Local Intracoronary Fibrinolysis with Distal Occlusion: A Series of Cases Using Marinade Technique.

No-reflow phenomenon is frequent in patients with ST-segment elevation myocardial infarction (STEMI) and has proven to be a strong predictor of mortality. Local fibrinolytic infusion with distal coronary occlusion (previously described as "marinade technique") can be useful in patients with acute myocardial infarction and intraluminal thrombus refractory to aspiration enabling the local effect of the drug, directly applied inside the thrombus, while protecting the microvasculature with prolonged inflation of a distal balloon. We present the early experience of four patients with inferior acute myocardial infarction and high thrombus burden successfully treated with marinade technique in one center.

Local Intracoronary Fibrinolysis in Acute Myocardial Infarction of Ectatic Coronary Arteries in the Post-Abciximab Era.

Percutaneous intervention in the context of coronary artery ectasia (CAE) is penalized with no-reflow phenomenon. The glycoprotein-IIb/IIIa-inhibitor abciximab was the most accepted method for pharmacology thrombus resolution in this scenario, nevertheless, this agent was recently withdrawn. We describe 5 patients treated with local intracoronary fibrinolysis administrated through predesigned catheters in the setting of AMI and CAE.

Pharmacoproteomics in cardiac hypertrophy and atherosclerosis.

Proteomics applications to study the molecular effects of drug administration (pharmacoproteomics) on left ventricular hypertrophy (LVH) and atherosclerosis are here reviewed. In most cases, an absence of complete normalization after treatment is revealed, in contrast to what is reported by classical approaches.

Transcriptome of hypertension-induced left ventricular hypertrophy and its regression by antihypertensive therapies.

Left ventricular hypertrophy (LVH), a common consequence of systemic hypertension associated with poor clinical outcome, is also a potentially reversible condition. Here, we probed the molecular pathways that underpin the development of LVH and their modulation by antihypertensive regimens that reversed LVH. Spontaneously hypertensive rats were studied at 12 (early LVH) and 48 weeks (late LVH), respectively, with normotensive Wistar-Kyoto rats as age-matched controls. Three treatment groups were maintained for 36 weeks on the following regimens: (1) quinapril, (2) doxazosin and quinapril combination, and (3) losartan. Gene expression profiling was performed with Affymetrix microarrays (GeneChip Rat-230A) and primary function-focused average linkage hierarchical cluster analysis. Of the 15 696 gene sequences expressed on the Affymetrix GeneChip Rat-230A, there was significant alteration in the expression of 295 (1.9%) of these transcripts in 'early' LVH and 143 (0.9%) in 'late' LVH. The predominant changes in gene expression were seen in metabolism, cell growth/proliferation, signal transduction, development and muscle contraction/cytoskeleton functional groups. Although sharing many effects on gene expression, the three treatments showed different expression profiles. Despite significant regression of LVH with treatment, 31 LVH-associated transcripts were unchanged by any of the treatment groups. Our data suggest that LVH regression does not normalize the LVH transcriptome. Therefore, regression of hypertension-induced LVH is associated with a distinct gene expression profile, suggesting the effect of both treatment and a previously unknown specific myocardial physiology after regression of LVH.

Potent arterial antithrombotic effect of direct factor-Xa inhibition with ZK-807834 administered to coronary artery disease patients.

