Background Conventional antiarrhythmic drugs that target cardiac ion channels carry proarrhythmic risks, highlighting the need for alternative therapeutic approaches. Cardiac nicotinic acetylcholine receptors (nAChRs) represent a novel electrophysiological target. Objectives The aim of this exploratory, proof-of-concept phase 2 trial was to evaluate the effect of varenicline, a partial nAChR agonist, on frequent premature ventricular complexes (PVCs) after myocardial infarction (MI) and to assess its short-term safety and biological target engagement. Methods In this multicenter, randomized, double-blind, placebo-controlled trial, adults with frequent PVCs (≥1,000/24 h) assessed using 72-hour ambulatory electrocardiographic monitoring at ≥4 weeks post-MI were randomly assigned (1:1) to varenicline 0.5 mg twice daily or matching placebo for 45 days, in addition to guideline-directed medical therapy. The primary endpoint was the percentage change in 24-hour PVC count from baseline to week 6. Key secondary endpoints included responder rate (≥50% reduction in PVC count) and the incidence of nonsustained ventricular tachycardia (VT). Results Among 118 randomized patients, varenicline produced a 60.1 percentage point greater reduction in PVC burden compared with placebo (95% CI: 21.3-98.8 percentage points; P = 0.001). The responder rate was higher with varenicline (67.8% vs 30.5%; RR: 2.22; 95% CI: 1.46-3.39; P < 0.0001), and nonsustained VT incidence was lower (20.3% vs 37.3%; RR: 0.49; 95% CI: 0.29-0.85; P = 0.007). No deaths or malignant ventricular arrhythmias occurred in the varenicline group, with comparable adverse event rates between groups. Conclusions In this phase 2 trial, varenicline significantly reduced PVC burden and nonsustained VT incidence in post-MI patients without evidence of a proarrhythmic effects. These findings support cardiac nAChRs as a potential antiarrhythmic target and justify further evaluation in larger outcome-driven trials. (Efficacy of Varenicline Tartrate in Treating Frequent Premature Ventricular Contractions: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial [Var-PVC]; NCT06780215)

BACKGROUND:Premature atrial contractions (PACs) are independently associated with atrial fibrillation, stroke, and heart failure, yet no pharmacological therapy is approved for PAC suppression. Experimental studies have identified a functional cardiac glutamatergic system in which N-methyl-D-aspartate receptors regulate atrial electrophysiology. Preclinical studies show that pharmacological antagonism of N-methyl-D-aspartate receptors with memantine suppresses atrial arrhythmias. METHODS:We conducted an investigator-initiated, phase 2, multicenter, randomized, double-blind, placebo-controlled trial. Symptomatic adults with frequent PACs (≥1000/24 h) were randomly assigned to receive memantine or placebo for 6 weeks. The primary end point was the percentage change in mean 24-hour PAC count from baseline to the end of treatment. The primary analysis was performed in the intention-to-treat population. Prespecified secondary end points included the responder rate (≥50% PAC reduction), percentage change in nonsustained atrial tachycardia burden, and cumulative incidence of new-onset atrial fibrillation. RESULTS:Among 241 patients included in the efficacy analysis, memantine resulted in a greater reduction in PAC count than placebo (between-group difference, 47.1 percentage points; P=0.0045). The responder rate was higher with memantine than with placebo (52.4% versus 23.1%; P<0.0001). Memantine also reduced nonsustained atrial tachycardia burden (between-group difference, 30.98 percentage points; P=0.0043) and was associated with a lower cumulative incidence of new-onset atrial fibrillation (4.8% versus 23.9%; P<0.0001). No clinically meaningful differences were observed in electrocardiographic intervals or left ventricular function, and no drug-related serious adverse events occurred. CONCLUSIONS:In patients with frequent symptomatic PACs, memantine reduced atrial ectopy and atrial tachyarrhythmia burden and demonstrated a favorable safety profile. These findings provide proof of concept for a novel, non-ion channel-based therapeutic strategy targeting the cardiac glutamatergic system. REGISTRATION:URL: https://www.clinicaltrials.gov; Unique identifier: NCT06501638.

