Clinical benefit of adenosine as an adjunct to reperfusion in ST-elevation myocardial infarction patients: An updated meta-analysis of randomized controlled trials

Background: Adenosine administered as an adjunct to reperfusion can reduce coronary no-reflow and limit myocardial infarct (MI) size in ST-segment elevation myocardial infarction (STEMI) patients. Whether adjunctive adenosine therapy can improve clinical outcomes in reperfused STEMI patients is not clear and is investigated in this meta-analysis of 13 randomized controlled trials (RCTs). Methods: We performed an up-to-date search for all RCTs investigating adenosine as an adjunct to reperfusion in STEMI patients. We calculated pooled relative risks using a fixed-effect meta-analysis assessing the impact of adjunctive adenosine therapy on major clinical endpoint including all-cause mortality, non-fatal myocardial infarction, and heart failure. Surrogate markers of reperfusion were also analyzed. Results: 13 RCTs (4273 STEMI patients) were identified and divided into 2 subgroups: intracoronary adenosine versus control (8 RCTs) and intravenous adenosine versus control (5 RCTs). In patients administered intracoronary adenosine, the incidence of heart failure was significantly lower (risk ratio [RR] 0.44 [95% CI 0.25–0.78], P = 0.005) and the incidence of coronary no-reflow was reduced (RR for TIMI flow<3 postreperfusion 0.68 [95% CI 0.47–0.99], P = 0.04). There was no difference in heart failure incidence in the intravenous adenosine group but most RCTs in this subgroup were from the thrombolysis era. There was no difference in non-fatal MI or all-cause mortality in both subgroups. Conclusion: We find evidence of improved clinical outcome in terms of less heart failure in STEMI patients administered intracoronary adenosine as an adjunct to reperfusion. This finding will need to be confirmed in a large adequately powered prospective RCT

Prothrombotic profile in patients with vasospastic or non vasospastic angina and non significant coronary stenosis

Background: Patients with vasospastic (VA) or non vasospastic angina (NVA) without significant coronary stenosis have a reduced risk of infarction but is unclear whether or not this may be attributable to a lack of prothrombotic profile - similar to that present in patients with stable coronary artery disease (CAD). Methods: Plasma levels of von Willebrand factor, total and free tissue factor pathway inhibitor, plasminogen activator inhibitor-1, and fibrinogen were analyzed in 15 patients with stable VA and 23 with NVA, all with vasoconstrictive response to acetylcholine although with different severity. Results were compared with those of 20 age-matched controls and 10 patients with CAD. Results: Plasma levels of von Willebrand factor in patients with VA or NVA were higher than in controls (207 ± 62 and 203 ± 69% vs 121 ± 38%, p < 0.001) and tended to be lower than in CAD patients (264 ± 65, p = 0.145). They also presented higher total tissue factor pathway inhibitor (123 ± 18 and 111 ± 25 vs 88 ± 14, ng/ml p < 0.001) and plasminogen activator inhibitor-1 levels than controls (51 ± 30 and 52 ± 31% vs 19 ± 9 ng/ml, p < 0.001) and similar to CAD patients (134 ± 23 and 62 ± 31, respectively, ns). Moreover, free tissue factor pathway inhibitor plasma levels were lower than controls (18 ± 5 and 17 ± 5 vs 23 ± 8 ng/ml, p = 0.002) and similar to CAD patients (14 ± 5, ns). Despite this prothrombotic condition none of VA or NVA patients presented a myocardial infarction during a 9 year follow-up, an observation also reported in larger series. Conclusions: During a stable phase of their disease, patients with VA or NVA present a prothrombotic profile that might eventually contribute to occurrence of myocardial infarction. The rarity of these events, however, may suggests that ill defined factors would protect these patients from coronary plaque rupture/fissure

Activation of cGMP/Protein Kinase G Pathway in Postconditioned Myocardium Depends on Reduced Oxidative Stress and Preserved Endothelial Nitric Oxide Synthase Coupling