It was the objective of this study to evaluate the anti-thrombotic potency of direct factor-Xa inhibition with ZK-807834 in stable coronary patients, using an ex-vivo model of arterial thrombus formation. Tissue factor pathway is important in atherothrombosis. Direct factor-Xa blockade may more potently reduce thrombosis and prevent coronary events. Badimon Perfusion Chamber 5-minute quantitative studies have shown 40-55% arterial thrombus reduction with abciximab, 23% with clopidogrel, but none with heparin. Coronary patients (n = 18, 59 +/- 9 years, 55% males) were blindly randomized to four groups receiving 24-hour infusion of a low, medium or high dose of direct factor- Xa inhibitor ZK-807834, or placebo. Arterial thrombus formation was measured in Badimon Chamber at baseline, end-of-infusion [EoI], and four hours and eight hours after EoI, and factor-X activity, prothrombin time [PT] ratio and plasma drug levels were measured simultaneously. For the low-, medium- and high-dose ZK-807834 groups, mean percent-reduction in thrombus size from baseline to EoI were 29%, 34% and 68%, respectively (p < 0.001), and at 8-h post EoI were 11%, 19% and 27%, respectively (p < 0.01). Mean PT-ratio prolongation showed a strong linear relationship (Pearson's r = 0.93) with ZK-807834 plasma concentration. Mean percent-reduction in factor-X activity from baseline was 13%, 42% and 58%, respectively. Placebo had no effect on thrombus size or factor-X activity. In conclusion, direct factor-Xa inhibition with ZK-807834 markedly reduces ex-vivo arterial thrombus formation and factor-X activity in a dose-dependent manner. Plasma levels of ZK-807834 show a strong linear correlation with PT ratio. This direct factor-Xa inhibitor may reduce the need for additional potent glycoprotein IIbIIIa inhibition.

Analysis of antihypertensive drugs in the heart of animal models: a proteomic approach.

Arterial hypertension is the most frequent chronic disease and it is an important cause of morbidity and mortality in the developed world. Arterial hypertension is associated with such adverse effects as accelerated arteriosclerosis and pathological left ventricular hypertrophy, among others. The molecular mechanisms affecting left ventricular hypertrophy remain mostly unknown. The advent of proteome profiling has facilitated the elucidation of disease-associated proteins, paving the way for molecular diagnostics and the identification of novel therapeutic targets. We explored the proteomic profile of pathological left ventricular hypertrophy in comparison with normal heart in a model of rats and investigated the proteomic changes in response to different antihypertensive regimens in order to elucidate their cardioprotective effects. Here we describe in depth the protocol for this type of study.

Fenofibrate induces plaque regression in hypercholesterolemic atherosclerotic rabbits: in vivo demonstration by high-resolution MRI.

INTRODUCTION: Fenofibrate has shown to reduce major cardiovascular events and slow angiographic progression of coronary atherosclerosis. The postulated mechanism of action is via the activation of peroxisomal proliferator-activated receptor-alpha (PPAR-alpha), a nuclear transcription factor that controls a variety of cellular functions. We investigated the anti-atherogenic effects of fenofibrate on previously established experimental atherosclerotic lesions. METHOD: Atherosclerotic lesions were induced in the abdominal aorta of New Zealand white (NZW) rabbits (n=19) by a combination of a double-balloon injury and a 9-month hypercholesterolemic diet. The rabbits were randomized into placebo or fenofibrate group. The corresponding treatments were added to the hypercholesterolemic diet. All rabbits underwent MRI examination at randomization and after 6 months of treatment, and were then sacrificed for histopathology. RESULTS: LDL-cholesterol was similarly elevated at randomization and follow-up, and was not significantly modified by fenofibrate therapy. HDL-cholesterol decreased (-27+/-10%, p=0.04) in the placebo and increased (+36.8+/-2%, p=0.04) in the fenofibrate group. MRI showed comparable vessel wall area (VWA) at randomization in both groups. At 15months, a significant increase in VWA was seen in the placebo group (15+/-4%, p=0.007), while fenofibrate treatment was associated with a regression (-11+/-4%, p=0.041) of previously established lesions. Fenofibrate also decreased macrophage and increased smooth muscle cell/collagen content of atherosclerotic lesions. CONCLUSION: MRI measurements can, in conjunction with in vitro histological measurements, contribute to the understanding of the actions of pharmacologic agents in experimental models of atherosclerosis. Fenofibrate significantly regresses atherosclerotic lesions and induced changes in plaque composition associated with a more "stable" phenotype (reduced macrophages and increased SMC). These observations support the potential anti-atherogenic effects of PPAR-alpha agonists.

Long-term treatment with an ACE inhibitor or an AT1 antagonist avoids hypertension-induced inflammation in the kidney.

