV and right ventricular (RV) systolic and diastolic myocardial movements. The mean LVEF of participants was 67.50 ± 5.48%. All 61 patients had LVEF ≥ 55%; thus, regardless of myocardial edema or injury noted on CMR, no patient showed LVEF < 45%. Compared to patients with no abnormalities identified in CMR, there were no statistical differences in echocardiographic measurements in patients with myocardial edema or injury, including tissue Doppler velocity. Additionally, the findings representative of myocardial deterioration—lateral E/E and septal E/E—showed no difference in patients with myocardial edema or injury. RV systolic functional measurement using TAPSE also indicated no difference in patients with myocardial edema or injury .The median time between vaccination and CMR examination was seven days . Based on the modified LLC, 22 patients (36.1%) showed abnormalities on T2-based imaging and were diagnosed with myocardial edema. Nineteen patients (31.1%) showed abnormalities on T1-based imaging and were diagnosed with myocardial injury. Seventeen patients (27.8%) showed simultaneous myocardial edema and injury, and twenty-four (39.3%) presented with either myocardial edema or injury. Thirty-seven patients (60.7%) showed no abnormalities on T1- and T2-based imaging. Two of the three patients with elevated serum troponin levels had myocardial edema and injury; however, the third patient showed negative findings.2, 26.7 ± 6.9 mL/m2, 47.9 ± 8.3 mL/m2, and 56.4 ± 8.4 g/m2, respectively. The LVEF was greater than 55% in all patients, with a mean LVEF of 64.6% ± 5.5%. The LV mass index was significantly lower in patients with myocardial edema or injury than those without myocardial edema or injury (p = 0.0014). However, LVEDVi, LVESVi, SVi, and LVEF did not differ between patients with and without myocardial abnormalities .On cine imaging, mean LVEDVi, LVESVi, SVi, and LV mass index for the 61 participants were 74.6 ± 12.2 mL/mp < 0.001) . The mean T1 value and ECV fraction of patients with myocardial injury were 1265.9 ± 37.6 ms and 30.2 ± 1.9%, respectively, which were significantly higher than those of patients without myocardial injury . Patients with myocardial abnormalities (edema or injury) showed higher T2 values, native T1 values, and ECV fractions than did the participants with negative CMR findings (< 0.001) . The intUnivariable logistic regression analyses revealed that myocardial abnormalities  were significantly associated with the female sex and lower weight, BMI, and BSA values. Among the laboratory parameters, Hb and hematocrit levels were associated with myocardial abnormalities on CMR. Echocardiographic parameters were not associated with any myocardial abnormalities .In the multivariable logistic regression analyses, a myocardial abnormality was significantly associated with age and female sex . BSA shoThe chest pain developed within 72 h to 7 days from the vaccination. Then the chest pain continued for approximately 7 to 10 days. All the patients were treated conservatively for 3–7 days to achieve symptomatic relief of chest pain. After this treatment period, patients presented reduced symptoms and favorable clinical courses.This study evaluated the clinical and radiological manifestations of teenagers with chest pain after COVID-19 mRNA vaccination and analyzed the risk factors for myocardial abnormalities. Among the 61 patients enrolled, only two cases were confirmed as myocarditis. However, myocardial abnormalities were detected on CMR images in 24 (39.3%) of the 61 patients. In addition, we found that myocardial abnormalities were significantly associated with older age and the female sex.Since chest pain is a significant symptom of myocarditis reported after mRNA vaccination , adolescIn this study, myocardial abnormalities accompanied by chest pain tended to be less severe than reported myocarditis after vaccination. There was no obvious LGE in any patient, and the elevation of T1 values, T2 values, and ECV fraction was marginal. On the contrary, previous studies reported that patients with myocarditis after vaccination usually showed LGE, obviously increased T1 and T2 values, and ECV fraction ,28,29,30Concerning the CMR findings, echocardiography did not reveal any definite myocardial abnormalities; none of our patients had LVEF < 45%. Instead, LVEF was >55% in all 61 patients, indicating proper contractile function. We assume that a subtle diastolic alteration may occur after mRNA vaccination, which could be recognized on echocardiography as