Cardiac contractility modulation for the treatment of heart failure with reduced ejection fraction.

There has been a progressive evolution in the management of patients with chronic heart failure and reduced ejection fraction (HFrEF), including cardiac resynchronisation therapy (CRT) in those that fulfil pre-defined criteria. However, there exists a significant proportion with refractory symptoms in whom CRT devices are not clinically indicated or ineffective. Cardiac contractility modulation (CCM) is a novel therapy that incorporates administration of non-excitatory electrical impulses to the interventricular septum during the absolute refractory period. Implantation is analogous to a traditional transvenous pacemaker system, but with the use of two right ventricular leads. Mechanistic studies have shown augmentation of left ventricular contractility and beneficial global effects on reverse remodeling, primarily through alterations in calcium handling. This appears to occur without increasing myocardial oxygen consumption. Data from clinical trials have shown translational improvements in functional capacity and quality of life, though long-term outcome data are lacking. This review explores the rationale, evidence base and limitations of this nascent technology.

Advanced care planning during the COVID-19 pandemic: ceiling of care decisions and their implications for observational data.

BACKGROUND: Observational studies investigating risk factors in coronavirus disease 2019 (COVID-19) have not considered the confounding effects of advanced care planning, such that a valid picture of risk for elderly, frail and multi-morbid patients is unknown. We aimed to report ceiling of care and cardiopulmonary resuscitation (CPR) decisions and their association with demographic and clinical characteristics as well as outcomes during the COVID-19 pandemic. METHODS: Retrospective, observational study conducted between 5th March and 7th May 2020 of all hospitalised patients with COVID-19. Ceiling of care and CPR decisions were documented using the Recommended Summary Plan for Emergency Care and Treatment (ReSPECT) process. Unadjusted and multivariable regression analyses were used to determine factors associated with ceiling of care decisions and death during hospitalisation. RESULTS: A total of 485 patients were included, of whom 409 (84·3%) had a documented ceiling of care; level one for 208 (50·9%), level two for 75 (18·3%) and level three for 126 (30·8%). CPR decisions were documented for 451 (93·0%) of whom 336 (74·5%) were 'not for resuscitation'. Advanced age, frailty, White-European ethnicity, a diagnosis of any co-morbidity and receipt of cardiovascular medications were associated with ceiling of care decisions. In a multivariable model only advanced age (odds 0·89, 0·86-0·93 p < 0·001), frailty (odds 0·48, 0·38-0·60, p < 0·001) and the cumulative number of co-morbidities (odds 0·72, 0·52-1·0, p = 0·048) were independently associated. Death during hospitalisation was independently associated with age, frailty and requirement for level two or three care. CONCLUSION: Ceiling of care decisions were made for the majority of patients during the COVID-19 pandemic, broadly in line with known predictors of poor outcomes in COVID-19, but with a focus on co-morbidities suggesting ICU admission might not be a reliable end-point for observational studies where advanced care planning is routine.

Long-term performance of left ventricular leads in cardiac resynchronisation therapy.

BACKGROUND: Cardiac resynchronisation therapy (CRT) confers symptomatic and survival benefits in chronic heart failure with reduced ejection fraction (HFrEF). There remains a paucity of data on long-term performance of left ventricular (LV) leads, particularly with newer quadripolar lead designs. METHODS: This single-centre study utilised an electronic, outpatient HFrEF database to identify CRT recipients (2008-2014). The primary endpoint was temporal trend in LV pacing thresholds during follow-up. Secondary outcomes were complications relating to acute or chronic lead failure and device-related infections. RESULTS: Two hundred eighty patients were included, with mean (±SD) age of 74.2 years (±9.0) and median follow-up of 7.6 years (interquartile range 4-9). Mean LV threshold was 1.37 V (±0.73) at implant and remained stable over the study period. No differences were observed based upon lead manufacturer. Compared to non-quadripolar leads (n = 216), those of quadripolar designs (n = 64) had a lower threshold at 6 months (1.20 vs 1.37 V; P = .04) and at the end of the study period (1.32 vs 1.46 V; P = .04). Patients with HFrEF of ischaemic aetiology had higher thresholds at implant (1.46 vs 1.34 V; P = .05), and this persisted until the end of follow-up (1.49 vs 1.34 V; P = .03). There was low incidence of acute (0.71%; 2/280) and chronic lead failure (1.79%; 5/280), with four cases (1.43%) of device infection. CONCLUSIONS: LV leads in the context of CRT have excellent chronic stability and low rates of adverse events. Those with newer quadripolar lead designs have lower thresholds at initial follow-up and in the longer term.