BACKGROUND: Hypertension causes an inflammatory response in the kidney. Many studies have demonstrated that activation of the renal renin-angiotensin system, and therefore an increase in local angiotensin II (AngII) production, participates in the renal inflammatory cell recruitment. Our aim was to investigate the role of AngII blockade in hypertension-induced inflammatory response. METHODS: To replicate chronic hypertension with renal disease, we used a model of spontaneously hypertensive rats with unilateral nephrectomy (UNX-SHR). These animals were studied for 48 weeks. We investigated the effect of long-term treatment with an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin II type 1 (AT1 ) antagonist, 2 strategies currently used in humans, on renal proinflammatory parameters. RESULTS: UNX-SHR rats presented elevated renal inflammatory cell infiltration and up-regulation of proinflammatory factors, including activation of nuclear factor chi B (NF-chi B) and related genes. Both ACE inhibition and AT 1 blockade decreased the number of inflammatory cells as well as the up-regulation of proinflammatory factors in the kidney. CONCLUSIONS: These results suggest that either AT 1 blockade or ACE inhibition can stop the renal inflammatory process in chronic hypertension-associated inflammatory response.

Long-term organ protection by doxazosin and/or quinapril as antihypertensive therapy.

BACKGROUND: Even with optimal blood pressure control, organ protection may also depend on the selected therapeutic regime. Angiotensin-converting enzyme inhibitors have been shown to provide excellent organ protection in hypertension, and may show dose-dependent protective effects. Adrenergic alpha blockers have been associated with an increased rate of heart failure in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) and Vasodilator-Heart Failure Trial (V-HeFT). This has been related to a proapoptotic effect of this drug in cardiomyocytes. Our purpose is to compare the heart and renal protection of a high quinapril dose, with a combined low quinapril dose plus doxazosin, in an animal model of chronic hypertension. METHODS: Uninephrectomized spontaneously hypertensive 12-week-old rats were treated for 36 weeks with either quinapril or a combination of doxazosin plus a low quinapril dose. Tight blood pressure control was achieved with both treatments. Renal and cardiac protection was assessed by different parameters, and cardiac apoptosis was evaluated by active caspase-3, apoptotic protein and heat shock protein levels. Untreated hypertensive and normotensive rats were included as controls. RESULTS: Both treatments showed significant heart and renal protection compared with untreated animals. Both therapeutic regimes showed similar protection in renal and cardiac pathology, coronary media fibrosis, myocardial apoptosis and cardiac index. Proteinuria and left ventricular hypertrophy regression were significantly lower in the quinapril group compared with the combined treatment group. CONCLUSIONS: Blood pressure control with a high quinapril dose provided higher organ protection than a combined therapy with a lower quinapril dose. This effect was not due to a deleterious effect of doxazosin.

Proteomic analysis of early left ventricular hypertrophy secondary to hypertension: modulation by antihypertensive therapies.

Untreated or poorly controlled arterial hypertension induced development of pathologic left ventricular hypertrophy (LVH), a common finding in hypertensive patients and a strong predictor of cardiovascular morbidity and mortality. The proteomic approach is a powerful technique to analyze a complex mixture of proteins in various settings. An experimental model of hypertension-induced early LVH was performed in spontaneously hypertensive rats, and the cardiac protein pattern compared with the normotensive Wistar Kyoto counterpart was analyzed. Fifteen altered protein spots were shown in the early stage of LVH. Compared with a previous animal model of established and regressed LVH, three protein spots were common in both models. These three altered protein spots corresponded to two unique proteins that were identified as Calsarcin-1 (CS-1) and ubiquinone biosynthesis protein COQ7 homolog. CS-1 is a negative regulator of the calcineurin/NF-AT pathway. Because upregulation in the expression levels of this protein was observed, the activation level of NF-kappaB by oxidative stress as an alternative pathway was investigated. It was found that antihypertensive therapies partially decreased oxidative stress and normalized the activation of NF-kappaB in the kidneys and aorta NF-kappaB activation but just moderately in the heart. This could be due to the interaction of any specific cardiac protein with any component of the NF-kappaB pathway. In this sense, CS-1 could be a good candidate because it is expressed preferentially in heart, to a lesser extent in smooth muscle cells, but not in kidney. Further investigations are necessary to elucidate the exact role of CS-1 and ubiquinone biosynthesis protein COQ7 in the setting of hypertension-induced LVH.

Comparison of the protein profile of established and regressed hypertension-induced left ventricular hypertrophy.