probable myocarditis, even with reasonable ranges of mitral E, without systolic dysfunction. However, echocardiographic information is insufficient to confirm mild myocardial abnormalities without a CMR examination.This study has several limitations. First, this was a single-center retrospective study with a small sample size. Second, although the enrolled patients presented with chest pain after vaccination, the myocardial change on CMR was not pathologically proven. Long-term surveillance should be conducted to determine the natural course of myocardial edema or injury associated with COVID-19 mRNA vaccines. This can help to identify characteristics of myocardial changes on CMR. However, many teenagers and children continue to being exposed to SARS-CoV-2, and COVID-19 vaccines are highly recommended for every teenager and child that is eligible. Therefore, our study will be a helpful guide for teenagers presenting with chest pain after vaccination.In teenagers who present with chest pain after COVID-19 mRNA vaccination, myocarditis is uncommon, and the clinical course is usually benign. However, myocardial abnormalities on CMR might be of frequent occurrences. Females in their late teens might be more vulnerable to myocardial abnormalities, with continuous chest pain one week after vaccination.


Haemodynamic monitoring of patients after cardiac surgery using echocardiographic evaluation of fluid responsiveness is both challenging and increasingly popular. We evaluated fluid responsiveness in the first hours after surgery by determining the variability of the velocity–time integral of the left ventricular outflow tract (VTI-LVOT).We conducted a cross-sectional study of 50 consecutive adult patients who underwent cardiac surgery and in whom it was possible to obtain VTI-LVOT measurements. We then determined the variability and correlations with our pulse pressure variation (PPV) measurements to predict fluid responsiveness.A strong positive correlation was seen between the VTI-LVOT variability index absolute values and PPV for predicting fluid responsiveness in the first hours after cardiac surgery. We also found that the VTI-LVOT variability index has high specificity and a high positive likelihood ratio compared with the gold standard using a cut-off point of ≥ 12%.The VTI-LVOT variability index is a valuable tool for determining fluid responsiveness during the first 6 postoperative hours in patients undergoing cardiac surgery. A current pillar in the treatment of patients in a critical condition, including patients who have undergone cardiac surgery, is the administration of intravenous fluids for initial resuscitation. While it is true that this is considered the basis for the management of shock, volume overload has been associated with longer mechanical ventilation time, kidney injury and even mortality , 2.Various studies have shown a better prognosis in critically ill patients who receive more conservative fluid resuscitation , 4. ThisVariation in stroke volume and its surrogates, induced by mechanical ventilation, were the first methods designed for the dynamic evaluation of fluid responsiveness. This is because during mechanical ventilation with positive pressure, pulmonary inflation reduces the preload and increases the afterload of the right ventricle. When this pressure is transmitted to the left side of the heart, the preload is also decreased at that level. When these variations induced by positive pressure reach cut-off points, both ventricles are preload-dependent –10.It was established in 2000 that pulse pressure variation (PPV), as a surrogate for stroke volume variability, can be used to predict the cardiac output response to volume expansion . This haMany other methods have been developed to assess stroke volume variation during mechanical ventilation. However, one limitation of such indices is the need for impractical and/or infeasible invasive devices. Thus, there is an increasing need for less invasive approaches . These mMost studies evaluating methods for fluid responsiveness prediction define this response as an increase in cardiac output or stroke volume after a fluid challenge, which requires invasive cardiac output measurements and fluid administration techniques that may be deleterious for the patient.Echocardiography is currently used to measure peripheral haemodynamic indicators such as variability of the inferior vena cava, carotid flow and radial artery peak flow, with good predictive value. There is convincing evidence for the