Oxidation of Protein Kinase A Regulatory Subunit PKARIα Protects Against Myocardial Ischemia-Reperfusion Injury by Inhibiting Lysosomal-Triggered Calcium Release.

BACKGROUND: Kinase oxidation is a critical signaling mechanism through which changes in the intracellular redox state alter cardiac function. In the myocardium, PKARIα (type-1 protein kinase A) can be reversibly oxidized, forming interprotein disulfide bonds in the holoenzyme complex. However, the effect of PKARIα disulfide formation on downstream signaling in the heart, particularly under states of oxidative stress such as ischemia and reperfusion (I/R), remains unexplored. METHODS: Atrial tissue obtained from patients before and after cardiopulmonary bypass and reperfusion and left ventricular (LV) tissue from mice subjected to I/R or sham surgery were used to assess PKARIα disulfide formation by immunoblot. To determine the effect of disulfide formation on PKARIα catalytic activity and subcellular localization, live-cell fluorescence imaging and stimulated emission depletion super-resolution microscopy were performed in prkar1 knock-out mouse embryonic fibroblasts, neonatal myocytes, or adult LV myocytes isolated from "redox dead" (Cys17Ser) PKARIα knock-in mice and their wild-type littermates. Comparison of intracellular calcium dynamics between genotypes was assessed in fura2-loaded LV myocytes, whereas I/R-injury was assessed ex vivo. RESULTS: In both humans and mice, myocardial PKARIα disulfide formation was found to be significantly increased (2-fold in humans, P=0.023; 2.4-fold in mice, P<0.001) in response to I/R in vivo. In mouse LV cardiomyocytes, disulfide-containing PKARIα was not found to impact catalytic activity, but instead led to enhanced AKAP (A-kinase anchoring protein) binding with preferential localization of the holoenzyme to the lysosome. Redox-dependent regulation of lysosomal two-pore channels by PKARIα was sufficient to prevent global calcium release from the sarcoplasmic reticulum in LV myocytes, without affecting intrinsic ryanodine receptor leak or phosphorylation. Absence of I/R-induced PKARIα disulfide formation in "redox dead" knock-in mouse hearts resulted in larger infarcts (2-fold, P<0.001) and a concomitant reduction in LV contractile recovery (1.6-fold, P<0.001), which was prevented by administering the lysosomal two-pore channel inhibitor Ned-19 at the time of reperfusion. CONCLUSIONS: Disulfide modification targets PKARIα to the lysosome, where it acts as a gatekeeper for two-pore channel-mediated triggering of global calcium release. In the postischemic heart, this regulatory mechanism is critical for protection from extensive injury and offers a novel target for the design of cardioprotective therapeutics.

Ultra-High-Density Activation Mapping to Aid Isthmus Identification of Atrial Tachycardias in Congenital Heart Disease.

OBJECTIVES: A new electroanatomic mapping system (Rhythmia, Boston Scientific, Marlborough, Massachusetts) using a 64-electrode mapping basket is now available; we systematically assessed its use in complex congenital heart disease (CHD). BACKGROUND: The incidence of atrial arrhythmias post-surgery for CHD is high. Catheter ablation has emerged as an effective treatment, but is hampered by limitations in the mapping system's ability to accurately define the tachycardia circuit. METHODS: Mapping and ablation data of 61 patients with CHD (35 males, age 45 ± 14 years) from 8 tertiary centers were reviewed. RESULTS: Causes were as follows: Transposition of Great Arteries (atrial switch) (n = 7); univentricular physiology (Fontans) (n = 8); Tetralogy of Fallot (n = 10); atrial septal defect (ASD) repair (n = 15); tricuspid valve (TV) anomalies (n = 10); and other (n = 11). The total number of atrial arrhythmias was 86. Circuits were predominantly around the tricuspid valve (n = 37), atriotomy scar (n = 10), or ASD patch (n = 4). Although the majority of peri-tricuspid circuits were cavo-tricuspid-isthmus dependent (n = 30), they could follow a complex route between the annulus and septal resection, ASD patch, coronary sinus, or atriotomy. Immediate ablation success was achieved in all but 2 cases; with follow-up of 12 ± 8 months, 7 patients had recurrence. CONCLUSIONS: We demonstrate the feasibility of the basket catheter for mapping complex CHD arrhythmias, including with transbaffle and transhepatic access. Although the circuits often involve predictable anatomic landmarks, the precise critical isthmus is often difficult to predict empirically. Ultra-high-density mapping enables elucidation of circuits in this complex anatomy and allows successful treatment at the isthmus with a minimal lesion set.

