Secondary mitral regurgitation: percutaneous edge-to-edge repair on the cutting edge?

PURPOSE OF REVIEW: Secondary mitral regurgitation commonly complicates heart failure. Although the evidence for its management is most robust for treating the underlying cardiomyopathy, treatment aimed at additionally reducing the severity of mitral regurgitation with a percutaneous edge-to-edge device, MitraClip, has recently emerged. RECENT FINDINGS: Despite the use of contemporary evidence-based heart failure therapies, patients with secondary mitral regurgitation and heart failure continue to remain at high risk for adverse clinical events; in both the MITRA-FR and COAPT trials, an extremely high event rate was evident in the medically managed arms over the respective 12-24-month follow-up. Data supporting the use of MitraClip to mitigate adverse outcomes in secondary mitral regurgitation is, however, conflicting. In MITRA-FR no difference was noted between MitraClip compared with the medically managed arm for the composite of all-cause death or heart failure hospitalization at 12 months. However, in COAPT, a significant reduction in the rate of heart failure re-hospitalization over 2 years was evident with MitraClip compared with medical therapy alone. SUMMARY: Recommendations exist for the use of MitraClip in patients with primary mitral regurgitation and prohibitive surgical risk. However, with the divergent results of two recent high-quality randomized trials, its role in patients with secondary mitral regurgitation remains controversial.

Modulation of high sensitivity C-reactive protein by soluble receptor for advanced glycation end products.

High sensitivity C-reactive protein (hs-CRP) is synthesized mainly by hepatocytes in response to tumor necrosis factor-alpha (TNF-alpha), interleukin-1 (IL-1), and interleukin-6 (IL-6). The interaction of advanced glycation end products (AGEs) with the receptor for advanced glycation end products (RAGE) increases the expression of the cytokines TNF-alpha, IL-1, and IL-6. Soluble receptor for advanced glycation end products (sRAGE) competes with RAGE for binding with AGEs. Hence, low sRAGE levels may increase interaction of AGEs with RAGE resulting in the increased production of cytokines. It is hypothesized that serum levels of sRAGE modulate serum levels of hs-CRP. The objectives are to determine if (i) serum levels of sRAGE are lower and those of TNF-alpha and hs-CRP are higher in non-ST-segment elevation myocardial infarction (NSTEMI) patients compared to control subjects; (ii) serum levels of TNF-alpha and hs-CRP are positively correlated; and (iii) sRAGE is negatively correlated with hs-CRP and TNF-alpha. The study consisted of 36 patients with NSTEMI and 30 age-matched healthy male subjects. Serum levels of sRAGE and TNF-alpha were determined by enzyme-linked immunoassay and hs-CRP was measured using near infrared immunoassay. Serum levels of sRAGE were lower, while those of TNF-alpha and hs-CRP were higher in patients with NSTEMI compared to controls. The levels of sRAGE were negatively correlated with those of TNF-alpha and hs-CRP, while TNF-alpha was positively correlated with hs-CRP in both the control subjects and NSTEMI patients. The data suggest that sRAGE modulates the synthesis of hs-CRP through TNF-alpha.

Pulmonary Embolism: The Value of the Angiographic Diagnosis.

We describe the case of a 55-year-old patient with a history of pulmonary embolism who presented in shock with ST-elevation on his electrocardiogram. He was triaged to the catheterization laboratory where he suffered a cardiac arrest. A pulmonary embolism was diagnosed angiographically, the thrombus was aspirated, and he received systemic thrombolysis. The combination of clot debulking and systemic thrombolysis acted synergistically to improve his right ventricular function by resolving his pulmonary hypertension. Although it is associated with a higher bleeding risk, the combination of clot aspiration with a thrombolytic agent in the treatment of massive pulmonary embolism in young patients might warrant further study.

Soluble receptors for advanced glycation end products (sRAGE) as a predictor of restenosis following percutaneous coronary intervention.