effectiveness of echocardiography in detecting vena cava collapse for predicting fluid responsiveness , 20. HowDue to these limitations, a method that has become more popular as a surrogate for the measurement of stroke volume in critically ill patients is the velocity–time integral of the left ventricular outflow tract (VTI-LVOT), as the area of this tract remains relatively constant during the respiratory cycle. Importantly, it is less affected by vascular compliance and intra-abdominal pressure compared with other methods. In 2007, Lamia et al.  reportedMost studies in which VTI-LVOT changes have been evaluated have correlated its modification after administration of a volume load. The only study to date that has focused on determining its value as a predictor of fluid responsiveness was carried out by Wang et al. . In thatAnother study in patients with sepsis showed that VTI-LVOT peak velocity variability with a cut-off of ≥ 12% had a good positive predictive value (91%) for fluid responsiveness, defined as an increase in cardiac index ≥ 15% after volume loading, with a negative predictive value of 100% .The goal herein was to determine the efficacy of ultrasound measurement of VTI-LVOT variability as a predictor of response to volume in patients undergoing cardiac surgery.This cross-sectional study investigated 50 consecutive adult patients who were admitted to the critical care unit at the Instituto Nacional de Cardiología Ignacio Chávez from 1 March to 30 October 2022, following cardiac surgery, in whom ultrasonographic evaluation was conducted upon arrival in postoperative critical care and in whom it was possible to obtain an adequate visualization of the five-chamber view. Patients with an open chest after surgery were excluded. For the ultrasonographic evaluation, the operator-obtained images were generated using a phased array sector probe at 2–3 MHz, from the patient’s right or left side, with sonographic equipment including the following modes: M-mode, 2D-mode, colour Doppler, pulsed wave Doppler, continuous wave Doppler and tissue Doppler. The use of sonographic equipment with advanced software technology was not necessary. The five-chamber view was obtained according to the guidelines of the American Society of Echocardiography for performing comprehensive transthoracic echocardiographic examinations in adults . PPV wasTo determine the fluid responsiveness through the VTI-LVOT variability index, we used the following formula:All patients were intubated and mechanically ventilated at a tidal volume of 8 mL/kg, without spontaneous inspiratory effort and without arrhythmias during measurements, as recommended for an adequate fluid responsiveness evaluation . None ofImages were processed and analysed after acquisition. One physician  acquired the images, after which, the images were processed and measured by three different physicians  using imaging software. We reduced bias by blinding the investigators who analysed, processed and measured the images. In all patients, as a regular measure of preload assessment, central venous pressure (CVP) was also measured invasively with a central venous catheter with the tip at the cavoatrial junction.A PPV value ≥ 12 and a VTI-LVOT variability index of ≥ 12% were considered positive for fluid responsiveness.We performed the Shapiro–Wilk test of normality for continuous variables and report these as median and interquartile ranges because all were nonparametric. Comparisons of continuous variables were made using the Kruskal–Wallis test. We report categorical variables as frequencies and percentages and used the chi‐square or Fisher’s exact probability tests, as appropriate, to compare expected values. We used Pearson’s test to calculate correlation coefficients, with the following r value strength categories: 0.1–0.29 = small; 0.3–0.49 = medium and 0.50–1.0 = strong. We used 2 × 2 tables to calculate sensitivity, specificity, predictive values and likelihood ratios. All statistical analyses were performed using Stata v. 14, and p values < 0.05 were considered statistically significant.Most of the patients  were classified as New York Heart Association functional class II (62%). The most frequent comorbidities were arterial hypertension (42%), diabetes mellitus (20%) and heart failure (30%). Twenty-six per cent and 18% had a reduced or severely reduced left ventricular (LV) ejection fraction, respectively . When the diagnostic accuracy for fluid responsiveness of the VTI-LVOT variability index was evaluated compared