Established left ventricular hypertrophy (LVH) showed a significant alteration in the cardiac protein profile compared with normal heart. The main finding of this work was to identify proteins differently expressed in hypertension-induced LVH and the fact that after regression of LVH (histologically determined), the proteome still maintains a number of expressed proteins characteristic of the hypertrophied heart. These unrecovered proteins play an essential role in the energy production pathway, in cellular stress defense and also in hypertrophy regulation.

Proteomic approach in the search of new cardiovascular biomarkers.

With the increasing incidence of cardiovascular diseases worldwide, specifically atherosclerosis and heart failure, the search for novel biomarkers remains a priority. As opposed to complex diagnostic techniques that may not be suitable to be applied to the wider population, biomarkers are useful for population screening. The search for novel biomarkers is based on knowledge of the molecular and cellular processes that take place in the development of a specific disease. Atherosclerosis and heart failure are characterized by a long period of silent disease progression, allowing early diagnosis and the potential of early therapeutic intervention. The use of the so-called proteomic techniques allows not only protein identification but partial characterization, which includes expression and also post-translational modification of these proteins. This allows for the discovery of previously unknown proteins involved in cardiovascular diseases, including some that may be suitable to be used as biomarkers. However, to approach this issue, we have to overcome difficulties such as tissue heterogeneity (vessel wall or myocardium) and the lack of fresh human samples. We discuss the proteomic study of human plaques, secreted proteins by pathologic and normal vessel wall, and left ventricular hypertrophy as potential sources of new biologic markers of cardiovascular disease.

Long-term blood pressure control prevents oxidative renal injury.

Arterial hypertension is a leading contributor to the progression of chronic renal disease. Short-term studies had addressed the role of oxidative stress in hypertensive nephropathy. We have now studied oxidative stress and caspase activation in a long-term model of hypertensive renal injury. Nontreated spontaneously hypertensive rats with uninephrectomy displayed severe arterial hypertension over a 36-week follow-up. Uncontrolled high blood pressure in the context of modest renal mass reduction resulted in significant histological renal injury. Blood pressure control by the angiotensin-converting enzyme (ACE) inhibitor, quinapril, or the AT1 receptor antagonist, losartan, decreased the degree of renal injury. Hypertensive renal injury was associated with evidence of activation of the apoptotic pathway (increased activation of caspase-3) and local renal (increased staining for 4-hydroxy-2-nonenal) and systemic [increased serum levels of 8-iso-prostaglandin F2alpha (8-iso-PGF2alpha)] lipid oxidation when compared with normotensive control rats. In addition, severe hypertension decreased the renal antioxidant defenses, as exemplified by decreased expression of Cu/Zn superoxide dismutase. Treatment with quinapril or losartan decreased caspase-3 activation, 4-hydroxy-2-nonenal staining, and 8-iso-PGF2alpha levels and increased Cu/Zn superoxide dismutase expression. These results suggest that hypertension-associated oxidative stress and its consequences may be decreased by either ACE inhibition or AT1 receptor antagonist, emphasizing the role of angiotensin II in hypertensive renal damage.

The selective peroxisomal proliferator-activated receptor-gamma agonist has an additive effect on plaque regression in combination with simvastatin in experimental atherosclerosis: in vivo study by high-resolution magnetic resonance imaging.