Effects of Ivabradine on Hemodynamic and Functional Parameters in Left Ventricular Systolic Dysfunction: a Systematic Review and Meta-analysis.

BACKGROUND: Ivabradine is licensed as add-on therapy in patients with severe left ventricular systolic dysfunction (LVSD), normal sinus rhythm, and suboptimal heart rate (HR) control, but effects are not fully established. This study sought to assess the impact of ivabradine therapy on hemodynamic and functional outcome measures in all patients with LVSD. METHODS: MEDLINE (1996-2017), Embase (1996-2017), Cochrane Central Register of Controlled Trials (CENTRAL), Cochrane Database of Systematic Reviews, ClinicalTrials.gov , and ISI Web of Science were searched for randomized clinical trials (RCTs) comparing standard medical therapy (SMT) plus ivabradine to SMT alone for patients with LVSD of any severity. Each trial was assessed using the Cochrane Collaborations Risk of Bias tool. RESULTS: Eight RCTs with 17,823 patients were included. Add-on use of ivabradine reduced resting HR (mean difference [MD] 10.3 bpm; p < 0.001), improved ejection fraction (EF) (MD 3.6%, p < 0.001), and preserved systolic blood pressure (MD 3.4 mmHg; p = 0.09). Stratified analyses according to severity of LVSD did not influence conferred benefits on HR and EF. Small improvements were noted in exercise tolerance (standardized MD 5.9 s; p = 0.004) and peak oxygen consumption (MD 2.9 ml/kg/min; p = 0.02). DISCUSSION: Adjunct therapy with ivabradine in patients with LVSD results in a favorable hemodynamic profile and correlates with improved functional capacity. Benefits appear to be broadly preserved irrespective of baseline EF. This was a meta-analysis of RCTs, though limited by exclusion of post hoc analyses, lack of access to patient level data, and inter-study variability in some baseline characteristics. Further, large-scale RCTs are warranted to evaluate effectiveness of ivabradine in cohorts with non-severe LVSD.

Tapasin-related protein TAPBPR is an additional component of the MHC class I presentation pathway.

Tapasin is an integral component of the peptide-loading complex (PLC) important for efficient peptide loading onto MHC class I molecules. We investigated the function of the tapasin-related protein, TAPBPR. Like tapasin, TAPBPR is widely expressed, IFN-γ-inducible, and binds to MHC class I coupled with ß2-microglobulin in the endoplasmic reticulum. In contrast to tapasin, TAPBPR does not bind ERp57 or calreticulin and is not an integral component of the PLC. ß2-microglobulin is essential for the association between TAPBPR and MHC class I. However, the association between TAPBPR and MHC class I occurs in the absence of a functional PLC, suggesting peptide is not required. Expression of TAPBPR decreases the rate of MHC class I maturation through the secretory pathway and prolongs the association of MHC class I on the PLC. The TAPBPR:MHC class I complex trafficks through the Golgi apparatus, demonstrating a function of TAPBPR beyond the endoplasmic reticulum/cis-Golgi. The identification of TAPBPR as an additional component of the MHC class I antigen-presentation pathway demonstrates that mechanisms controlling MHC class I expression remain incompletely understood.

Persistent Prothrombotic State in a Patient With Alström Syndrome.

We present the case of a patient with Alström syndrome who was found to have evidence of a prothrombotic state on autopsy after sudden cardiac death. To the best of our knowledge, this case of persistent prothrombotic milieu is the first described in a patient with Alström syndrome.

Diagnostic yield of a heart failure referral pathway using N-terminal pro-brain natriuretic peptide.