Altres ajuts: Redes Temáticas de Investigación Cooperativa Sanitaria (RETICS-RECAVA RD06/0014/0025); Comisión Interministerial en Ciencia y Tecnología (CICYT SAF/2008-03067); and Fondo Investigación Sanitaria (FIS-PI121738).The cGMP/protein kinase G (PKG) pathway is involved in the cardioprotective effects of postconditioning (PoCo). Although PKG signaling in PoCo has been proposed to depend on the activation of the phosphatidylinositol 3-kinase (PI3K)/Akt cascade, recent data bring into question a causal role of reperfusion injury signaling kinase (RISK) in PoCo protection. We hypothesized that PoCo increases PKG activity by reducing oxidative stress-induced endothelial nitric oxide synthase (NOS) uncoupling at the onset of reperfusion. Isolated rat hearts were submitted to 40 minutes of ischemia and reperfusion with and without a PoCo protocol. PoCo reduced infarct size by 48% and cGMP depletion. Blockade of cGMP synthesis (1 H -[1,2,4]oxadiazolo[4,3- a ]quinoxalin-1-one) and inhibition of PKG (KT5823) or NOS (l-NAME) abolished protection, but inhibition of PI3K/Akt cascade (LY294002) did not (n=5 to 7 per group). Phosphorylation of the RISK pathway was higher in PoCo hearts. However, this difference is due to increased cell death in control hearts because in hearts reperfused with the contractile inhibitor blebbistatin, a drug effective in preventing cell death at the onset of reperfusion, RISK phosphorylation increased during reperfusion without differences between control and PoCo groups. In these hearts, PoCo reduced the production of superoxide (O −) and protein nitrotyrosylation and increased nitrate/nitrite levels in parallel with a significant decrease in the oxidation of tetrahydrobiopterin (BH) and in the monomeric form of endothelial NOS. These results demonstrate that PoCo activates the cGMP/PKG pathway via a mechanism independent of the PI3K/Akt cascade and dependent on the reduction of O − production at the onset of reperfusion, resulting in attenuated oxidation of BH and reduced NOS uncoupling

Targeting reperfusion injury in patients with ST-segment elevation myocardial infarction : trials and tribulations

Altres ajuts: D.J.H. and D.M.Y. are funded by the British Heart Foundation and the Rosetrees Trust, and are supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre of which D.M.Y. is a senior investigator. G.H. is supported by the German Research Foundation (He 1320/18-3; SFB 1116 B8)

Targeting reperfusion injury in patients with ST-segment elevation myocardial infarction: trials and tribulations

D.J.H. and D.M.Y. are funded by the British Heart Foundation and the Rosetrees Trust, and are supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre of which D.M.Y. is a senior investigator. D.G.-D. is funded by the Cardiovascular Research Network of the Spanish Institute of Health Instituto de Salud Carlos III (ISCiii RETICS-RIC, RD12/0042/0021). G.H. is supported by the German Research Foundation (He 1320/18-3; SFB 1116 B8). B.I. is funded by the Carlos III Institute of Health and European Regional Development Fund (ERDF/FEDER) (PI13/01979), and the ISCiii Cardiovascular Research Network (RD12/0042/0054). Funding to pay the Open Access publication charges for this article was provided by Red de Investigacion Cardiovascular del Instituto de Salud Carlos III, grupo Hospital Universitari Vall d'Hebron (RETICS 2012 RD12/0042/0021).S

Cardiomyocyte hypertrophy induced by Endonuclease G deficiency requires reactive oxygen radicals accumulation and is inhibitable by the micropeptide humanin

The endonuclease G gene (Endog), which codes for a mitochondrial nuclease, was identified as a determinant of cardiac hypertrophy. How ENDOG controls cardiomyocyte growth is still unknown. Thus, we aimed at finding the link between ENDOG activity and cardiomyocyte growth. Endog deficiency induced reactive oxygen species (ROS) accumulation and abnormal growth in neonatal rodent cardiomyocytes, altering the AKT-GSK3 beta and Class-II histone deacethylases (HDAC) signal transduction pathways. These effects were blocked by ROS scavengers. Lack of ENDOG reduced mitochondrial DNA (mtDNA) replication independently of ROS accumulation. Because mtDNA encodes several subunits of the mitochondrial electron transport chain, whose activity is an important source of cellular ROS, we investigated whether Endog deficiency compromised the expression and activity of the respiratory chain complexes but found no changes in these parameters nor in ATP content. MtDNA also codes for humanin, a micropeptide with possible metabolic functions. Nanomolar concentrations of synthetic humanin restored normal ROS levels and cell size in Endog-deficient cardiomyocytes. These results support the involvement of redox signaling in the control of cardiomyocyte growth by ENDOG and suggest a pathway relating mtDNA content to the regulation of cell growth probably involving humanin, which prevents reactive oxygen radicals accumulation and hypertrophy induced by Endog deficiency.This work was supported by Grant SAF2013-44942R from the Ministerio de Economia y Competitividad (MINECO) to DS, Grant 20153810 from Fundacio La Marato de TV3 to DS, Program ``Redes Tematicas de Investigacion Cooperativa en Salud´´ (RETICS) Grants RD12/0042/0035, RD12/0042/0056 and RD12/0042/0021, Red de Investigacion Cardiovascular (RIC) from the Institute de Salud Carlos-III (ISCIII) to DS, DG-D and JV, Grant 2009SGR-346 from the Agencia de Gestic d'Ajuts Universitaris i de Recerca (AGAUR) from the Government of Catalonia to DS. AB is supported by Fundacio La Marato de TV3 and GB is supported by a predoctoral contract from the Universitat de Lleida.S