Ablation of Complex Fractionated Electrograms Improves Outcome in Persistent Atrial Fibrillation of Over 2 Year's Duration.

AIM: There is controversy and sparse data on whether substrate based techniques in addition to pulmonary vein isolation (PVI) confer benefit in the catheter ablation of persistent atrial fibrillation (AF), especially if long standing. We performed an observational study to assess whether substrate based ablation improved freedom from atrial arrhythmia. METHODS: A total of 286 patients undergoing first ablation procedures for persistent AF with PVI only(n = 79), PVI plus linear ablation(n = 85), or PVI plus complex fractionated electrogram (CFAE) and linear ablation(n = 107) were followed. Primary end point was freedom from atrial arrhythmia at one year. RESULTS: Mean duration of pre-procedure time in AF was 28+/-27 months.There were no differences in baseline characteristics between groups except a higher proportion of patients with a severely dilated LA in those receiving PVI+CFAEs+lines. Freedom from atrial arrhythmia was higher with a PVI+CFAE+lines strategy then for PVI alone (HR 1.56, 95% CI: 1.04-2.34, p=0.032) but was not higher with PVI+lines. Benefit of substrate modification was conferred for preprocedure times in AF of over 30 months. The occurrence of atrial tachycardia was higher when lines were added to the ablation strategy (HR 0.08, 95% CI: 0.01-0.59, p=0.014). Freedom from atrial arrhythmia at 1 year was higher with lower patient age, use of general anaesthetic (GA), normal or mildly dilated left atrium and decreasing time in AF. CONCLUSIONS: In patients with long standing persistent AF of over 30 months duration,CFAE ablation resulted in improved freedom from atrial arrhythmia. Increased freedom from atrial arrhythmia occurs in patients who are younger and have smaller atria, and with GA procedures. Linear ablation did not improve outcome and resulted in a higher incidence of atrial tachycardia.

First clinical use of novel ablation catheter incorporating local impedance data.

INTRODUCTION: Successful catheter ablation is limited by both poor spatial resolution of abnormal local signals and inability to deliver an effective lesion due to poor tissue contact. We report first worldwide use of the Intellanav MiFi OI catheter (Boston Scientific), providing ultra-high density mapping and incorporating a "DirectSense" algorithm to measure local tissue impedance (LI). METHODS AND RESULTS: 31 patients (65±6 years, 20 male) underwent ablation. LI from the catheter, generator impedance (GI) and maximum electrogram amplitude were recorded in the blood pool, and in regions from healthy to dense scar before, during and after ablation. The catheter demonstrated clear nearfield signal where standard bipolar recordings included farfield signal. LI was lower in dense scar than either healthy tissue or blood pool, and demonstrated an exponential relationship with maximum electrogram amplitude. Maximum LI drop on ablation linearly correlated with initial LI. The median LI drop for successful lesions, resulting in lack of local tissue capture, was 16.0Ω (12.1-19.8 Ω) for LV and 14.6 Ω (10.0-18.3 Ω) for LA, which was larger than for unsuccessful lesions (LV: 9.4 Ω [5.4-15.6 Ω] P = 0.001; LA: 6.8 Ω [4.7-13.0 Ω], P = 0.049). LI percentage drop was also significantly larger for successful than unsuccessful lesions (LV: 17.1 Ω [14.0-19.6 Ω] vs. 10.6 Ω (7.1-16.5 Ω) P = 0.002; LA: 14.2 Ω [10.8-19.5 Ω] vs. 7.5Ω [5.1-11.0 Ω], P = 0.005). CONCLUSION: This novel catheter gives reproducible recordings of local impedance, which are dependent on scar level. Absolute LI drop, and also percentage drop, on ablation may give an indication of tissue contact and subsequent effective lesion formation.

Improved outcome and cost effectiveness in ablation of persistent atrial fibrillation under general anaesthetic.