OBJECTIVES: We sought to investigate the anti-atherogenic effects of a selective peroxisomal proliferator-activated receptor-gamma (PPAR-gamma) agonist and simvastatin, as well as their combination, over time, in a rabbit model of experimental atherosclerosis. BACKGROUND: The PPARs are nuclear transcription factors that control a variety of cellular functions, with the potential effects required to induce plaque regression and stabilization. METHODS: Atherosclerosis was induced in rabbits (n = 37) by the combination of double-balloon injury and a nine-month high-cholesterol (HC) diet. The rabbits were randomized into a continued HC diet, a normal chow (NC) diet, NC plus simvastatin, NC plus PPAR-gamma agonist, and NC plus simvastatin plus PPAR-gamma agonist. All rabbits underwent magnetic resonance imaging (MRI) at randomization and after six months of treatment and were then sacrificed for histopathologic study. RESULTS: All groups had a similar vessel wall area by MRI (8.45 +/- 0.65 mm(2), p = NS between groups) at randomization. Significant progression was seen in the HC diet group (15 +/- 4%, p < 0.01). In the NC and NC plus PPAR-gamma agonist groups, progression was abolished (-2.5 +/- 3% and -4.5 +/- 5%, respectively; p = NS). The NC plus simvastatin and NC plus simvastatin plus PPAR-gamma agonist groups had significant plaque regression (-12 +/- 4% [p < 0.05] and -22 +/- 4% [p < 0.01], respectively). Regression was independent of plasma lipid levels. All NC groups had similar lipid profiles at the end of treatment. Histopathologic analysis of the NC groups showed a decreased macrophage content and matrix metalloproteinase activity and an increased smooth muscle cell/collagen content of lesions. CONCLUSIONS: Our data indicate that normalization of plasma lipid levels abolishes progression of atherosclerosis. Simvastatin elicits regression of atherosclerotic lesions, and the combination simvastatin plus PPAR-gamma agonist has additive regression effects on plaque. This is paralleled by structural alterations in plaque composition, which may increase plaque stability. These observations support the beneficial effects of statins on atherosclerosis and show additional anti-atherogenic benefits of combining a PPAR-gamma agonist with simvastatin.

Statins in hypertensive patients: potential explanations for the ASCOT-LLA study results.

The recently published Lipid-Lowering Arm of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT-LLA) provides interesting evidence for the use of statins in hypertensive patients with average cholesterol concentrations and other cardiovascular risk factors. The clinical benefit of atorvastatin in these patients is probably explained by both lipid-dependent and lipid-independent effects of the drug. Many of these effects are related to inhibition of the synthesis of isoprenoid, which serves as lipid attachment for a variety of proteins implicated in intracellular signalling. These proteins have an important role in cell growth, actin cytoskeleton organisation, membrane trafficking, gene expression, cell proliferation/migration and programmed cell death. In this article we summarise the different effects of statins inrelation to the results observed in the ASCOT-LLA study.

[Acute myocardial dysfunction after nasal infiltration with cocaine]. / Disfunción miocárdiaca aguda reversible tras anestesia intranasal con cocaína.

We report the case of a patient with severe myocardial dysfunction after nasal infiltration of cocaine during septoplasty. Complete recovery of myocardial function was observed in twelve days. Several reports have described chronic cardiomyopathy in long-term cocaine users, but only one case of acute cardiomyopathy. None of these cases were related to the medical use of cocaine.

Role of risk factors in the modulation of tissue factor activity and blood thrombogenicity.

BACKGROUND: Several studies suggest a role for an increased circulating pool of tissue factor (TF) in atherothrombotic diseases. Furthermore, certain cardiovascular risk factors, such as diabetes, hyperlipemia, and smoking, are associated with a higher incidence of thrombotic complications. We hypothesized that the observed increased blood thrombogenicity (BT) observed in patients with type 2 diabetes mellitus may be mediated via an increased circulating tissue factor activity. We have extended our study to smokers and hyperlipidemic subjects. METHODS AND RESULTS: Poorly controlled patients with type 2 diabetes mellitus (n=36), smokers (n=10), and untreated hyperlipidemic subjects (n=10) were studied. Circulating TF was immunocaptured from plasma, relipidated, and quantified by factor Xa (FXa) generation in the presence of factor VIIa. BT was assessed as thrombus formation on the Badimon perfusion chamber. Patients with improvement in glycemic control showed a reduction in circulating TF (362+/-135 versus 243+/-74 pmol/L per min FXa, P=0.0001). A similar effect was observed in BT (15 445+/-1130 versus 12 072+/-596 microm/mm2, P=0.01). Two hours after smoking 2 cigarettes, TF was increased (217+/-72 versus 283+/-106 pmol/L per min FXa, P=0.003). Hyperlipidemic subjects showed higher TF (237+/-63 versus 195+/-44 pmol/L per min FXa, P=0.035) than healthy volunteers. CONCLUSIONS: These findings suggest that high levels of circulating TF may be the mechanism of action responsible for the increased thrombotic complications associated with the presence of these cardiovascular risk factors. These observations strongly emphasize the usefulness of the management of the patients based on their global risk assessment.