A Network of Macrophages Supports Mitochondrial Homeostasis in the Heart.

Cardiomyocytes are subjected to the intense mechanical stress and metabolic demands of the beating heart. It is unclear whether these cells, which are long-lived and rarely renew, manage to preserve homeostasis on their own. While analyzing macrophages lodged within the healthy myocardium, we discovered that they actively took up material, including mitochondria, derived from cardiomyocytes. Cardiomyocytes ejected dysfunctional mitochondria and other cargo in dedicated membranous particles reminiscent of neural exophers, through a process driven by the cardiomyocyte's autophagy machinery that was enhanced during cardiac stress. Depletion of cardiac macrophages or deficiency in the phagocytic receptor Mertk resulted in defective elimination of mitochondria from the myocardial tissue, activation of the inflammasome, impaired autophagy, accumulation of anomalous mitochondria in cardiomyocytes, metabolic alterations, and ventricular dysfunction. Thus, we identify an immune-parenchymal pair in the murine heart that enables transfer of unfit material to preserve metabolic stability and organ function. VIDEO ABSTRACT.

Risk of recurrent stroke and mortality after cryptogenic stroke in diabetic patients.

BACKGROUND: Diabetes mellitus is a highly prevalent and growing chronic disease that is associated with increased risk of recurrence among several stroke subtypes. However, evidence on the prognostic role of diabetes in the setting of cryptogenic stroke (CS) remains scarce. METHODS: From April 2019 to November 2021, we recruited prospectively 78 consecutive patients with CS. Patients were classified according to the presence of diabetes. Main outcome was the composite of stroke recurrence and death. Secondary outcome was stroke recurrence. RESULTS: Mean age of the cohort was 78 ± 7.7 years and 18 patients (23%) had diabetes. After a median clinical follow-up of 23 months the incidence of stroke recurrence and mortality [HR 5.8 (95% CI 1.9-19), p = 0.002] and the incidence of stroke recurrence [HR 16.6 (95% CI 1.8-149), p = 0.012], were higher in patients with diabetes. After adjusting for potential confounders diabetes was identified as an independent predictor of stroke recurrence and death in patients with CS [HR 33.8 (95% CI 2.1-551), p = 0.013]. Other independent predictors of stroke recurrence and mortality were hypertension [HR 31.4 (95% CI 1.8-550), p = 0.018], NTproBNP [HR 1.002 (95% CI 1.001-1.004), p = 0.013] and chronic kidney disease (CKD) [HR 27.4 (95% CI 1.4-549) p = 0.03]. Furthermore, diabetes was an independent predictor of stroke recurrence [HR 103 (95% CI 1.3-8261), p = 0.038]. CONCLUSION: Diabetic patients with CS are at higher risk of stroke recurrence and death. Hypertension CKD and NTproBNP are also independent predictors of stroke recurrence and death after CS.

The impact of type 2 immunity and allergic diseases in atherosclerosis.

Allergic diseases are allergen-induced immunological disorders characterized by the development of type 2 immunity and IgE responses. The prevalence of allergic diseases has been on the rise alike cardiovascular disease (CVD), which affects arteries of different organs such as the heart, the kidney and the brain. The underlying cause of CVD is often atherosclerosis, a disease distinguished by endothelial dysfunction, fibrofatty material accumulation in the intima of the artery wall, smooth muscle cell proliferation, and Th1 inflammation. The opposed T-cell identity of allergy and atherosclerosis implies an atheroprotective role for Th2 cells by counteracting Th1 responses. Yet, the clinical association between allergic disease and CVD argues against it. Within, we review different phases of allergic pathology, basic immunological mechanisms of atherosclerosis and the clinical association between allergic diseases (particularly asthma, atopic dermatitis, allergic rhinitis and food allergy) and CVD. Then, we discuss putative atherogenic mechanisms of type 2 immunity and allergic inflammation including acute allergic reactions (IgE, IgG1, mast cells, macrophages and allergic mediators such as vasoactive components, growth factors and those derived from the complement, contact and coagulation systems) and late phase inflammation (Th2 cells, eosinophils, type 2 innate-like lymphoid cells, alarmins, IL-4, IL-5, IL-9, IL-13 and IL-17).

Electrocardiogram and CMR to differentiate tachycardia-induced cardiomyopathy from dilated cardiomyopathy in patients admitted for heart failure.

