A new era in the management of type 2 diabetes: Is cardioprotection at long last a reality?

The EMPA-REG OUTCOME and the LEADER trials have revealed a new era in the management of type 2 diabetes. The SGLT2 inhibitor empagliflozin demonstrated a lower rate of the primary composite outcome of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke compared to placebo. Liraglutide, a GLP-1 analogue, succeeded to demonstrate reduction on a composite outcome including first occurrence of cardiovascular death, nonfatal myocardial infarction or non-fatal stroke. These two medications act through different mechanisms and has consequently shown different patterns of cardiovascular benefit. In one hand, empagliflozin showed an earlier effect compared to those observed using liraglutide. On the other hand, the difference between empagliflozin and placebo was driven by a significant reduction in death from cardiovascular causes, with and striking disconnect showing no significant between-group difference in the risk of myocardial infarction or stroke. In contrast, liraglutide reduced consistently all components of the composite endpoint. Based on the different temporal pattern of achieving clinical benefit one might flirt with the idea that liraglutide seems to provide a chronic “protection” that better fits in a longer metabolic effect with an impact in the progression of atherosclerosis, whilst empagliflozin provides an acute effect compatible with an immediate hemodynamic action. After years going from “bench to bedside” in order to discover the holy grail of cardioprotection, these 2 new studies suggest that we may have reached this state and it is time to go from “bed back to bench side” to understand the mechanisms of this potential paradigm shift

Role of PI3K in myocardial ischaemic preconditioning: mapping pro-survival cascades at the trigger phase and at reperfusion

The Reperfusion Injury Salvage Kinase (RISK) pathway is considered the main pro-survival kinase cascade mediating the ischaemic preconditioning (IPC) cardioprotective effect. To assess the role of PI3K-Akt, its negative regulator PTEN and other pro-survival proteins such as ERK and STAT3 in the context of IPC, C57BL/6 mouse hearts were retrogradely perfused in a Langendorff system and subjected to 4 cycles of 5 min. ischaemia and 5 min. reperfusion prior to 35 min. of global ischaemia and 120 min. of reperfusion. Wortmannin, a PI3K inhibitor, was administered either at the stabilization period or during reperfusion. Infarct size was assessed using triphenyl tetrazolium staining, and phosphorylation levels of Akt, PTEN, ERK, GSK3β and STAT3 were evaluated using Western blot analyses. IPC reduced infarct size in hearts subjected to lethal ischaemia and reperfusion, but this effect was lost in the presence of Wortmannin, whether it was present only during preconditioning or only during early reperfusion. IPC increased the levels of Akt phosphorylation during both phases and this effect was fully abrogated by PI3K, whilst its downstream GSK3β was phosphorylated only during the trigger phase after IPC. Both PTEN and STAT3 were phosphorylated during both phases after IPC, but this was PI3K independent. IPC increases ERK phosphorylation during both phases, being only PI3K-dependent during the IPC phase. In conclusion, PI3K-Akt plays a major role in IPC-induced cardioprotection. However, PTEN, ERK and STAT3 are also phosphorylated by IPC through a PI3K-independent pathway, suggesting that cardioprotection is mediated through more than one cell signalling cascade

A critical review on the translational journey of cardioprotective therapies!

The failure to translate novel cardioprotective therapies tested in pre-clinical studies into the clinical setting for patient benefit can be attributed to a number of factors at different stages of the research process. This review focuses on the evidences and the gaps with regard to the translational journey of cardioprotective interventions. Gaps are classified into 3 main groups: 1) those related to pre-clinical studies, 2) those associated with the validation of infarct size as a good surrogate and 3) those based on design and interpretation of randomized clinical trials on cardioprotection. Addressing these gaps might increase the chances to successfully translate cardioprotective therapies into improving both post-STEMI heart failure and cardiovascular death rates

Remote ischaemic conditioning reduces infarct size in animal in vivo models of ischaemia-reperfusion injury: a systematic review and meta-analysis

AIMS: The potential of remote ischaemic conditioning (RIC) to ameliorate myocardial ischaemia-reperfusion injury (IRI) remains controversial. We aimed to analyse the pre-clinical evidence base to ascertain the overall effect and variability of RIC in animal in vivo models of myocardial IRI. Furthermore, we aimed to investigate the impact of different study protocols on the protective utility of RIC in animal models and identify gaps in our understanding of this promising therapeutic strategy. METHODS AND RESULTS: Our primary outcome measure was the difference in mean infarct size between RIC and control groups in in vivo models of myocardial IRI. A systematic review returned 31 reports, from which we made 22 controlled comparisons of remote ischaemic preconditioning (RIPreC) and 21 of remote ischaemic perconditioning and postconditioning (RIPerC/RIPostC) in a pooled random-effects meta-analysis. In total, our analysis includes data from 280 control animals and 373 animals subject to RIC. Overall, RIPreC reduced infarct size as a percentage of area at risk by 22.8% (95% CI 18.8-26.9%), when compared with untreated controls (P < 0.001). Similarly, RIPerC/RIPostC reduced infarct size by 22.2% (95% CI 17.1-25.3%; P < 0.001). Interestingly, we observed significant heterogeneity in effect size (T2 = 92.9% and I2 = 99.4%; P < 0.001) that could not be explained by any of the experimental variables analysed by meta-regression. However, few reports have systematically characterized RIC protocols, and few of the included in vivo studies satisfactorily met study quality requirements, particularly with respect to blinding and randomization. CONCLUSIONS: RIC significantly reduces infarct size in in vivo models of myocardial IRI. Heterogeneity between studies could not be explained by the experimental variables tested, but studies are limited in number and lack consistency in quality and study design. There is therefore a clear need for more well-performed in vivo studies with particular emphasis on detailed characterization of RIC protocols and investigating the potential impact of gender. Finally, more studies investigating the potential benefit of RIC in larger species are required before translation to humans