OBJECTIVE: To determine the diagnostic yield of a 'high' N-terminal pro-brain natriuretic peptide (NT-proBNP) in patients with suspected heart failure (HF) referred from primary to secondary care. METHODS: In this retrospective study, cardiac diagnoses were quantified in consecutive patients with an NT-proBNP>400 ng/L referred from primary care centres to a specialist HF service. RESULTS: Among 654 consecutive patients (age: 78.5±9.72 years; 45.9% men; left ventricular ejection fraction (LVEF): 55.4±12.5% (mean±SD)), the primary diagnoses were: valvular disease (39.4%), HF (29.2%; 13.3% with LVEF<40%) and atrial fibrillation (AF; 17.3%). In terms of primary or secondary diagnoses, 68% of patients had valve disease, 46.9% had AF and 29.2% had HF. A cardiac diagnosis was made in 85.9%. In multivariable analyses, NT-proBNP predicted HF with LVEF<40% (OR: 10.2, 95% CI: 5.63 to 18.3) and HF with any LVEF (OR: 6.13, 95% CI: 3.79 to 9.93). In canonical linear discriminant analyses, NT-proBNP correctly identified 54.5% of patients with HF. The remainder were misclassified as valvular disease, AF or no cardiac diagnosis. CONCLUSION: Among patients with an NT-proBNP>400 ng/L referred through a primary care HF pathway, most patients had valve disease or AF rather than HF. NT-proBNP cannot discriminate among HF, valve disease and AF. On this basis, NT-proBNP may be best employed in detecting cardiac disease in general rather than HF per se.

Outcomes after transvenous defibrillator implantation in cardiac sarcoidosis: A systematic review.

Introduction: Sarcoidosis is a systemic inflammatory disorder associated with ventricular arrhythmias (VAs) and sudden death in the context of cardiac involvement. Guidelines advocate implantable cardioverter-defibrillator (ICD) implantation in specific subcohorts, but there is a paucity of data on outcomes. Methods and Results: A systematic review was performed to assess outcomes in patients with definite or probable cardiac sarcoidosis (CS) treated with ICD. Observational studies were identified from multiple databases from inception to 21st May 2021. Outcomes of interest included appropriate and inappropriate ICD therapies in addition to all-cause mortality. Study quality was assessed individually using the Newcastle Ottawa Scale (NOS).Eight studies were identified comprising 530 patients, with follow-up period of 24-66 months (weighted average 40 months). Mean age was 53.9 years with ejection fraction of 41.3%. Overall incidence of appropriate therapy was 38.1% during follow-up. Left ventricular systolic dysfunction (LVSD) with ejection fraction <40% was a predictor of appropriate therapy in the majority of studies, as were sustained VAs during electrophysiological testing (EP) in one study. There was no interaction with device indication (i.e. primary or secondary). Where documented, inappropriate therapy was primarily driven by atrial arrhythmias. All-cause mortality was 6.0% over a median follow-up period of 42 months. Only three studies achieved good quality in the comparability domain of NOS. Conclusions: Appropriate ICD therapy in patients with CS is commonly associated with LVSD, which can act as a surrogate for scar burden. The utility of EP testing in this setting remains unclear.

Sudden cardiac arrest of a 16-year-old boy with left main coronary artery atresia: a case report.

BACKGROUND: In many cases, the cause of exercise-induced cardiopulmonary arrest in young persons is thought to be fatal arrhythmia, and one of the causes is ischaemic heart disease. Left main coronary artery atresia (LMCAA) is an extremely rare disease in which there is a congenital defect of the left main coronary artery, causing heart failure and exercise-induced angina attacks at a young age. Thus, it is disease that should be differentiated when examining young persons with chest pain. CASE SUMMARY: A 16-year-old boy experienced sudden cardiopulmonary arrest during soccer practice, was brought to our hospital for emergency treatment after return of spontaneous circulation. Elective coronary angiography revealed findings indicating an osmium defect in the left coronary artery (LCA) and blood flow via collateral circulation from the right coronary artery. Contrast-enhanced coronary computed tomography (CT) angiography showed a defect in the LCA ostium and LMCAA was diagnosed in the patient. After coronary artery bypass grafting was performed, but the patient was discharged in an ambulatory state with a wearable cardiac defibrillator. Postoperative course has been favourable. DISCUSSION: Left main coronary artery atresia is an extremely rare disease in which there is a congenital defect of the left main trunk of the coronary artery and should be differentiated when encountering cases of heart failure or exercise-induced angina/arrhythmia attacks in young persons who are not at risk for atherosclerosis. Exercise electrocardiogram may show a false negative result, and therefore coronary CT is useful for diagnosis.

Leadless pacemakers - The path to safer pacing?