In patients admitted for heart failure (HF) with reduced left ventricular ejection fraction (LVEF) and a concomitant supraventricular tachyarrhythmia (SVT) it is a challenge to predict LVEF recovery and differentiate tachycardia-induced cardiomyopathy (TIC) from dilated cardiomyopathy (DCM). The role of the electrocardiogram (ECG) and cardiac magnetic resonance (CMR) and in this acute setting remains unsettled. Forty-three consecutive patients admitted for HF due to SVT and LVEF < 50% undergoing CMR in the acute phase, were retrospectively included. Those who had LVEF > 50% at follow up were classified as TIC and those with LVEF < 50% were classified as DCM. Clinical, CMR and ECG findings were analyzed to predict LVEF recovery. Twenty-five (58%) patients were classified as TIC. Patients with DCM had wider QRS (121.2 ± 26 vs 97.7 ± 17.35 ms; p = 0.003). On CRM the TIC group presented with higher LVEF (33.4 ± 11 vs 26.9 ± 6.4%; p = 0.019) whereas late gadolinium enhancement (LGE) was more frequent in DCM group (61 vs 16%; p = 0.004). On multivariate analysis, QRS duration ≥ 100 ms (p = 0.027), LVEF < 40% on CMR (p = 0.047) and presence of LGE (p = 0.03) were independent predictors of lack of LVEF recovery. Furthermore, during follow-up (median 60 months) DCM patients were admitted more frequently for HF (44 vs 0%; p < 0.001) than TIC patients. In patients with reduced LVEF admitted for HF due to SVT, QRS ≥ 100 ms, LVEF < 40% and LGE are independently associated with lack of LVEF recovery and worse clinical outcome.

A Comprehensive Model to Predict Atrial Fibrillation in Cryptogenic Stroke: The Decryptoring Score.

OBJETIVE: Cryptogenic stroke (CS) represents up to 30% of ischemic strokes (IS). Since atrial fibrillation (AF) can be detected in up to 30% of CS, there is a clinical need for estimating the probability of underlying AF in CS to guide the optimal secondary prevention strategy. The aim of the study was to develop the first comprehensive predictive score including clinical conditions, biomarkers, and left atrial strain (LAS), to predict AF detection in this setting. METHODS: Sixty-three consecutive patients with IS or transient ischemic attack with ABCD2 scale ≥ 4 of unknown etiology were prospectively recruited. Clinical, laboratory, and echocardiographic variables were collected. All patients underwent 15 days wearable Holter-ECG monitoring. Main objective was the Decryptoring score creation to predict AF in CS. Score variables were selected by a univariate analysis and, thereafter, score points were derived according to a multivariant analysis. RESULTS: AF was detected in 15 patients (24%). Age > 75 (9 points), hypertension (1 point), Troponin T > 40 ng/L (8.5 points), NTproBNP > 200 pg/ml (0.5 points), LAS reservoir < 25.3% (24.5 points) and LAS conduct < 10.4% (0.5 points) were included in the score. The rate of AF detection was 0% among patients with a score of < 10 and 80% among patients with a score > 35. The comparison of the predictive validity between the proposed score and AF-ESUS score resulted in an AUC of 0.94 for Decryptoring score and of 0.65 for the AF-ESUS score(p < 0.001). CONCLUSION: This novel score offers an accurate AF prediction in patients with CS; however these results will require validation in an independent cohort using this model before they may be translated into clinical practice.

Bmi1-Progenitor Cell Ablation Impairs the Angiogenic Response to Myocardial Infarction.

Objective- Cardiac progenitor cells reside in the heart in adulthood, although their physiological relevance remains unknown. Here, we demonstrate that after myocardial infarction, adult Bmi1+ (B lymphoma Mo-MLV insertion region 1 homolog [PCGF4]) cardiac cells are a key progenitor-like population in cardiac neovascularization during ventricular remodeling. Approach and Results- These cells, which have a strong in vivo differentiation bias, are a mixture of endothelial- and mesenchymal-related cells with in vitro spontaneous endothelial cell differentiation capacity. Genetic lineage tracing analysis showed that heart-resident Bmi1+ progenitor cells proliferate after acute myocardial infarction and differentiate to generate de novo cardiac vasculature. In a mouse model of induced myocardial infarction, genetic ablation of these cells substantially deteriorated both heart angiogenesis and the ejection fraction, resulting in an ischemic-dilated cardiac phenotype. Conclusions- These findings imply that endothelial-related Bmi1+ progenitor cells are necessary for injury-induced neovascularization in adult mouse heart and highlight these cells as a suitable therapeutic target for preventing dysfunctional left ventricular remodeling after injury.