Plasma B-type natriuretic peptide levels are poorly related to the occurrence of ischemia or ventricular arrhythmias during symptom-limited exercise in low-risk patients

The usefulness of B-type natriuretic peptide (BNP) as a marker of ischemia is controversial. BNP levels have predicted arrhythmias in various settings, but it is unknown whether they are related to exercise-induced ischemic ventricular arrhythmias. We analyzed in 63 patients (64 ±14 years, 65% male, 62% with known coronary disease) undergoing exercise stress single-photon emission computed tomography (SPECT) the association between plasma BNP values (before and 15 min after exercise) and the occurrence of ischemia or ventricular arrhythmias during the test. Exercise test (8.1 ±2.7 min, 7.4 ±8.1 metabolic equivalents, 82 ±12% of maximal predicted heart rate) induced reversible perfusion defects in 23 (36%) patients. Eight (13%) patients presented significant arrhythmias (≥ 7 ventricular premature complexes/min, couplets, or non-sustained ventricular tachycardia during exercise or in the first minute of recovery). Median baseline BNP levels were 17.5 (12.4-66.4) pg/ml in patients developing scintigraphic ischemia and 45.6 (13.2-107.4) pg/ml in those without ischemia (p = 0.137). The BNP levels increased after exercise (34.4 (15.3-65.4)% increment over baseline, p < 0.001), but the magnitude of this increase was not related to SPECT positivity (35.7 (18.8-65.4)% vs. 27.9 (5.6-64.0)% in patients with and without ischemia, respectively, p = 0.304). No significant association was found between BNP values (at baseline or their change during the test) and ventricular arrhythmias. Plasma BNP values - at baseline or after exercise - were not associated with myocardial ischemia or with ventricular arrhythmia during exercise SPECT. These results highlight the limited usefulness of this biomarker to assess acute ischemia

Validation of numerical flow simulations against in vitro phantom measurements in different type B aortic dissection scenarios

An aortic dissection (AD) is a serious condition defined by the splitting of the arterial wall, thus generating a secondary lumen [the false lumen (FL)]. Its management, treatment and follow-up are clinical challenges due to the progressive aortic dilatation and potentially severe complications during follow-up. It is well known that the direction and rate of dilatation of the artery wall depend on haemodynamic parameters such as the local velocity profiles, intra-luminal pressures and resultant wall stresses. These factors act on the FL and true lumen, triggering remodelling and clinical worsening. In this study, we aimed to validate a computational fluid dynamic (CFD) tool for the haemodynamic characterisation of chronic (type B) ADs. We validated the numerical results, for several dissection geometries, with experimental data obtained from a previous in vitro study performed on idealised dissected physical models. We found a good correlation between CFD simulations and experimental measurements as long as the tear size was large enough so that the effect of the wall compliance was negligible.Postprint (published version

The use of a binary composite endpoint and sample size requirement: influence of endpoints overlap

Although composite endpoints (CE) are common in clinical trials, the impact of the relationship between the components of a binary CE on the sample size requirement (SSR) has not been addressed. We performed a computational study considering 2 treatments and a CE with 2 components: the relevant endpoint (RE) and the additional endpoint (AE). We assessed the strength of the components’ interrelation by the degree of relative overlap between them, which was stratified into 5 groups. Within each stratum, SSR was computed for multiple scenarios by varying the events proportion and the effect of the therapy. A lower SSR using CE was defined as the best scenario for using the CE. In 25 of 66 scenarios the degree of relative overlap determined the benefit of using CE instead of the RE. Adding an AE with greater effect than the RE leads to lower SSR using the CE regardless of the AE proportion and the relative overlap. The influence of overlapping decreases when the effect on RE increases. Adding an AE with lower effect than the RE constitutes the most uncertain situation. In summary, the interrelationship between CE components, assessed by the relative overlap, can help to define the SSR in specific situations and it should be considered for SSR computation.Peer ReviewedPostprint (published version