Endocardial transvenous permanent pacemakers (TVPs) are a mainstay within cardiology and used to treat a range of bradyarrhythmias. However, their use is associated with potential complications both at the time of implantation and longer term. The concept of a leadless pacemaker, where a self-contained device is placed within the right ventricle, has obvious attractions. Two leadless systems have been developed, though only one is currently available. Results from clinical trials have been promising but a number of hurdles need to be circumvented before leadless devices can usurp TVPs. At present, use is restricted to specialist centres, for a limited indication and for patients in whom conventional implantation is contraindicated. This article provides a contemporary critique of design types, evidence base and existing limitations of this nascent technology.

Assessment of coronary physiology - the evidence and implications.

Use of angiography for the assessment of coronary lesions is limited by its inability to provide information regarding the functional significance of stenoses. A number of studies have demonstrated the presence of ischaemia to be the most important determinant of the benefit associated with coronary revascularisation in stable coronary artery disease. Assessment of intra-coronary physiology can guide percutaneous coronary intervention, and is often used for angiographically borderline stenoses. There is now increasing evidence to suggest that more routine use can improve clinical outcomes. Fractional flow reserve (FFR) is the most established measure of intra-coronary physiology, but is currently under-utilised. The main drawback of FFR is the dependence on a pharmacological infusion to maintain hyperaemia. An alternative technique which measures flow at a specific point in the cardiac cycle (instantaneous wave-free ratio) has been developed which obviates the need for hyperaemia and may replace FFR as the default measure.

Recent developments and controversies in transcatheter aortic valve implantation.

Interventional cardiology has been revolutionised by transcatheter aortic valve implantation (TAVI), which has become established as the benchmark treatment for severe aortic stenosis in patients at high risk for surgical aortic valve replacement (AVR). Increased procedural familiarity and progression in device technology has enabled improvements to be made in complication rates, which have led to a commensurate expansion in the use of TAVI; it is now a viable alternative to AVR in patients at intermediate surgical risk, and has been used in cohorts such as those with bicuspid aortic valves or pure, severe aortic regurgitation. Given the rapid expansion in the use of TAVI, including cohorts of younger patients with fewer co-morbidities, attention must be paid to further reducing remaining complications, such as cardiac tamponade or stroke. To this end, novel techniques and devices have been devised and trialled, with varying levels of success. Furthermore, significant work has gone into refining the technique with exploration of alternative imaging modalities, as well as alternative access routes to provide greater options for patients with challenging vascular anatomy. Whilst significant progress has been made with TAVI, areas of uncertainty remain such as the management of concomitant coronary artery disease and the optimum post-procedure antiplatelet regimen. As such, research in this field continues apace, and is likely to continue as use of TAVI becomes more widespread. This review provides a summary of the existing evidence, as well as an overview of recent developments and contentious issues in the field of TAVI.

Prevalence and Predictors of Sepsis Death in Patients With Chronic Heart Failure and Reduced Left Ventricular Ejection Fraction.

Background Noncardiovascular death is increasingly common in people with chronic heart failure ( CHF ), yet its causes remain poorly characterized. We aimed to define the prevalence of sepsis death in people with CHF and to ascertain its risk marker profile. Methods and Results We conducted a prospective cohort study of 1802 patients with CHF and left ventricular ejection fraction ≤45% attending CHF clinics in 4 United Kingdom hospitals between 2006 and 2014. Mode of death was defined over a 10.3-year follow-up period (mean 4 years). Competing risk regression defined mode-specific hazard ratios for sepsis, other noncardiovascular, progressive heart failure, and sudden cardiac death in relation to established heart failure prognostic markers. Of 737 deaths, 173 (23.5%) were due to sepsis; respiratory tract infections accounted for 69.9% (n=121) of these events. Those who died from sepsis were older, had higher platelet counts, and had a higher prevalence of chronic obstructive pulmonary disease than those who died from other causes. Sepsis death was independently associated with older age (hazard ratio=1.05; 95% confidence interval 1.03-1.07), greater prevalence of chronic obstructive pulmonary disease (2.43; 1.74-3.40), male sex (1.73; 1.16-2.60), lower log serum vitamin D (0.68; 0.49-0.95), and higher platelet count (1.002; 1.000-1.005) than nonsepsis death. Established heart failure prognostic markers exhibited different patterns of association with sepsis death, other noncardiovascular death, progressive heart failure death, and sudden cardiac death. Conclusions Sepsis is a major contributor to death in people with CHF and has a different risk marker profile from other modes of death, suggesting that it may be amenable to targeted preventative strategies.