Anterior ST-segment elevation secondary to right coronary occlusion: The sheep in wolf's clothing.

We present a case of an anterior ST-segment elevation acute coronary syndrome secondary to occlusion of a non-dominant right coronary artery. Usually, an anterior ST-segment elevation corresponds to a left anterior descending artery occlusion; however, in rare cases it can be secondary to a non-dominant right coronary artery occlusion. The two causal entities may be adequately differentiated by the detailed analysis of the ECG. The electrocardiographic criteria that allow the proper prediction of the culprit artery in anterior ST-segment elevation acute coronary syndrome are reviewed.

Prevalence, Vascular Distribution, and Multiterritorial Extent of Subclinical Atherosclerosis in a Middle-Aged Cohort: The PESA (Progression of Early Subclinical Atherosclerosis) Study.

BACKGROUND: Data are limited on the presence, distribution, and extent of subclinical atherosclerosis in middle-aged populations. METHODS AND RESULTS: The PESA (Progression of Early Subclinical Atherosclerosis) study prospectively enrolled 4184 asymptomatic participants 40 to 54 years of age (mean age, 45.8 years; 63% male) to evaluate the systemic extent of atherosclerosis in the carotid, abdominal aortic, and iliofemoral territories by 2-/3-dimensional ultrasound and coronary artery calcification by computed tomography. The extent of subclinical atherosclerosis, defined as presence of plaque or coronary artery calcification ≥1, was classified as focal (1 site affected), intermediate (2-3 sites), or generalized (4-6 sites) after exploration of each vascular site (right/left carotids, aorta, right/left iliofemorals, and coronary arteries). Subclinical atherosclerosis was present in 63% of participants (71% of men, 48% of women). Intermediate and generalized atherosclerosis was identified in 41%. Plaques were most common in the iliofemorals (44%), followed by the carotids (31%) and aorta (25%), whereas coronary artery calcification was present in 18%. Among participants with low Framingham Heart Study (FHS) 10-year risk, subclinical disease was detected in 58%, with intermediate or generalized disease in 36%. When longer-term risk was assessed (30-year FHS), 83% of participants at high risk had atherosclerosis, with 66% classified as intermediate or generalized. CONCLUSIONS: Subclinical atherosclerosis was highly prevalent in this middle-aged cohort, with nearly half of the participants classified as having intermediate or generalized disease. Most participants at high FHS risk had subclinical disease; however, extensive atherosclerosis was also present in a substantial number of low-risk individuals, suggesting added value of imaging for diagnosis and prevention. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01410318.

Left Atrial Strain Predicts Stroke Recurrence and Death in Patients With Cryptogenic Stroke.

Left atrial strain (LAS) has been widely studied as a predictor of atrial fibrillation (AF) after cryptogenic stroke (CS). However, the evidence about its prognostic role in terms of stroke recurrence and death in this setting remains scarce. A total of 92 consecutive patients with ischemic stroke or transient ischemic attack with ABCD2 scale ≥4 of unknown etiology were prospectively recruited. Echocardiography, including LAS was performed during admission. The primary outcome measure was the composite of stroke recurrence or death. The mean age was 77.5 ± 7.7, and 58% of patients were female. After a median follow up of 28 months, the primary outcome measure occurred in 15 patients (16%). The primary outcome was more frequent in patients with diabetes (53% vs 21%, p = 0.02), chronic kidney disease (33% vs 10%, p = 0.034), and a history of heart failure (13% vs 0%, p = 0.025). LAS reservoir (LASr) and LAS conduit (LAScd) were lower in patients developing the primary outcome (21% ± 7% vs 28.8% ± 11%, p = 0.017 and 7.7% ± 3.9% vs 13.7% ± 7%, p = 0.007, respectively). On multivariate analysis, LASr (hazard ratio 0.9, 95% confidence interval 0.85 to 0.99, p = 0.048) and diabetes (hazard ratio 3.3, 95% confidence interval 1.03 to 10.4, p = 0.045) were associated with stroke recurrence or all-cause death after CS. On the log-rank test (using the discriminatory cut-off value of LASr <23%), LASr (p = 0.009) was associated with higher risk of the primary outcome. In conclusion, lower values of the LAS reservoir were associated with a higher risk of stroke recurrence or death after CS. LAS may identify patients at higher risk of thromboembolism and stress conditions.