BACKGROUND: Interaction of advanced glycation end products (AGEs) with their receptor (RAGE) increases expression of inflammatory mediators (tumor necrosis factor alpha [TNF-α] and soluble vascular cell adhesion molecule-1 [sVCAM-1]) and induces oxygen radicals that are implicated in atherosclerosis. Balloon-injury-induced atherosclerosis is associated with increased expression of AGEs and RAGE. The soluble receptor for AGE (sRAGE), which acts as a decoy for RAGE ligands (AGEs), prevents atherosclerosis in this model. HYPOTHESIS: We evaluated: 1) whether post-percutaneous coronary intervention (PCI) restenosis is associated with low pre-PCI serum sRAGE, high serum AGEs, TNF-α, and sVCAM-1, and high AGE/sRAGE ratio; 2) whether pre-PCI and post-PCI levels of these markers are similar in patients with or without restenosis; and 3) whether sRAGE and AGE/sRAGE ratio have predictive value for post-PCI restenosis. METHODS: Angiography was performed in 46 patients with non-ST-segment elevation myocardial infarction for assessment of restenosis. Serum sRAGE, AGEs, TNF-α, and sVCAM-1 were measured in these patients and 20 control subjects. RESULTS: : Nineteen of the 46 patients developed post-PCI restenosis, which was associated with lower sRAGE and higher TNF-α and sVCAM-1 levels, and higher AGE/sRAGE ratio compared with patients without restenosis. Pre-PCI and post-PCI levels of these biomarkers were similar in both groups, except in patients with restenosis, in whom the post-PCI level of sRAGE was lower and TNF-α was higher than the pre-PCI levels. The sensitivity and negative predictive value of sRAGE were 100%, and were higher than those of AGE/sRAGE ratio in identifying post-PCI restenosis. CONCLUSIONS: Both low serum sRAGE levels and high AGE/sRAGE ratio have predictive value for post-PCI restenosis.

Prognostic implications of C-reactive protein and troponin following percutaneous coronary intervention.

BACKGROUND: C-reactive protein (CRP), a marker of inflammation, plays a role in the pathophysiology of atherosclerotic events. The relationship between CRP levels and myocardial necrosis assessed by troponin T (TnT) in patients undergoing percutaneous coronary intervention (PCI) has not been established. In addition, the long-term significance of TnT rise following PCI is not clear. OBJECTIVES: To examine the relationship between CRP and the rise in TnT levels, and evaluate the long-term prognostic implications of TnT rise following PCI. METHODS: A total of 1208 patients underwent successful nonemergent PCI. Baseline demographic characteristics, CRP and TnT levels were prospectively collected before and 12 h to 18 h following PCI. Long-term follow-up data over two years were available. RESULTS: Among the patients studied (mean age 62 years), 64% presented with acute coronary syndrome. A PCI procedure was associated with a significant increase in TnT levels (higher than 0.1 microg/L) in 238 patients (20%). Multivariate logistic regression identified presentation with acute coronary syndrome or myocardial infarction, no statin use at the time of the procedure, increased CRP and increasing length of stent as independent predictors of TnT rise following PCI. Periprocedural TnT rise was not associated with adverse events in follow-up examinations (OR 1.09, 95% CI 0.73 to 1.65). CONCLUSIONS: Myocardial necrosis commonly occurred in otherwise successful PCI and was particularly prevalent in the proinflammatory milieu of a recent myocardial infarction. This response was blunted with statin therapy. However, there was no long-term adverse sequelae of these troponin rises following otherwise uncomplicated PCI.

Low levels of soluble receptor for advanced glycation end products in non-ST elevation myocardial infarction patients.

BACKGROUND: Interaction of the receptors for advanced glycation end products (RAGEs) with advanced glycation end products (AGEs) results in expression of inflammatory mediators (tumor necrosis factor-alpha [TNF-α] and soluble vascular cell adhesion molecule-1 [sVCAM-1]), activation of nuclear factor-kappa B and induction of oxidative stress - all of which have been implicated in atherosclerosis. Soluble RAGE (sRAGE) acts as a decoy for the RAGE ligand and is protective against atherosclerosis. OBJECTIVES: To determine whether levels of serum sRAGE are lower, and whether levels of serum AGEs, TNF-α and sVCAM-1 are higher in non-ST elevation myocardial infarction (NSTEMI) patients than in healthy control subjects; and whether sRAGE or the ratio of AGEs to sRAGE (AGEs/sRAGE) is a predictor/biomarker of NSTEMI. METHODS: Serum levels of sRAGE, AGEs, TNF-α and sVCAM-1 were measured in 46 men with NSTEMI and 28 age- and sex-matched control subjects. Angiography was performed in the NSTEMI patients. RESULTS: sRAGE levels were lower, and levels of AGEs, TNF-α, sVCAM-1 and AGEs/sRAGE were higher in NSTEMI patients than in control subjects. sRAGE levels were negatively correlated with the number of diseased coronary vessels, serum AGEs, AGEs/sRAGE, TNF-α and sVCAM-1. The sensitivity of the AGEs/sRAGE test is greater than that of the sRAGE test, while the specificity and predictive values of the sRAGE test are greater than those of the AGEs/sRAGE test for identifying NSTEMI patients. CONCLUSIONS: Serum levels of sRAGE were low in NSTEMI patients, and were negatively correlated with extent of lesion, inflammatory mediators, AGEs and AGEs/sRAGE. Both sRAGE and AGEs/sRAGE may serve as biomarkers/predictors for identifying NSTEMI patients.

