TIMI myocardial perfusion frame count: a new method to assess myocardial perfusion and its predictive value for short-term prognosis.

OBJECTIVES: We sought to develop a new quantitative method to evaluate the degree of myocardial perfusion. BACKGROUND: Currently available methods for assessing myocardial perfusion, both TIMI myocardial perfusion grading (TMPG) and myocardial blush grading (MBG), are subjective. METHODS: TIMI Myocardial Perfusion Frame Count (TMPFC), an objective method that measures the filling and clearance of contrast in the myocardium using cine-angiographic frame-counting, was developed to quantify myocardial perfusion. Myocardial perfusion of 45 normal coronary arteries in 15 patients, and 137 culprit arteries in 137 patients immediately after primary angioplasty, was successfully assessed with TMPFC. RESULTS: The mean TMPFC in the normal arteries was 83.47 +/- 17.96 frames (95% CI: 78.07 frames

Higher levels of collagen and facilitated healing protect against ventricular rupture following myocardial infarction.

The mechanism of cardiac rupture after MI (myocardial infarction) is not fully understood. Rupture has not been reported in most laboratory species, including the rat, but does occur in mice. We have reported previously that beta2-TG mice (transgenic mice with cardiac-restricted overexpression of beta2-adrenergic receptors) had a lower incidence of rupture compared with NTG (non-transgenic) littermates. We hypothesized that the difference in the incidence of rupture between rodents and specific mouse strains is due to the difference in collagen content following MI. In the present study, we compared the difference in matrix remodelling post-MI between beta2-TG and NTG mice and between mice and rats. MI was induced by ligation of the left main coronary artery. Following MI, tensile strength, insoluble and soluble collagen content and gelatinase expression were determined in the infarcted and non-infarcted myocardium. Better preserved tensile strength measured as TTR [tension-to-rupture; 88+/-14 and 58+/-3% of the respective sham group values for beta2-TG compared with NTG mice (P<0.05); 108+/-7 and 32+/-4% of the respective sham group values for rats compared with 129sv mice (P<0.01)] and less severe acute infarct expansion after MI were found in rats compared with mice or in beta2-TG compared with NTG mice. These differences were associated with a higher content of pre-existing fibril collagen in the normal myocardium of beta2-TG compared with NTG mice (1.6-fold) or rats compared with 129sv mice (2-fold) and an accelerated fibrotic healing in the infarcted myocardium. Additionally, a less pronounced increase in MMP-9 (matrix metalloproteinase-9) activity was observed in the infarcted myocardium of rats compared with 129sv mice. We conclude that a higher collagen level is associated with facilitated fibrotic healing of an infarct and preserves the tensile strength of infarcted myocardium, thereby preventing cardiac rupture and acute ventricular remodelling.

Down-regulation of mitofusin-2 expression in cardiac hypertrophy in vitro and in vivo.

Mitofusin-2 (Mfn2) suppresses smooth muscle cell proliferation through inhibition of the Ras-extracellular signal-regulated kinases (ERK1/2) pathway. Since the ERK1/2 pathway is implicated in mediating hypertrophic signaling, we studied the changes in Mfn2 in cardiac hypertrophy using in vitro and in vivo models. Phenylephrine was used to induce hypertrophy in neonatal rat ventricular myocytes (NRVMs). In vivo hypertrophy models included spontaneously hypertensive rats (SHR), pressure-overload hypertrophy by transverse aortic constriction (TAC), hypertrophy of non-infarcted myocardium following myocardial infarction (MI), and cardiomyopathy due to cardiac-restricted overexpression of beta(2)-adrenergic receptors (beta(2)-TG). We determined hypertrophic parameters and analysed expression of atrial natriuretic peptide (ANP) and Mfn2 by real-time PCR. Phosphorylated-ERK1/2 (phospho-ERK) was measured by Western blot. Mfn2 was downregulated in phenylephrine treated NRCMs (by approximately 40%), hypertrophied hearts from SHR (by approximately 80%), mice with TAC (at 1 and 3 weeks, by approximately 50%), and beta(2)-TG mice (by approximately 20%). However, Mfn2 was not downregulated in hypertrophied hearts with 15 weeks of TAC, nor in hypertrophied non-infarcted myocardium following MI. phospho-ERK1/2 was increased in hypertrophied myocardium at 1 week post-TAC, but not in non-infarcted myocardium after MI, indicating that downregulated Mfn2 may be accompanied by an increase of phospho-ERK1/2. This study shows, for the first time, downregulated Mfn2 expression in hypertrophied hearts, which depends on the etiology and time course of hypertrophy. Further study is required to examine the causal relationship between Mfn2 and cardiac hypertrophy.