with the PPV based on their cut-off points (≥ 12% for both), the sensitivity and specificity were 70% and 93% at admission and 44% and 92% at 6 h, respectively. Positive predictive values of 96% and 80% and negative predictive values of 60% and 71% were seen at admission and 6 h, respectively. Positive likelihood ratios of 11.3 and 6 were seen at admission and 6 h, respectively  for predicting fluid responsiveness. These conditions may have increased the accuracy of our measurements, as invasive mechanical ventilation constitutes the optimal circumstances for these evaluations . HoweverWe routinely quantify CVP, not as a parameter of fluid responsiveness (as it depends on both cardiac and venous return function and does not help determine volume status reliably), as has already been extensively studied, but because CVP values > 12 mmHg are generally considered a limit for making additional efforts to replace fluids and limit volume overload. Herein, the 2 mmHg increase in CVP at 6 h coincides with the decrease in PPV and the VTI-LVOT variability index.Variations in flow through the aorta measured by ultrasound have been found to be useful, specifically in patients in septic shock with mechanical ventilation and preserved ventricular function , 28. HerThe high specificity shown herein at both admission and after 6 h is useful for ruling out the presence of fluid responsiveness. Furthermore, the high predictive positive value at admission may help determine whether those with a VTI-LVOT variability index ≥ 12% will indeed have a high probability to be fluid responsive, as confirmed by the positive likelihood ratio of 11.3. It is important to note that the decrease in diagnostic accuracy at 6 h is consistent with the dynamic process of fluid resuscitation, in that for the first 6 h, most patients are replete in intravascular volume. This was supported herein by the decrease in individuals responding to volume in the first 6 h compared with at admission.During mechanical ventilation in the presence of LV dysfunction, the increase in pleural pressure that facilitates LV ejection  is more pronounced. Thus, the effect of squeezing the pulmonary blood volume during early inspiration on the LV ejection is amplified, so a high PPV may be due to this variation, which would result in a false-positive PPV. However, few studies have addressed the issue of fluid responsiveness in patients with congestive heart failure, probably because fluid administration is rarely indicated in such patients. In some studies involving patients with LV dysfunction who are in sinus rhythm, PPV (or stroke volume variation) has been shown to predict fluid responsiveness with acceptable accuracy , 31.This study was carried out in a single hospital centre and must be replicated in other centres to assess the reproducibility of our results. Because our sample was relatively small, it will be necessary to evaluate a larger population to achieve better statistical power. Unlike other studies in which response to volume was evaluated with invasive ‘gold standard’ methods, we used a non-invasive method with the best diagnostic performance, which could degrade the reliability. Finally, it will be necessary in the future to consider both interobserver variability across centres and the need for personnel trained in these techniques.We found a strong positive correlation and adequate diagnostic accuracy between the VTI-LVOT variability index and PPV to predict fluid responsiveness in patients who underwent cardiac surgery.


A 7-year-old castrated male Munchkin cat was presented with anorexia. This cat had been diagnosed with chronic kidney disease due to polycystic kidney disease. Tachycardia with a systolic murmur (grade III/VI) was auscultated and for further diagnosis, echocardiography was performed. Based on echocardiography, persistent left cranial vena cava (PLCVC) was suspected due to enlargement of the coronary sinus and confirmed by saline contrast echocardiography. The dilated coronary sinus compressed the left atrium, and left ventricular hypertrophy with the systolic anterior motion of the mitral valve, aortic regurgitation, and mitral regurgitation were identified. After medical management using atenolol, left atrial function and other hemodynamics of the heart were improved, including the disappearance of regurgitation and normalization of left ventricular wall thickness. This case report describes the echocardiographic characteristics, diagnostic procedures, and disease progression in a cat with