Inhibiting matrix metalloproteinase-2 reduces protein release into coronary effluent from isolated rat hearts during ischemia-reperfusion.

BACKGROUND: Previous studies have shown that the disruption of the coronary endothelium and the increase in its permeability during ischemia-reperfusion (I/R), are linked to matrix metalloproteinase-2 (MMP-2) activity. Studies from our group have shown that during I/R, activity of MMP-2 in the coronary effluent increases and this increase is associated with cardiac dysfunction, which in turn, can be prevented by MMP inhibitors. Therefore, we hypothesize that inhibiting MMPs reduces the MMP-2 dependent disruption of the coronary endothelium and subsequent protein release during I/R. METHODS: Isolated rat hearts were perfused in the Langendorff mode at a constant pressure and subjected to 15, 20 or 30 min no-flow ischemia followed by 30 min of reperfusion. The MMP inhibitors, o-phenanthroline (Phen, 100 microM) or doxycycline (Doxy, 30 microM) an inhibitors of MMPs, were added to the perfusion solution 10 min before ischemia and for the first 10 min of reperfusion. The coronary effluents were collected during perfusion for protein analysis. Creatine kinase was measured as an index of cellular damage. Endothelial integrity was assessed by measuring coronary flow and by measuring the levels of serotransferrin and interstitial albumin in the coronary effluent. Additionally, damage to the endothelium was assessed histologically by light microscopy analysis of the cellular structure of the myocardium. MMP-2 activity was measured by zymography in hearts subjected to 15, 20 and 30 min of ischemia without reperfusion. RESULTS: MMP-2 activity was increased in heart tissue at the end of ischemia and was correlated with duration of ischemia. The post-ischemia decrease in coronary flow, and the increase in the release of serotransferrin and albumin were attenuated by Phen. Edema (another indirect marker of endothelial damage) was observed in I/R heart and the edema was abolished in I/R heart treated with MMP inhibitors. CONCLUSION: MMP inhibition not only reduces cardiac mechanical dysfunction but also reduces endothelial damage resulting from cardiac I/R injury.

Large and small vessel vasoconstriction following coronary artery stenting. Effect of intra coronary nitroglycerine and relation to LDL cholesterol.

UNLABELLED: Percutaneous coronary intervention (PCI) with stent placement induces epicardial coronary vasoconstriction, which is resolved by intracoronary (IC) nitroglycerine (NTG). The effect of stenting on microvascular coronary circulation and coronary blood flow (CBF) is less well established, and the effect of NTG on CBF following stenting is unknown. We examined the time course, extent, and influence of NTG, on PCI induced coronary vasoconstriction. Secondarily we also did an explorative analysis to evaluate the effect of increased levels of low density lipoprotein cholesterol (LDL-Cholesterol) on CBF after stenting. METHODS: Single vessel PCI stent was performed in 19 patients (age 62+/-10 years). Immediately after PCI, a 0.014 Doppler flow-wire was positioned distal to the stent, and IC NTG 0.2 mg was given. Quantitative coronary angiography (QCA) and CBF measurements were taken at baseline, and at 10, 20 and 30 min following PCI. Further IC NTG 200 mug was given after the measurement at 30 min, and the measurements were repeated at 31 and 33 min. Coronary flow velocity reserve (CFVR) was measured with adenosine IC bolus. RESULTS: Compared to baseline, there were significant reductions in CBF (24.5+/-18.3%), (35+/-30 vs. 28+/-25 ml/min, p=0.001) and coronary arterial diameter (5.1+/-5.4%) (2.63+/-0.54 vs. 2.50 mm+/-0.53, p=0.008) within 30 min following PCI. Subsequent IC NTG reversed both small (28+/-25 vs. 44+/-30 ml/min, p<0.001) and large (2.50+/-0.53 vs. 2.80+/-0.59 mm, p=0.001) vessel PCI induced vasoconstriction. LDL-cholesterol was significantly correlated to the percent reduction of blood-flow within 30 min (r=0.515, p=0.024, n=19) and to the maximal CBF after NTG (r=0.520, p=0.022, n=19). CONCLUSION: Following PCI, both large and small vessel vasoconstriction are seen as manifest by a reduction in coronary conduit vessel diameter and in CBF. These effects are reversed by NTG. Serum levels of LDL are modestly related to the reduction of CBF and to the degree of NTG induced vasodilatation of coronary micro-vasculature.