Ischemic Heart Disease Modifies the Association of Atrial Fibrillation With Mortality in Heart Failure With Reduced Ejection Fraction.

Background The CASTLE - AF (Catheter Ablation versus Standard Conventional Therapy in Patients With Left Ventricular Dysfunction and Atrial Fibrillation) trial recently reported that catheter ablation of atrial fibrillation ( AF ) improves survival in heart failure (HF) with reduced ejection fraction ( HF r EF ). However, established AF was not associated with mortality in trials of contemporary HF r EF pharmacotherapies. We investigated whether HF r EF pathogenesis may influence the conclusions of studies evaluating the prognostic impact of AF . Methods and Results Using a prospective cohort study of 791 patients with HFr EF , with AF determined using 24-hour ambulatory ECG monitoring, univariable and multivariable Cox regression analyses were used to define the association between AF and mode-specific mortality (mean follow-up of 5.4 years). One-year HF-related hospitalization was assessed with binary logistic regression analysis. One-year cardiac remodeling was assessed in a subgroup (n=378) using echocardiography. AF was present in 28.2% of patients, with 9.4% of these being paroxysmal. While AF was associated with increased risk of all-cause mortality (hazard ratio, 1.27; 95% confidence interval 1.03-1.57), with diverging survival curves after 1 year of follow-up, this association was lost in age-sex-adjusted analyses. However, AF was associated with increased risk of age-sex-adjusted all-cause mortality in people with ischemic pathogenesis, with a statistically significant interaction between pathogenesis and AF. This was predominantly attributed to progressive HF deaths. After 1 year, HF hospitalization and cardiac remodeling were not associated with AF , even in people with ischemic pathogenesis. Conclusions AF is associated with increased risk of death in HF r EF of ischemic pathogenesis, predominantly due to progressive HF deaths during long-term follow-up. HF r EF pathogenesis should be considered in trial design and interpretation.

Socioeconomic deprivation and mode-specific outcomes in patients with chronic heart failure.

OBJECTIVE: To characterise the association between socioeconomic deprivation and adverse outcomes in patients with chronic heart failure (CHF). METHODS: We prospectively observed 1802 patients with CHF and left ventricular ejection fraction (LVEF) ≤45%, recruited in four UK hospitals between 2006 and 2014. We assessed the association between deprivation defined by the UK Index of Multiple Deprivation (IMD) and: mode-specific mortality (mean follow-up 4 years); mode-specific hospitalisation; and the cumulative duration of hospitalisation (after 1 year). RESULTS: A 45-point difference in mean IMD score was noted between patients residing in the least and most deprived quintiles of geographical regions. Deprivation was associated with age, sex and comorbidity, but not CHF symptoms, LVEF or prescribed drug therapy. IMD score was associated with the risk of age-sex adjusted all-cause mortality (6% higher risk per 10-unit increase in IMD score; 95% CI 2% to 10%; P=0.004), and non-cardiovascular mortality (9% higher risk per 10-unit increase in IMD score; 95% CI 3% to 16%; P=0.003), but not cardiovascular mortality. All-cause, but not heart failure-specific, hospitalisation was also more common in the most deprived patients. Overall, patients spent a cumulative 3.3 days in hospital during 1 year of follow-up, with IMD score being associated with the age-sex adjusted cumulative duration of hospitalisations (4% increase in duration per 10-unit increase in IMD score; 95% CI 3% to 6%; P<0.0005). CONCLUSIONS: Socioeconomic deprivation in people with CHF is linked to increased risk of death and hospitalisation due to an excess of non-cardiovascular events.

Mortality Reduction Associated With ß-Adrenoceptor Inhibition in Chronic Heart Failure Is Greater in Patients With Diabetes.