Aims: Outcome of persistent atrial fibrillation (AF) ablation remains suboptimal. Techniques employed to reduce arrhythmia recurrence rate are more likely to be embraced if cost-effectiveness can be demonstrated. A single-centre observational study assessed whether use of general anaesthesia (GA) in persistent AF ablation improved outcome and was cost-effective. Methods and results: Two hundred and ninety two patients undergoing first ablation procedures for persistent AF under conscious sedation or GA were followed. End points were freedom from listing for repeat ablation at 18 months and freedom from recurrence of atrial arrhythmia at 1 year. Freedom from atrial arrhythmia was higher in patients who underwent ablation under GA rather than sedation (63.9% vs. 42.3%, hazard ratio (HR) 1.87, 95% confidence interval (CI): 1.23-2.86, P = 0.002). Significantly fewer GA patients were listed for repeat procedures (29.2% vs. 42.7%, HR 1.62, 95% CI: 1.01-2.60, P = 0.044). Despite GA procedures costing slightly more, a saving of £177 can be made per patient in our centre for a maximum of two procedures if all persistent AF ablations are performed under GA. Conclusions: In patients with persistent AF, it is both clinical and economically more effective to perform ablation under GA rather than sedation.

Coarse fibrillatory waves in atrial fibrillation predict success of electrical cardioversion.

BACKGROUND: To determine whether the presence of "coarse" fibrillatory waves (Fw) seen on surface ECGs of patients with persistent atrial fibrillation (AF) predict maintenance of sinus rhythm (SR) at 6 weeks after electrical cardioversion (ECV). METHODS: Preprocedure ECGs from 94 consecutive patients with persistent AF scheduled to undergo ECV at a single centre were classified as having coarse Fw (≥0.1 mV) or fine Fw (<0.1 mV) in leads II or V1 . The primary outcome was ECG rhythm at 6-week clinical follow-up. Demographic and echocardiographic data were also collected. RESULTS: Thirty-two patient ECGs (34%) had coarse Fw on baseline ECG in either or both leads II or V1 with no significant differences in baseline demographics compared to those patients with fine Fw. At 6 weeks post-ECV, in the coarse Fw group 72% of patients maintained SR vs. 42% in the fine Fw group (χ2 , p = .006) with the odds ratio (OR) of maintaining SR at 6 weeks in the presence of coarse Fw being 3.5 (95% CI: 1.4-8.9, p = .007). Across the overall study population, there were no other significant univariate predictors of SR at 6 weeks post-ECV. CONCLUSION: Classifying persistent AF using the maximal Fw amplitude on a surface ECG is a simple and reproducible method of predicting medium-term success of ECV, independent of traditional risk factors.

Palpitations in a 72-year-old woman.

CLINICAL INTRODUCTION: A 72-year-old woman presented with an 8-year history of palpitations occurring every few weeks. They were sudden in onset, were associated with dizziness and could last for up to 2 hours. She was prescribed bisoprolol which reduced the frequency of events but did not abolish them. Baseline ECG and echocardiography were normal. She was referred for electrophysiological study. Despite initial difficulties, diagnostic catheters were placed in the right ventricular (RV) apex and in the coronary sinus (CS) via the right internal jugular vein and superior vena cava (SVC) (figure 1A). A narrow complex tachycardia was easily induced, and ablation was then delivered during tachycardia with the ablation catheter positioned as shown in (figure 1A). This terminated tachycardia 4 s after onset of energy delivery and on follow-up she has remained asymptomatic. She later underwent a CT scan (figure 1B,C; online supplementary video).DC1SP110.1136/heartjnl-2017-311734.supp1Supplementary file 1 heartjnl;103/19/1554/F1F1F1Figure 1(A) Fluoroscopy of catheter placement. (B) Sagittal contrast-enhanced CT image. (C) Axial contrast-enhanced CT. QUESTION: What anatomical abnormality caused difficulty in catheter placement during the procedure?Azygous continuation of the inferior vena cava (IVC)Giant Eustachian valveDextrocardiaRenal tumour compressing IVC.

Flow rates through intravenous access devices: an in vitro study.