PLCVC after medical management using atenolol. Additionally, this is the first report of a cat with PLCVC, coexisting with polycystic kidney disease. Persistent left cranial vena cava (PLCVC) is a congenital vascular anomaly that occurs when part of the left cardinal vein does not regress and becomes a remnant vessel (PLCVC) during embryonic development. This remnant vessel drains blood from the left side of the head, neck, and forelimb into the right atrium, through the coronary sinus . In humaPLCVC has been reported to occur along with cardiovascular anomalies, although it may also occur independently , 6–8, 10Polycystic kidney disease (PKD) is an inheritable disorder characterized by the gradual formation of fluid-filled cysts in the kidneys, and in certain instances, in additional organs, such as the liver and pancreas . PKD is This case report describes the echocardiographic features, diagnostic process, and disease progression in a cat with PLCVC after medical management using atenolol. Additionally, this case demonstrates a novel occurrence of PLCVC coexisting with PKD in a cat.®], symbiotics [Renal-advanced®], and omega-3 fatty acids [Duomega®]), intermittent subcutaneous fluids and amlodipine . Because the cat had been anorexic for several days before the presentation, an overall examination was performed.A 7-year-old castrated male, Munchkin cat weighing 3.8 kg was admitted for a check-up of previously diagnosed chronic kidney disease (CKD) induced by PKD. The cat had been diagnosed with PKD at a young age. During regular check-ups, CKD and hypertension  were diagnosed 1 year prior to the current presentation. The renal panels and blood pressure were monitored monthly. The cat had been administered renal supplements  and a systolic heart murmur (grade III/VI) were noted, and systolic arterial blood pressure was normotensive . Complete blood counts  and serum chemistry profiles  revealed mild leukocytosis , increased blood urea nitrogen , creatinine , and symmetric dimethylarginine , with normal total thyroxine  and free thyroxine  levels. Results of hepatic enzymes and electrolytes were within normal limits. Urinalysis revealed decreased urine concentration with a urinary specific gravity of 1.011 (RI > 1.035). However, no overt proteinuria was noted.As this cat was diagnosed with PKD, abdominal ultrasound showed cysts with variable sizes in both kidneys. Cysts of varying sizes occupied most of the renal parenchyma and renal calculi were also observed in both kidneys . FurtherA heart murmur was auscultated during the cardiac examination. Thoracic radiography revealed mild cardiomegaly and a mild broncho-interstitial lung pattern. Electrocardiography (ECG) revealed sinus tachycardia with no other remarkable findings . Two-dimensional echocardiography  exhibited left ventricular posterior wall (LVPW) thickening (6.4 mm) with mild left atrial enlargement  and systolic anterior motion (SAM) of the mitral valve in the M-mode. Mild mitral regurgitation (MR) with a maximum velocity of 3.92 m/s and aortic regurgitation (AR) with a maximal velocity of 1.28 m/s due to dynamic left ventricular outflow tract obstruction (DLVOTO) were observed on color and continuous-wave Doppler images. Additionally, the maximal velocity of the left ventricular outflow tract (LVOT) was 4.5 m/s, which was reached at end-systole. The left ventricular contractility was normal to increased . The trans-mitral flow velocity on pulsed-wave Doppler imaging was 1.22 m/s with the fusion of early and late diastolic waves due to the fast heart rate (229 bpm), and the mitral annular tissue velocity on tissue Doppler imaging was 0.08 m/s with the fusion of early and late waves.Additionally, a round anechoic structure was observed in both the right parasternal and left apical views near the LA . This stSaline contrast echocardiography was performed to diagnose PLCVC. An agitated saline solution was administered to the left cephalic vein of the cat, and microbubbles entering the dilated CS, followed by the right atrium (RA), were identified , 4, whicConsidering the compressive effect of the dilated CS on LA, two-dimensional speckle tracking echocardiography (2D-STE) was performed to evaluate LA movements and function. Only one peak of longitudinal strain was found in the LA because early and late diastolic movements were summated owing to the fast heart rate. The global peak longitudinal strain of the LA (PALS) measured in the left apical four chambers view was 37.7%, which indicated normal to increased movement of the LA with the presence of dilated CS.