Non-atherosclerotic acute cardiac syndromes: spontaneous coronary artery dissection and Takotsubo syndrome. Comparison of long-term clinical outcomes.

BACKGROUND: Spontaneous coronary artery dissection (SCAD) and Takotsubo syndrome (TTS) constitute two common causes of nonatherosclerotic acute cardiac syndrome particularly frequent in women. Currently, there is no information comparing long-term clinical outcomes in unselected patients with these conditions. METHODS: We compared the baseline characteristics, in-hospital outcomes, and the 12-month and long-term clinical outcomes of two large prospective registries on SCAD and TTS. RESULTS: A total of 289 SCAD and 150 TTS patients were included; 89% were women. TTS patients were older with a higher prevalence of cardiovascular risk factors. Precipitating triggers were more frequent in TTS patients, while emotional triggers and depressive disorders were more common in the SCAD group. Left ventricular ejection fraction was lower in TTS patients, but SCAD patients showed higher cardiac biomarkers. In-hospital events (43.3% vs. 5.2%, P <0.01) occurred more frequently in TTS patients. TTS patients also presented more frequent major adverse events at 12-month (14.7% vs. 7.1%, HR 5.3, 95% CI: 2.4-11.7, P <0.01) and long-term (median 36 vs. 31 months, P =0.41) follow-up (25.8% vs. 9.6%, HR 4.5, 95% CI: 2.5-8.2, P <0.01). Atrial fibrillation was also more frequent in TTS patients. Moreover, TTS patients presented a higher 12-month and long-term mortality (5.6% vs. 0.7%, P =0.01; and 12.6% vs. 0.7%, P <0.01) mainly driven by noncardiovascular deaths. CONCLUSION: Compared to SCAD, TTS patients are older and present more cardiovascular risk factors but less frequent depressive disorder or emotional triggers. TTS patients have a worse in-hospital, mid-term, and long-term prognosis with higher noncardiac mortality than SCAD patients.

Intracoronary thrombus assessment with cardiac computed tomography angiography in a deferred stenting strategy: the MATURE prospective study (MSCT to Assess ThrombUs REsolution).

BACKGROUND: Cardiac computed tomography angiography (CCTA) is precise in noninvasive coronary atherosclerosis characterization but its value in the diagnosis of intracoronary thrombus remains unknown. Therefore, our aim was to evaluate CCTA for intracoronary thrombus and stenosis detection in patients with acute coronary syndromes with high thrombus burden selected for a deferred stenting strategy. METHODS: We systematically performed a CCTA in consecutive patients following a deferred stenting strategy, 24 h before the scheduled repeated coronary angiography including optical coherence tomography (OCT) imaging. Intracoronary thrombus and residual stenosis were blindly and independently evaluated by both techniques. Agreement was determined per lesion using the weighted Kappa ( K ) coefficient and absolute intraclass correlation coefficient (ICC). A stratified analysis according to OCT-detected thrombus burden was also performed. RESULTS: Thirty lesions in 28 consecutive patients were analyzed. Concordance between CCTA and repeated coronary angiography in thrombus detection was good ( K = 0.554; P < 0.001), but both showed poor agreement with OCT. CCTA needed >11.5% thrombus burden on OCT to obtain adequate diagnostic accuracy. The lesions detected by angiography were more frequently classified as red thrombus (76.5 vs. 33.3%; P = 0.087) on OCT. CCTA showed an excellent concordance with coronary angiography in diameter measurement (ICC = 0.85; P < 0.001) and was able to identify all the patients with severe residual stenosis. CONCLUSIONS: Although CCTA showed just a good concordance with angiography in intracoronary thrombus detection, the agreement in residual stenosis was excellent. Thus, in patients with a high-thrombus burden selected for a deferred stenting strategy CCTA may substitute repeat angiography.