Cardiogenic shock caused by severe coronary artery spasm immediately after coronary stenting.

Coronary artery spasm is common during percutaneous coronary intervention and is easily relieved by intracoronary administration of vasodilators. We report the case of a patient who had severe, protracted, generalized spasm of the entire left coronary artery system during coronary artery stenting. The spasm, which was unresponsive to intracoronary vasodilators administered via guiding catheter, resulted in pulmonary edema and cardiogenic shock. Local injection of nitroglycerin via a transit catheter in the coronary artery eventually resolved the spasm and reversed the cardiogenic shock. To our knowledge, this is the 1st report of such a case in the English-language medical literature.

Thrombin generation and fibrinolytic activities among patients receiving reduced-dose alteplase plus abciximab or undergoing direct angioplasty plus abciximab for acute myocardial infarction.

The purpose of this study was to determine the impact of these 2 reperfusion strategies (reduced-dose alteplase plus abciximab or direct angioplasty plus abciximab) on fibrinolytic and thrombin generation activities. The effect of reduced-dose alteplase plus abciximab and direct angioplasty plus abciximab on hemostatic factors is unknown. Of 70 patients with acute myocardial infarction of < or = 6 hours, 34 were randomized to reduced-dose alteplase (35 to 50 mg in 1 hour) and 36 to direct angioplasty. A standard bolus and infusion dose of abciximab was administered to all patients. Blood specimens were collected at baseline, and at 1, 4, 12, and 24 hours. The following parameters were assayed: fibrinogen, plasminogen and antiplasmin activities, tissue plasminogen activator antigen, D-dimer, prothrombin fragments F1 + 2, and thrombin/antithrombin III complexes. Among patients treated with reduced-dose alteplase plus abciximab, the fibrinogen level decreased by 28.4% in the first hour (11.7 +/- 3.4 vs 7.8 +/- 2.5 micromol/L, p <0.001). Correspondingly, plasminogen and antiplasmin activities decreased by 43.8% (p <0.001) and 59.1% (p <0.001), respectively. Prothrombin fragments F1 + 2 increased from 2.2 +/- 1.7 to 4.2 +/- 1.6 nmol/L (1 hour) (p <0.001) and thrombin/antithrombin III increased from 16.3 +/- 15.0 to 33.5 +/- 19.9 microg/L (1 hour) (p <0.001). Conversely, in the direct angioplasty group, there was a marginal elevation in fibrinogen level at 1 hour (10.2 +/- 2.4 vs 10.6 +/- 2.0 micromol/L, p = 0.064) despite a significant reduction in plasminogen and an increase in tissue plasminogen activator levels. There was no significant change in prothrombin fragments F1 + 2 and thrombin/antithrombin III levels. Thus, there was considerable fibrinolytic activity with reduced-dose alteplase plus abciximab; thrombin generation was not prevented. Among patients treated with direct angioplasty, there was some endogenous fibrinolytic activity, but there was no significant thrombin generation.

Acute and long-term clinical and angiographic outcome after S-Stent implantation: S-Stent multicenter safety and efficacy trial.

The purpose of this study is to demonstrate safety and effectiveness of the S-Stent in de novo coronary lesions treated with conventional percutaneous coronary balloon angioplasty. Between January 2000 and June 2001, 120 patients were prospectively enrolled at four study centers. Patients were treated with coronary stenting in a total of 137 lesions. Procedural success was achieved in 100% of 137 attempted lesions. Clinical success was 99.8%. In-hospital mortality was 0.8%; myocardial infarction occurred in 0.8% and stent thrombosis in 0.8%. After stent implantation, the minimal lumen diameter increased from 0.92 +/- 0.43 to 2.74 +/- 0.36 mm (P < 0.0001) and the percent diameter stenosis decreased from 68.0 +/- 16.2 to 4.5 +/- 12.0 (P < 0.0001). At 6-month follow-up, the percent diameter stenosis was 33.5 +/- 21.3 and the angiographic restenosis rate was 16.5%. Target lesion revascularization was required in 12 patients (10.1%). We conclude that the use of S-Stent for coronary intervention resulted in a high procedural success rate and low angiographic restenosis at 6 months after implantation.

Combined fibrinolysis using reduced-dose alteplase plus abciximab with immediate rescue angioplasty versus primary angioplasty with adjunct use of abciximab for the treatment of acute myocardial infarction: Asia-Pacific Acute Myocardial Infarction Trial (APAMIT) pilot study.