®) and clopidogrel  in addition to previously prescribed amlodipine . A follow-up evaluation was performed after 3 weeks. On day 21, the cat’s appetite and activity levels returned to normal. Both heart rate (140 bpm) and blood pressure (130 mmHg) were within the normal range, and echocardiography revealed the absence of SAM, AR, and MR with a reduction in LA size (LA/Ao 1.36). The maximal velocity of LVOT flow was also reduced (1.06 m/s) to the normal range. Additionally, the LVPW thickness decreased to 5.63 mm from the previously measured 6.4 mm on day 0. SAM, AR, and MR were not consistently detected at subsequent visits on day 84. LA size (LA/Ao 1.3) and maximal velocity of the LVOT flow (0.91 m/s) were mildly reduced. Additionally, PALS was increased to 57.5% on day 84, which indicated increased LA movements with the presence of dilated CS and disappearance of DLVOTO and MR. However, the LA strain showed dyssynchronization on day 0 and 84, which indicated myocardial segmental dyskinesia, possibly caused by compression of the dilated CS or independently. However, the systolic arterial blood pressure decreased to 110 mmHg with a heart rate of 160 bpm. Due to the decreased blood pressure, the dose of amlodipine was reduced . The cat remained asymptomatic, and vital signs returned to normal. The cat survived for 8 months after the last examination and lost to follow-up.Due to the presence of left ventricular hypertrophy, SAM of the mitral valve and suspected diastolic dysfunction with a fast heart rate, the cat was prescribed atenolol . Reduced left ventricle (LV) volume can cause pseudohypertrophy of the LV wall . Also, rPKD1 or PKD2 genes may play crucial roles in cardiac development and function. Cardiovascular diseases are among the most common causes of mortality in human ADPKD patients (The cat was diagnosed with PKD in addition to PLCVC. Because PKD in cats is known to be rooted in genetic causes , it is lpatients . AlthougThis case report had some limitations. First, CT angiography was not performed. CT scans are required to confirm various vascular malformations, including the presence of RCVC and bridging veins. The lack of visualization of PLCVC and vascular structures in this cat is a major limitation, as complex or different types of malformations may occur , 9. If pSecond, the exact etiology of myocardial thickening in this cat could not be definitively determined. At the time of the initial evaluation, the presence of myocardial hypertrophy along with DLVOTO suggested a possibility of HCM. However, decrease in myocardial thickness during monitoring process implied potential for pseudohypertrophy caused by hypovolemic state of the left-sided heart. Otherwise, DLVOTO caused by hypovolemic state may have resulted in secondary hypertrophy of the LV, which resolved after atenolol administration. It is believed that this hypovolemic state could have possibly resulted from other conditions such as CKD  as this To the best of our knowledge, this is the first report of a cat with PLCVC and concurrent PKD. In this report, we describe a cat with PLCVC, including a diagnostic approach using echocardiography, hemodynamic changes in the left side of the heart, and response to medical treatment using echocardiographic measurements. In cats with PKD, identifying concurrent cardiovascular anomalies, including PLCVC, is important because kidney function is closely related to the cardiovascular hemodynamic changes that may be caused by PLCVC. This case report emphasizes the importance of diagnosing cardiovascular malformations, such as PLCVC, that can coexist with PKD in cats. Recognizing coexisting congenital diseases is crucial for patient management and prognostic evaluation.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.Ethical approval was not required for the studies involving animals in accordance with the local legislation and institutional requirements because this is a case report of a patient. Written informed consent was obtained from the owners for the participation of their animals in this study.Y-EC: Conceptualization, Data curation, Writing – original draft, Writing – review & editing. W-BR: Conceptualization, Data curation, Writing – original draft, Writing – review & editing. S-JS: Data curation, Writing – review & editing. M-KL: Data curation, Writing – review & editing. M-HK: Supervision, Writing – original draft, Writing – review & editing. H-MP: Supervision, Writing – review & editing.