Magnetic resonance in patients with cardiovascular devices. SEC-GT CRMTC/SEC-Heart Rhythm Association/SERAM/SEICAT consensus document.

Magnetic resonance has become a first-line imaging modality in various clinical scenarios. The number of patients with different cardiovascular devices, including cardiac implantable electronic devices, has increased exponentially. Although there have been reports of risks associated with exposure to magnetic resonance in these patients, the clinical evidence now supports the safety of performing these studies under specific conditions and following recommendations to minimize possible risks. This document was written by the Working Group on Cardiac Magnetic Resonance Imaging and Cardiac Computed Tomography of the Spanish Society of Cardiology (SEC-GT CRMTC), the Heart Rhythm Association of the Spanish Society of Cardiology (SEC-Heart Rhythm Association), the Spanish Society of Medical Radiology (SERAM), and the Spanish Society of Cardiothoracic Imaging (SEICAT). The document reviews the clinical evidence available in this field and establishes a series of recommendations so that patients with cardiovascular devices can safely access this diagnostic tool.

Usefulness of Tissue Tracking by Cardiac Magnetic Resonance to Predict Events in Patients With Hypertrophic Cardiomyopathy.

Hypertrophic cardiomyopathy (HC) is the most common cardiovascular inherited disease, and it is associated with arrhythmic events, heart failure, and death. Strain analysis by tissue tracking (TT) techniques on cardiac magnetic resonance (CMR) is a novel noninvasive diagnostic tool. However, the usefulness of CMR-TT to identify patients with HC at risk of adverse outcomes remains unknown. CMR strain parameters by CMR-TT were prospectively measured in a cohort of 136 consecutive patients with HC. Clinical (death or readmission for heart failure) and arrhythmic (any ventricular tachycardia) events during follow-up were prospectively recorded. Global radial systolic strain rate and global radial diastolic strain rate showed the best area under the receiver operating characteristic curve (ROC curve) to predict adverse clinical events. On Cox multivariate regression models, a global radial systolic strain rate value <1.4/s and a global radial diastolic strain rate value ≥ -1.38/s were independently associated with clinical events at follow-up (adjusted hazard ratio 6.57, 95% confidence interval [CI] 2.01 to 21.49, p = 0.002; adjusted hazard ratio 5.96, 95% CI 1.79 to 19.89, p = 0.004, respectively). Regarding arrhythmic events, global radial peak strain <27% showed the best area under the ROC curve and remained independently associated with ventricular tachycardia after adjustment for confounders (odds ratio 7.33, 95% CI 1.07 to 50.41, p = 0.043). CMR strain parameters by TT predict clinical and arrhythmic events in patients with HC.

Advanced Echocardiography With Left Atrial Strain and Indexed Left Atrial Three-Dimensional Volume for Predicting Underlying Atrial Fibrillation After Cryptogenic Stroke.

Cryptogenic stroke (CS) represents 1/3 of ischemic strokes. Atrial fibrillation (AF) can be detected in up to 30% of CS. Therefore, there is a clinical need for predicting AF to guide the optimal secondary prevention strategy. The evidence about the role of advanced echocardiography, including left atrial 3-dimensional (3D) index volume and left atrial strain (LAS) techniques, to predict underlying AF in this setting is lacking. From April 2019 to November 2021, 78 consecutive patients with ischemic stroke or transient ischemic attack with ABCD2 scale ≥4 of unknown etiology were prospectively recruited. Echocardiography was performed during admission. All patients underwent 15 days of wearable Holter monitoring. The primary outcome measure was AF detection during follow-up. Twenty-two patients (28%) developed AF. Patients in the AF group were older (81 ± 6.3 vs 76.5 ± 7.8 years; p = 0.012). Left atrial (LA) diastolic indexed volume was higher in the AF group (37.2 ± 12.8 vs 29.7 ± 11 ml/m2 p = 0.01). Three-D LA indexed volume was also higher in patients with AF (41.4 ± 14 vs 32.2 ± 10 ml/m2 p = 0.009). LAS reservoir, LAS conduct, and LAS contraction (LASct) were significantly lower in patients with AF (19 ± 5.6 vs 32% ± 10.3%; 9 ± 4.5 vs 15 ± 7.6; 10 ± 5.3 vs 17 ± 6.4, respectively, all p <0.001). On multivariate analysis, LASct <13.5% and LA 3D indexed volume >44.5 ml/m2 were independent predictors of AF (odds ratio 10.9 [95% confidence interval 1.09 to 108.2], p = 0.042). In conclusion, LASct <13.5% and LA 3D indexed volume >44.5 ml/m2 are independent predictors of underlying AF in patients with CS. Our results show the usefulness of advanced echocardiography in this challenging clinical setting.