OBJECTIVE: Diabetes increases mortality in patients with chronic heart failure (CHF) and reduced left ventricular ejection fraction. Studies have questioned the safety of ß-adrenoceptor blockers (ß-blockers) in some patients with diabetes and reduced left ventricular ejection fraction. We examined whether ß-blockers and ACE inhibitors (ACEIs) are associated with differential effects on mortality in CHF patients with and without diabetes. RESEARCH DESIGN AND METHODS: We conducted a prospective cohort study of 1,797 patients with CHF recruited between 2006 and 2014, with mean follow-up of 4 years. ß-Blocker dose was expressed as the equivalent dose of bisoprolol (mg/day) and ACEI dose as the equivalent dose of ramipril (mg/day). Cox regression analysis was used to examine the interaction between diabetes and drug dose on all-cause mortality. RESULTS: Patients with diabetes were prescribed larger doses of ß-blockers and ACEIs than were patients without diabetes. Increasing ß-blocker dose was associated with lower mortality in patients with diabetes (8.9% per mg/day; 95% CI 5-12.6) and without diabetes (3.5% per mg/day; 95% CI 0.7-6.3), although the effect was larger in people with diabetes (interaction P = 0.027). Increasing ACEI dose was associated with lower mortality in patients with diabetes (5.9% per mg/day; 95% CI 2.5-9.2) and without diabetes (5.1% per mg/day; 95% CI 2.6-7.6), with similar effect size in these groups (interaction P = 0.76). CONCLUSIONS: Increasing ß-blocker dose is associated with a greater prognostic advantage in CHF patients with diabetes than in CHF patients without diabetes.

Endothelial Insulin Receptor Restoration Rescues Vascular Function in Male Insulin Receptor Haploinsufficient Mice.

Reduced systemic insulin signaling promotes endothelial dysfunction and diminished endogenous vascular repair. We investigated whether restoration of endothelial insulin receptor expression could rescue this phenotype. Insulin receptor knockout (IRKO) mice were crossed with mice expressing a human insulin receptor endothelial cell-specific overexpression (hIRECO) to produce IRKO-hIRECO progeny. No metabolic differences were noted between IRKO and IRKO-hIRECO mice in glucose and insulin tolerance tests. In contrast with control IRKO littermates, IRKO-hIRECO mice exhibited normal blood pressure and aortic vasodilatation in response to acetylcholine, comparable to parameters noted in wild type littermates. These phenotypic changes were associated with increased basal- and insulin-stimulated nitric oxide production. IRKO-hIRECO mice also demonstrated normalized endothelial repair after denuding arterial injury, which was associated with rescued endothelial cell migration in vitro but not with changes in circulating progenitor populations or culture-derived myeloid angiogenic cells. These data show that restoration of endothelial insulin receptor expression alone is sufficient to prevent the vascular dysfunction caused by systemically reduced insulin signaling.

A contemporary review of peripartum cardiomyopathy.

Peripartum cardiomyopathy reflects the presence of cardiac failure in the absence of determinable heart disease and occurs in late third trimester of pregnancy or up to 6 months postpartum. A full understanding of pathophysiological mechanisms is lacking, but excess prolactin levels, haemodynamic alterations, inflammation and nutritional deficiencies have all been implicated. Its clinical presentation has distinct overlap with physiological alterations in healthy pregnancy and this presents a diagnostic challenge. However, echocardiography can provide significant benefit in accurate assessment and narrowing of differentials. Pharmacotherapy is broadly aligned with established guidelines for cardiac failure, but specific therapies are indicated for treatment of clinical sequelae. Moreover, an individualistic approach is required based on clinical context to manage delivery. Further research appears imperative to optimise management strategies and reduce disease burden.

Management strategies for atrial fibrillation.

Atrial fibrillation is the most prevalent cardiac arrhythmia, affecting 10% of those aged over 80 years. Despite multiple treatment options, it remains an independent prognostic marker of mortality due to its association with clinical sequelae, particularly cerebrovascular events. Management can be broadly divided into treatment of the arrhythmia, via rhythm or rate control, and stroke thromboprophylaxis via anticoagulation. Traditional options for pharmacotherapy include negatively chronotropic drugs such as ß-blockers, and/or arrhythmia-modifying drugs such as amiodarone. More recently, catheter ablation has emerged as a suitable alternative for selected patients. Additionally, there has been extensive research to assess the role of novel oral anticoagulants as alternatives to warfarin therapy. There is mounting evidence to suggest that they provide comparable efficacy, while being associated with lower bleeding complications. While these findings are promising, recent controversies have arisen with the use of novel oral anticoagulants. Further research is warranted to fully elucidate mechanisms and establish antidotes so that treatment options can be appropriately directed.