STUDY OBJECTIVE: Fluid administration using intravenous (IV) access devices is required in many settings. There are a lack of quantitative data comparing traditional cannulas and modern access devices. We aimed to investigate flow rates through modern intravenous access devices using an in vitro system. DESIGN: This is an experimental study. SETTING AND MEASUREMENTS: Rates of flow of intravenous fluids (crystalloid and colloid) were measured through various access devices using a uroflowmeter. Standardized conditions and repeat measurements ensured validity. Fluid was administered with or without the addition of a pressure bag and needle-free valve. MAIN RESULTS: Increasing the size of cannulas improved flow. Fourteen-gauge cannulas had significantly higher mean flow rates compared to 14G central venous lines in all conditions (136% higher with no pressure bag/valve; 95% CI, +130% to +152%; P < .001). Both the emergency infusion device and rapid infusion catheter produced significantly increased mean flows compared to a 14G cannula (12% higher for emergency infusion catheter; 95% CI, +7% to +15%; P = .008, and 15% higher for rapid infusion catheter; 95% CI, +12% to +21%; P = .004). The needle-free valve significantly impaired flow on 16G and wider IV access devices (36% lower with no pressure bag using 14G cannula; 95% CI, -29% to -46%; P = .003), but flow reductions in narrower IV access were insignificant. Pressure bags significantly improved flow in all devices, in all combinations. CONCLUSIONS: Flow rates in IV devices can be maximized by pressure bag use and removal of needle-free valves. The rapid infusion catheter and emergency infusion catheter allow some increase in flow over a 14G cannula. Familiarity with varying flow rates across IV access devices could better inform clinical decisions.

Applicability of a risk score for prediction of the long-term benefit of the implantable cardioverter defibrillator in patients receiving cardiac resynchronization therapy.

AIMS: The Goldenberg risk score, comprising five clinical risk factors (New York Heart Association class >2, atrial fibrillation, QRS duration >120 ms, age >70 years, and urea >26 mg/dL), may help identify patients in whom the survival benefit of the defibrillator may be limited. We aim at assessing whether this score can accurately predict the long-term all-cause mortality risk of patients receiving cardiac resynchronization therapy (CRT) and identify those who are more likely to benefit from the defibrillator. METHODS AND RESULTS: In this retrospective observational cohort study, 638 patients with ischaemic or non-ischaemic dilated cardiomyopathy who had CRT-defibrillator (CRT-D) (n = 224) vs. CRT-pacemaker (CRT-P) (n = 414) implantation were prospectively followed up for survival outcomes. The long-term outcome of patients with CRT-D vs. CRT-P was compared within risk score categories and in patients with severe renal dysfunction. Mean follow-up in surviving and deceased patients was 62.7 and 32.5 months, respectively. This score showed higher discriminative performance in all-cause mortality prediction in CRT-D vs. CRT-P patients (area under the curve 0.718 ± 0.041 vs. 0.650 ± 0.032, respectively, P = 0.001). In those with scores 0-2, a CRT-D device decreased mortality rates in the first 4 years of follow-up compared with CRT-P (11.3 vs. 24.7%, P = 0.041), but this effect attenuated with longer follow-up duration (21.2 vs. 32.7%, P = 0.078). In this group, the benefit of CRT-D during the follow-up was seen after adjusting for traditional mortality predictors (hazard ratio 0.339, P = 0.001). No significant differences in mortality rates were seen in patients with score ≥3 (57.9% with CRT-D vs. 56.9%, P = 0.8) and those with severe renal dysfunction (92.9% in CRT-D vs. 76.2%, P = 0.17). Similar results were seen following propensity score matching. CONCLUSION: A simple risk stratification score comprising five clinical risk factors may help identify CRT patients who are more likely to benefit from the presence of the defibrillator.

Diagnostic accuracy of cardiothoracic ratio on admission chest radiography to detect left or right ventricular systolic dysfunction: a retrospective study.

OBJECTIVES: To determine the diagnostic accuracy of the cardiothoracic ratio on postero-anterior or antero-posterior chest radiographs in predicting left ventricular or right ventricular dysfunction on echocardiography in an inpatient population. DESIGN: Retrospective study. SETTING: Two secondary care hospitals in the United Kingdom. PARTICIPANTS: Four hundred consecutive inpatient echocardiograms were screened for inclusion along with chest radiographs (both postero-anterior and antero-posterior). The cardiothoracic ratio was calculated from chest radiographs along with quantitative and qualitative measures of left ventricular or right ventricular dysfunction on echocardiography. MAIN OUTCOME MEASURES: Sensitivity and specificity of cardiothoracic ratio across a range of values to detect moderate/severe left ventricular and/or right ventricular dysfunction on echocardiography. RESULTS: Overall, 272 records met inclusion criteria. The prevalence of left ventricular/right ventricular dysfunction on echocardiography was 26% in an inpatient population with high clinical suspicion of cardiac disease referred for echocardiography. Over a range of cardiothoracic ratio values on postero-anterior films, a value of >0.55 yielded the best sensitivity (62.5%) and specificity (76.5%) for diagnosing left ventricular/right ventricular impairment (positive likelihood ratio 2.56), with a positive predictive value of 29.5%. Cardiothoracic ratio on antero-posterior film was not predictive of left ventricular/right ventricular impairment on echocardiography. CONCLUSIONS: In conclusion, in the context of an acute admission, cardiothoracic ratio measured on postero-anterior or antero-posterior films has limited value in detecting moderate left ventricular and/or right ventricular systolic dysfunction. Previously established absolute values may be unreliable by modern standards.