Influence of air pollutants on circulating inflammatory cells and microRNA expression in acute myocardial infarction.

Air pollutants increase the risk and mortality of myocardial infarction (MI). The aim of this study was to assess the inflammatory changes in circulating immune cells and microRNAs in MIs related to short-term exposure to air pollutants. We studied 192 patients with acute coronary syndromes and 57 controls with stable angina. For each patient, air pollution exposure in the 24-h before admission, was collected. All patients underwent systematic circulating inflammatory cell analyses. According to PM2.5 exposure, 31 patients were selected for microRNA analyses. STEMI patients exposed to PM2.5 showed a reduction of CD4+ regulatory T cells. Furthermore, in STEMI patients the exposure to PM2.5 was associated with an increase of miR-146a-5p and miR-423-3p. In STEMI and NSTEMI patients PM2.5 exposure was associated with an increase of miR-let-7f-5p. STEMI related to PM2.5 short-term exposure is associated with changes involving regulatory T cells, miR-146a-5p and miR-423-3p.

MKK6 deficiency promotes cardiac dysfunction through MKK3-p38γ/δ-mTOR hyperactivation.

Stress-activated p38 kinases control a plethora of functions, and their dysregulation has been linked to the development of steatosis, obesity, immune disorders, and cancer. Therefore, they have been identified as potential targets for novel therapeutic strategies. There are four p38 family members (p38α, p38ß, p38γ, and p38δ) that are activated by MKK3 and MKK6. Here, we demonstrate that lack of MKK6 reduces the lifespan in mice. Longitudinal study of cardiac function in MKK6 KO mice showed that young mice develop cardiac hypertrophy which progresses to cardiac dilatation and fibrosis with age. Mechanistically, lack of MKK6 blunts p38α activation while causing MKK3-p38γ/δ hyperphosphorylation and increased mammalian target of rapamycin (mTOR) signaling, resulting in cardiac hypertrophy. Cardiac hypertrophy in MKK6 KO mice is reverted by knocking out either p38γ or p38δ or by inhibiting the mTOR pathway with rapamycin. In conclusion, we have identified a key role for the MKK3/6-p38γ/δ pathway in the development of cardiac hypertrophy, which has important implications for the clinical use of p38α inhibitors in the long-term treatment since they might result in cardiotoxicity.

The human heart can increase its size to supply more blood to the body's organs. This process, called hypertrophy, can happen during exercise or be caused by medical conditions, such as high blood pressure or inherited genetic diseases. If hypertrophy is continually driven by illness, this can cause the heart to fail and no longer be able to properly pump blood around the body. For hypertrophy to happen, several molecular changes occur in the cells responsible for contracting the heart, including activation of the p38 pathway. Within this pathway is a p38 enzyme as well as a series of other proteins which are sequentially turned on in response to stress, such as inflammatory molecules or mechanical forces that alter the cell's shape. There are different types of p38 enzyme which have been linked to other diseases, making them a promising target for drug development. However, clinical trials blocking individual members of the p38 family have had disappointing results. An alternative approach is to target other proteins involved in the p38 pathway, such as MKK6, but it is not known what effect this might have. To investigate, Romero-Becerra et al. genetically modified mice to not have any MKK6 protein. As a result, these mice had a shorter lifespan, with hypertrophy developing at a young age that led to heart problems. Romero-Becerra et al. used different mice models to understand why this happened, showing that a lack of MKK6 reduces the activity of a specific member of the p38 family called p38α. However, this blockage boosted a different branch of the pathway which involved two other p38 proteins, p38γ and p38δ. This, in turn, triggered another key pathway called mTOR which also promotes hypertrophy of the heart. These results suggest that drugs blocking MKK6 and p38α could lead to side effects that cause further harm to the heart. A more promising approach for treating hypertrophic heart conditions could be to inhibit p38γ and/or p38δ. However, before this can be fully explored, further work is needed to generate compounds that specifically target these proteins.