The 10th Biennial Hatter Cardiovascular Institute workshop: cellular protection—evaluating new directions in the setting of myocardial infarction, ischaemic stroke, and cardio-oncology

Due to its poor capacity for regeneration, the heart is particularly sensitive to the loss of contractile cardiomyocytes. The onslaught of damage caused by ischaemia and reperfusion, occurring during an acute myocardial infarction and the subsequent reperfusion therapy, can wipe out upwards of a billion cardiomyocytes. A similar program of cell death can cause the irreversible loss of neurons in ischaemic stroke. Similar pathways of lethal cell injury can contribute to other pathologies such as left ventricular dysfunction and heart failure caused by cancer therapy. Consequently, strategies designed to protect the heart from lethal cell injury have the potential to be applicable across all three pathologies. The investigators meeting at the 10th Hatter Cardiovascular Institute workshop examined the parallels between ST-segment elevation myocardial infarction (STEMI), ischaemic stroke, and other pathologies that cause the loss of cardiomyocytes including cancer therapeutic cardiotoxicity. They examined the prospects for protection by remote ischaemic conditioning (RIC) in each scenario, and evaluated impasses and novel opportunities for cellular protection, with the future landscape for RIC in the clinical setting to be determined by the outcome of the large ERIC-PPCI/CONDI2 study. It was agreed that the way forward must include measures to improve experimental methodologies, such that they better reflect the clinical scenario and to judiciously select combinations of therapies targeting specific pathways of cellular death and injury

Pronóstico de la insuficiencia cardíaca aguda basado en datos clínicos de congestión

Antecedentes y objetivos: Evaluar si los síntomas/signos de congestión en pacientes con insuficiencia cardíaca aguda (ICA) atendidos en los servicios de urgencias hospitalarios (SUH) permiten predecir la evolución a corto plazo. Pacientes y métodos: Pacientes consecutivos diagnosticados de ICA en 45 SUH del registro EAHFE. Recogimos variables clínicas de congestión sistémica (edemas en miembros inferiores, ingurgitación yugular, hepatomegalia) y pulmonar (disnea de esfuerzo, disnea paroxística nocturna, ortopnea y crepitantes pulmonares) analizando su asociación con la mortalidad por cualquier causa a 30 días, de forma cruda y ajustada por diferencias entre grupos. Resultados: Analizamos 18.120 pacientes (mediana = 83 anos, rango intercuartil [RIC] = 76-88; mujeres = 55,7%). El 44,6% presentaba > 3 síntomas/signos congestivos. Individualmente, el riesgo ajustado de muerte a 30 días se incrementó un 14% para la existencia de ingurgitación yugular (hazard ratio [HR] = 1,14; intervalo de confianza al 95% [IC 95%] = 1,01-1,28) y un 96% para la disnea de esfuerzo (HR = 1,96; IC 95% = 1,55-2,49). Valorados conjuntamente, el riesgo se incrementó progresivamente con el número de síntomas/signos presentes; así

Intensive Teenage Activity Is Associated With Greater Muscle Hyperintensity on T1W Magnetic Resonance Imaging in Adults With Dysferlinopathy

Practice of sports during childhood or adolescence correlates with an earlier onset and more rapidly progressing phenotype in dysferlinopathies. To determine if this correlation relates to greater muscle pathology that persists into adulthood, we investigated the effect of exercise on the degree of muscle fatty replacement measured using muscle MRI. We reviewed pelvic, thigh and leg T1W MRI scans from 160 patients with genetically confirmed dysferlinopathy from the Jain Foundation International clinical outcomes study in dysferlinopathy. Two independent assessors used the Lamminen-Mercuri visual scale to score degree of fat replacement in each muscle. Exercise intensity for each individual was defined as no activity, minimal, moderate, or intensive activity by using metabolic equivalents and patient reported frequency of sports undertaken between the ages of 10 and 18. We used ANCOVA and linear modeling to compare the mean Lamminen-Mercuri score for the pelvis, thigh, and leg between exercise groups, controlling for age at assessment and symptom duration. Intensive exercisers showed greater fatty replacement in the muscles of the pelvis than moderate exercisers, but no significant differences of the thigh or leg. Within the pelvis, Psoas was the muscle most strongly associated with this exercise effect. In patients with a short symptom duration of <15 years there was a trend toward greater fatty replacement in the muscles of the thigh. These findings define key muscles involved in the exercise-phenotype effect that has previously been observed only clinically in dysferlinopathy and support recommendations that pre-symptomatic patients should avoid very intensive exercise