Warfarin-induced purple toe syndrome successfully treated with apixaban.

Purple toe syndrome is a recognised adverse effect of warfarin therapy. The literature has described resolution of the ischaemic symptoms on withdrawal of the warfarin and switching to a low molecular weight heparin alternative. We present a case of an 82-year-old man with bilateral blanching vivacious toes and a livedo-reticularis type rash developing 2 weeks after being loaded with warfarin for first detected atrial fibrillation. Vascular surgical review and haematology thrombotic screen did not yield any other pathology and a diagnosis of purple toe syndrome due to warfarin was carried out. The warfarin was stopped and oral anticoagulation started with an oral factor Xa inhibitor, apixaban with resolution of his symptoms. This is the first case report of one of the novel oral anticoagulants being used to treat purple toe syndrome.

Effects of oral lycopene supplementation on vascular function in patients with cardiovascular disease and healthy volunteers: a randomised controlled trial.

AIMS: The mechanisms by which a 'Mediterranean diet' reduces cardiovascular disease (CVD) burden remain poorly understood. Lycopene is a potent antioxidant found in such diets with evidence suggesting beneficial effects. We wished to investigate the effects of lycopene on the vasculature in CVD patients and separately, in healthy volunteers (HV). METHODS AND RESULTS: We randomised 36 statin treated CVD patients and 36 healthy volunteers in a 2∶1 treatment allocation ratio to either 7 mg lycopene or placebo daily for 2 months in a double-blind trial. Forearm responses to intra-arterial infusions of acetylcholine (endothelium-dependent vasodilatation; EDV), sodium nitroprusside (endothelium-independent vasodilatation; EIDV), and NG-monomethyl-L-arginine (basal nitric oxide (NO) synthase activity) were measured using venous plethysmography. A range of vascular and biochemical secondary endpoints were also explored. EDV in CVD patients post-lycopene improved by 53% (95% CI: +9% to +93%, P = 0.03 vs. placebo) without changes to EIDV, or basal NO responses. HVs did not show changes in EDV after lycopene treatment. Blood pressure, arterial stiffness, lipids and hsCRP levels were unchanged for lycopene vs. placebo treatment groups in the CVD arm as well as the HV arm. At baseline, CVD patients had impaired EDV compared with HV (30% lower; 95% CI: -45% to -10%, P = 0.008), despite lower LDL cholesterol (1.2 mmol/L lower, 95% CI: -1.6 to -0.9 mmol/L, P<0.001). Post-therapy EDV responses for lycopene-treated CVD patients were similar to HVs at baseline (2% lower, 95% CI: -30% to +30%, P = 0.85), also suggesting lycopene improved endothelial function. CONCLUSIONS: Lycopene supplementation improves endothelial function in CVD patients on optimal secondary prevention, but not in HVs. TRIAL REGISTRATION: ClinicalTrials.gov NCT01100385.

Cardiac resynchronisation therapy: pacemaker versus internal cardioverter-defibrillator in patients with impaired left ventricular function.