We conducted a randomized feasibility pilot study comparing combined fibrinolysis with immediate rescue angioplasty vs. primary angioplasty with adjunctive abciximab in patients with acute myocardial infarction (AMI). Seventy patients with ST segment elevation AMI of

Relationship between plasma lipoprotein (a), apolipoprotein (a) phenotypes, and other coronary heart disease risk factors in a Melbourne South Asian population.

BACKGROUND: High plasma lipoprotein(a) [Lp(a)] level is a strong and important risk factor for cardiovascular disease (CVD). Small-sized apolipoprotein(a) [apo(a)] isoforms (F, B, S1, and S2) are inversely correlated with the high levels of Lp(a) in plasma and significantly associated with CVD. Although the effects of apo(a) phenotypes and various risk factors on Lp(a) status in South Asian population may have been studied in other countries, there are no reports involving these risk factors in Australia. METHODS AND RESULTS: Factors contributing to variation in Lp(a) were surveyed in 402 (216 males and 186 females) South Asian Melburnians. There was a negative relationship between low alcohol beer per day and Lp(a) in men (P < 0.05). Approximately 21% of the variance of Lp(a) concentration in men and 6% in women were explained by age. Age was positively associated with Lp(a) concentrations in men but negatively in women. The most commonly occurring phenotype was apo(a) S3. In this phenotype, Lp(a) concentrations ranged from non-detectable to 811 mg/l. After adjusting for age, an inverse correlation was observed between Lp(a) concentration and apo(a) phenotypes (P < 0.01). CONCLUSIONS: Although Lp(a) has been reported to be genetically determined, there are clearly other factors contributing to variations in Lp(a) concentrations in a South Asian population.

Platelet-endothelial cell adhesion molecule-1 gene polymorphism and its soluble level are associated with severe coronary artery stenosis in Chinese Singaporean.

OBJECTIVES: Platelet-endothelial cell adhesion molecule-1 (PECAM-1) mediates the transendothelial migration of circulating leukocytes, a characteristic change in vascular inflammation leading to atherosclerotic plaque development. We hypothesized that genetic variation and soluble level of PECAM-1 could be associated with coronary artery disease (CAD). DESIGN AND METHODS: We analyzed two single nucleotide polymorphisms (SNPs) of PECAM-1 gene C+373G (Leu125Val) at exon 3, which encodes the first extracellular (Ig)-like domain that mediates the homophilic binding of PECAM-1, and G+1688A (Ser563Asn) at exon 8 in 144 angiographically documented (> or =70% stenosis) patients with CAD and 150 age- and sex-matched controls in the Chinese population in Singapore, using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) strategy. Level of plasma soluble PECAM-1 (sPECAM-1) was measured by ELISA. RESULTS: The Leu125Val polymorphism was associated with CAD (P < 0.01). Also, the level of sPECAM-1 is was found to be elevated in CAD patients (P = 0.005). Moreover, subjects with the homozygous GG genotype of the Leu125Val polymorphism had higher sPECAM-1 levels (P = 0.005). The level of sPECAM-1 was further correlated to soluble platelet selectin (sP-selectin, also measured by ELISA), platelet count, and total white blood cell count (WBC), suggesting that platelets are a major source of sPECAM-1 and platelet activation and inflammation may contribute to PECAM-1 elevations in CAD patients. CONCLUSION: The Leu125Val polymorphism of PECAM-1 and the level of sPECAM-1 are associated with CAD in Chinese in Singapore. The level of sPECAM-1 is also associated with platelet activation and inflammation and correlated to the Leu125Val polymorphism. Our data suggest that PECAM-1 plays an important role in the development of atherosclerosis.

Tyrosine kinase inhibitors suppress alpha1-adrenoceptor mediated contraction in human radial, internal mammary arteries and saphenous vein.

The aim of this study is to determine whether the tyrosine kinase plays a role in the contractile response of human radial artery (RA), internal mammary artery (IMA) and saphenous vein (SV) to alpha(1)-adrenoceptor (AR) stimulation. The tyrosine kinase inhibitors, genistein and tyrphostin, significantly inhibited alpha(1)-AR mediated contractile response in a dose-dependent and non-competitive manner. Genistein at 10 microM inhibited 39%, 54% and 72% of PE-induced maximum contraction, and tyrphostin at 50 microM inhibited 41%, 68% and 39% of the contraction in the human RA, IMA and SV respectively. These results suggest that tyrosine kinases participate in regulation of signal transduction that is associated with alpha(1)-AR mediated contractile response in human blood vessels.

Brugada-type ECG with polymorphic ventricular tachycardia: a red herring for isolated right ventricular infarction.