Editorial on the Research TopicInsights in heart failure and transplantation: 2022Just over 50 years from the first Heart Transplant ever performed by Dr Christiaan Barnard in 1967 in Cape Town, heart transplantation has become the mainstay therapy for patients with advanced heart failure. Today, the main limitation of the applicability of such treatment is the well-recognized shortage of organ donors in the modern era. Not only are donor hearts lacking but also the number of patients requiring a heart transplant is incessantly increasing, due to population aging and improved survival of patients living with heart failure. As a result, between 5% and 10% of patients die while on waiting lists.Cameli et al.).Even though bridge solutions to heart transplant are becoming more and more familiar with left ventricular assist devices, the problem overall remains largely unsolved. Different proposals have been advanced over the last decades trying to face this brain teaser. Some of them have already become reality in some countries, such as acceptance of hearts from HCV-positive donors, thanks to curative treatments now available, and protocols to widen the spectrum of donors. Particularly, the ADONHERS protocol, developed in Italy in Emilia-Romagna and Tuscany regions, aims at assessing the eligibility of the so-called marginal donors, namely those with >55 years or <55 years with multiple cardiovascular risk factors, employing stress-echocardiography to rule out subtle coronary artery disease . One hundred ten patients have been collected and results show valvular disease to be the most common indication for cardiac surgery in this special population. Among them, tricuspid valve disease was the one most largely observed, mostly as a results of intense surveillance protocols requiring frequent endomyocardial biopsies to rule out rejection. Another relatively common indication was coronary artery vasculopathy, even though percutaneous coronary intervention is usually preferred in this case. Surgery in heart transplant patients may be challenging because of surgical reintervention and may be complicated by a higher rate of infections due to the immunosuppressive regimens. For these reasons, surgery after heart transplantation is rarely performed unless in highly selected cases. According to data from this register, the Authors conclude that surgery in this context is relatedly safe, with low in-hospital mortality and postoperative complications in carefully selected patients. Nonetheless, the overall in-hospital and 1-year mortality after surgery were 9.1% and 13.8%, respectively, which are not neglectable after all. Therefore, the surgical option is certainly feasible but not free from safety concerns and should be considered only in specific conditions with indubitable benefit as compared to the interventional alternative.The largest available dataset of heart transplant patients undergoing cardiac surgery from three different continents and sixty high-volume centers has been published in this Research Topic .The relevance of comorbidities in patients with heart failure with preserved ejection fraction is already largely recognized. Treatment of non-cardiovascular comorbidities has recently received a class I recommendation in the latest ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure for patients with a preserved ejection fraction. Diabetes is one of the major risk factors for cardiovascular diseases and specifically for heart failure. There is a close interplay between diabetes and heart failure which is not completely understood yet. Complex pathophysiological processes may eventually lead to heart failure in diabetic patients, also independently from the presence of ischemic heart disease or hypertension, which has led to the discussed definition of diabetic cardiomyopathy in the past years. Beside the hermetic etiological process, heart failure patients with concomitant type 2 diabetes experience a more relevant reduction in the functional capacity. Also, diabetes showed to be the most powerful predictor of limited exercise capacity in patients with heart failure with preserved ejection fraction (Treewaree et al. published in the present issue has proved their benefit in terms of improvement of cardiovascular outcomes and quality of life in patients with heart failure with preserved and mildly reduced ejection fraction, anticipating the proposed recommendations in the 2023 Focus Update of the 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure.Sodium-glucose co-transporter 2 inhibitors were originally thought to be used in diabetic patients, but they have unexpectedly seen a massive spread among the cardiological community because of their clear benefit in patients with heart failure. Initially their use has been assessed in patients with a reduced ejection fraction, but recent randomized controlled trails have shown significant prognostic benefit also for that orphan disease which is heart failure with preserved ejection fraction. Indeed, besides diuretics for fluid retention, no drugs have ever proved benefit in this subset of patients. Sodium-glucose co-transporter 2 inhibitors come as the first specific therapy, notably with a class I recommendation, for patients with a preserved ejection fraction. As such, they represent the only drugs with a class IA recommendation across the whole range of ejection fraction in patients with heart failure. A systematic review and meta-analysis from Much evidence regarding both heart transplant and heart failure is continuously emerging, providing deeper insights into diseases' pathophysiology which eventually improve their clinical management. Aside from the papers highlighted herein, many other high-quality works have been published in this topic which well deserve a lecture. From biomarkers to echocardiography, from cardiac resynchronization therapy to left ventricular assist devices, this Research Topic covers a wide range of important subjects concerning heart failure.