OBJECTIVE: Studies have shown beneficial effects of cardiac resynchronisation therapy (CRT) on mortality among patients with heart failure. However the incremental benefits in survival from CRT with a defibrillator (CRT-D) are unclear. The choice of appropriate device remains unanswered. METHOD: This is a single-centre observational study in a tertiary cardiac centre. Patients (n=500) implanted with a CRT device with pacing alone (CRT-P) (n=354) and CRT-D (n=146) were followed for at least 2 years (mean 29 months, SD 14 months). The primary end point was all-cause mortality. RESULTS: A total of 116 deaths (23.2%) were recorded: 88 (24.8%) and 28 (19.2%), in the CRT-P and CRT-D groups, respectively. At 1 year there was a trend favouring CRT-D (HR 0.54, 95% CI 0.27 to 1.07, p=0.08) but this was attenuated by the 2nd year and became insignificant at the end of follow-up (HR 0.76, 95% CI 0.50 to 1.170, p=0.21). There was no survival benefit from having an internal cardioverter-defibrillator if patients were deemed non-responders to CRT. 27% of the CRT-P patients with ischaemic cardiomyopathy met indications for potential internal cardioverter-defibrillator implantation for primary prevention. These were older patients with poorer baseline function in comparison with CRT-D patients with devices for primary prevention. Once these differences were adjusted for, there was no difference in outcome between the groups. CONCLUSIONS: CRT-D did not offer additional survival advantage over CRT-P at longer-term follow-up, as the clinical benefit of a defibrillator attenuated with time. Further work is needed to define which subset of patients benefit from CRT-D.

Direct stenting is an independent predictor of improved survival in patients undergoing primary percutaneous coronary intervention for ST elevation myocardial infarction.

AIMS: Randomised trials have shown that direct stenting (DS) is associated with improved markers of reperfusion during primary percutaneous coronary intervention (PPCI) for ST elevation myocardial infarction (STEMI). However, data evaluating its impact on long-term clinical outcomes are lacking. We set out to evaluate the effect of DS on mortality in a contemporary population of patients undergoing PPCI for STEMI. METHODS: Consecutive patients undergoing PPCI for STEMI at two high-volume UK heart attack centres between September 2008- December 2010 (n=1562) were included in the analysis. Local databases were analysed for patient demographics, as well as details on PPCI strategy, including use of DS versus predilatation (PD) followed by stenting, manual thrombus aspiration (MT) and glycoprotein IIb/IIIa inhibitors (GPIs). National databases were interrogated for in-hospital, 30-day and one-year mortality. To determine the impact of PPCI strategy on one-year survival, multivariate logistic analysis was performed. RESULTS: Altogether 489 patients underwent DS (31.3%) and 1073 (68.7%) received PD prior to stenting. Patients receiving DS had reduced mortality at 30 days (2.04 versus 4.66%, p=0.01) and one year (3.27 versus 8.48%, p=0.0001). After multivariate adjustment, PD remained an independent predictor of one-year mortality (odds ratio 2.42, 95% confidence interval 1.08-5.45, p=0.032) along with age, cardiogenic shock, number of diseased vessels, and left main or proximal left anterior descending artery intervention. However, neither GPI use nor MT improved survival in either univariate or multivariate analyses. CONCLUSIONS: In a contemporary, unselected population of patients undergoing PPCI for STEMI, DS - when compared with stenting after PD - is independently predictive of improved 30-day and one-year survival.

Therapeutic potential of p38 MAP kinase inhibition in the management of cardiovascular disease.

p38 mitogen-activated protein kinases (p38 MAPKs) are key signalling molecules that regulate cellular behavior in response to environmental stresses. They regulate pro-inflammatory cytokines and therefore p38 MAPKs are implicated in the pathogenesis of many inflammatory-driven conditions, including atherosclerosis. Therapeutic inhibition of p38 MAPKs to attenuate inflammation has been the focus of comprehensive research in the last 2 decades, following the discovery of p38α as the molecular target of pyrindinyl imidazole compounds, which suppress the cytokines tumor necrosis factor-α and interleukin-1. The potential of p38 MAPK inhibitors was initially explored within archetypal inflammatory conditions such as rheumatoid arthritis and Crohn's disease, but early studies demonstrated poor clinical efficacy and unacceptable side effects. Subsequent clinical trials evaluating different p38 MAPK inhibitor compounds in disease models such as chronic obstructive pulmonary disease (COPD) and atherosclerosis have shown potential clinical efficacy. This review aims to provide succinct background information regarding the p38 MAPK signaling pathway, a focus of p38 MAPKs in disease, and a brief summary of relevant pre-clinical studies. An update of human clinical trial experience encompassing a clinically orientated approach, dedicated to cardiovascular disease follows. It provides a current perspective of the therapeutic potential of p38 MAPK inhibitors in the cardiovascular domain, including safety, tolerability, and pharmacokinetics.