We present a patient with Brugada-type ECG abnormalities and recurrent polymorphic ventricular tachycardia (VT). Subsequent investigations confirmed the diagnosis of isolated right ventricular myocardial infarction. The VT resolved after the 1st day and was not inducible subsequently. This case illustrates the importance of a careful study of the ECG to exclude other conditions in a patient with Brugada-type ECG abnormalities.

Markers of low-grade inflammation and soluble cell adhesion molecules in Chinese patients with coronary artery disease.

BACKGROUND: Inflammation plays an important role in atherosclerosis. Markers of low-grade chronic inflammation, such as C-reactive protein (CRP) and soluble cell adhesion molecules (sCAMs), have been associated with coronary artery disease (CAD). OBJECTIVE: To evaluate the significance of inflammatory markers as novel risk factors for CAD in the Chinese population. METHODS: High-sensitivity CRP (hs-CRP); sCAMs, including vascular cell adhesion molecule-1 (sVCAM-1), intercellular cell adhesion molecule-1 (sICAM-1), P-selectin (sP-selectin) and E-selectin (sE-selectin); and white blood cell (WBC) count were measured in 170 angiographically defined CAD patients (70% or greater stenosis affecting at least one vessel) and 177 healthy control subjects in the Chinese population in Singapore. RESULTS: The levels of hs-CRP, sVCAM-1 and sP-selectin, and the WBC count were higher in CAD patients than in control subjects (P<0.001, P<0.05, P<0.05 and P<0.001, respectively). There were no significant differences in the levels of sICAM-1 and sE-selectin between the two groups. Patients with unstable angina or myocardial infarction had higher levels of hs-CRP, and higher WBC and monocyte counts than those with stable angina or atypical chest pain (all P<0.05). The level of sP-selectin in patients with multivessel disease was higher than in those with single-vessel disease (P<0.05). Overall, the levels of hs-CRP and sCAMs showed a significant correlation with the lipid profile and the WBC count. CONCLUSIONS: The present study suggests that inflammatory markers, including hs-CRP and WBC count, together with sP-selectin and sVCAM-1, could serve as markers of atherogenesis in Chinese patients with CAD, with potential diagnostic and therapeutic implications.

Differences in inflammation, MMP activation and collagen damage account for gender difference in murine cardiac rupture following myocardial infarction.

Cardiac rupture remains a fatal complication of acute myocardial infarction (MI) with its mechanism partially understood. We hypothesized that damage to the collagen matrix of infarcted myocardium is the central mechanism of rupture and therefore responsible for the difference in the incidence of rupture between genders. We examined left ventricular (LV) remodeling during the acute phase post-MI in 129sv mice. Following induction of MI, we monitored rupture events and assessed the extent of LV remodeling by echocardiography. Muscle tensile strength, content of insoluble and soluble collagen, expression and activity of matrix metalloproteinases (MMPs) and density of inflammatory cells were determined in the infarcted and non-infarcted myocardium. We then tested the effects of MMP inhibition on rupture. Compared to female mice, males with MI displayed greater extent of LV remodeling, reduced muscle tensile strength, loss of insoluble collagen, local inflammatory response and MMP-9 activation, changes associated with a 3 times higher incidence of rupture than in females. MMP-9 expression by circulating blood mononuclear cells was also increased in male mice with acute MI. Treatment of male mice with an MMP inhibitor reduced MMP activity and halved rupture incidence. Our findings demonstrate that the differences in the severity of inflammation, MMP activation and damage to collagen matrix account for gender difference in cardiac rupture. Our study illustrates the breakdown of fibril collagen as a central mechanism of cardiac rupture.

Effects of molybdenum, silicon and nickel on alpha1-adrenoceptor-induced constriction of rat isolated aorta.

1. To determine the effects of trace elements on alpha1-adrenoceptor-mediated vasoconstriction, we studied the effects of molybdenum (Mo), silicon (Si) and nickel (Ni) on vasoconstrictor response to an alpha1-adrenoceptor agonist in rat aorta. 2. Cumulative concentration-contraction curves were obtained for phenylephrine (1 nmol/L-10 micromol/L) in the absence and presence of Mo, Si and Ni (0.3, 1 and 3 micromol/L) in rat aorta rings. Increasing the concentration of Mo and Si from 0.3 to 3 micromol/L shifted the cumulative concentration-contraction curve to the right, but did not reduce the maximal contractile response to phenylephrine. In contrast, Ni at 1 and 3 micromol/L shifted the cumulative concentration-contraction curve to the right and, at 3 micromol/L, reduced the maximum contractile response to phenylephrine. 3. We conclude that micromolar concentrations of Mo, Si and Ni affected alpha1-adrenoceptor-induced vasoconstriction and that Ni significantly inhibited the maximal contractile response to phenylephrine in rat isolated aorta.