Atrial fibrillation (AF), the most prevalent sustained cardiac arrhythmia, is closely linked to disturbed intracellular Ca2+ homeostasis. Visinin-like protein 1 (VILIP-1), newly identified in cardiomyocytes, has been implicated in modulating Ca2+ signaling, yet its role in AF remains undefined. In this study, we integrated bulk RNA sequencing, single-cell transcriptomics, and electrophysiological profiling from human AF patients and rodent AF models to identify VILIP-1 as a key mediator of Ca2+ dysregulation in AF. VILIP-1 was significantly upregulated in atrial tissues from AF patients and in pacing-induced rat AF models, with enhanced membrane localization in cardiomyocytes. Atrial cardiomyocyte-specific overexpression of VILIP-1 led to pathological Ca2+ leakage, promoting delayed afterdepolarizations (DADs) and action potential duration (APD) alternans, which fostered AF substrate formation and increased arrhythmia susceptibility. Mechanistically, VILIP-1 augmented the surface abundance of sodium-calcium exchanger 1 (NCX-1) via a myristoylation-dependent trafficking mechanism, thereby disrupting Ca2+ handling and initiating AF. Pharmacologically, repaglinide and desloratadine, two FDA-approved drugs that identified to target VILIP-1 or its myristoylation, attenuated AF susceptibility by reducing NCX-1 surface expression and restoring intracellular Ca2+ homeostasis. Collectively, our findings define VILIP-1 as a critical upstream modulator of atrial Ca2+ homeostasis and establish it as a promising therapeutic target for AF, with efficacy validated in human and rodent models.

Transmitter systems are molecular networks that facilitate signal transmission between neurons or between neurons and effector cells. Well-established examples include the glutamatergic, cholinergic, GABAergic, dopaminergic, serotonergic, and histaminergic systems. Traditionally, the heart was thought to lack its own endogenous transmitter systems (ETSs). However, recent studies have identified several such systems within cardiomyocytes and cardiac pacemaker cells. This review focuses on the endogenous glutamatergic, cholinergic, and GABAergic systems in the heart, providing a comprehensive analysis of their molecular composition, electrophysiological functions, arrhythmogenic implications, and therapeutic potential. Based on these findings, this review proposes a transmitter-based model of cardiac bioelectric regulation and highlights innovative strategies for targeting ETSs to prevent and treat arrhythmias.

Cardiomyocyte hypertrophy is a key remodeling response to cardiac stress and an independent risk factor for heart failure. However, the molecular mechanism of cardiomyocyte hypertrophy is not yet fully understood. We here found Polo-like kinase 1 (PLK1) was crucial in regulating endothelin-1 (ET-1)-induced cardiomyocyte hypertrophy. Notably, PLK1 expression was significantly elevated in ET-1-induced hypertrophic cardiomyocytes and pressure overload-induced hypertrophic cardiac tissue. Knocking down Plk1 reduced the cell size of hypertrophic cardiomyocytes and suppressed the expression of hypertrophic markers, including ANP, BNP and β-MHC. The PLK1 inhibitor BI2536 had similar effects on hypertrophic cardiomyocytes. Mechanistically, the ERK1/2 pathway was identified as the key downstream pathway mediating the effects of PLK1 on ET-1-induced cardiomyocyte hypertrophy. Finally, the deficiency of PLK1 attenuated the hypertrophy of hiPSC-CMs. In summary, our study revealed that PLK1 regulates ET-1-induced cardiomyocyte hypertrophy through the ERK1/2 pathway, providing insights into the pathogenesis and potential therapies for pathological cardiac hypertrophy.

The deformable in situ spatiotemporal bioelectronic chemical patch (DinST-BioC-Patch) plays a pivotal role in elucidating the pathogenesis of major diseases, yet it faces challenges in intricate bio-interface adaptability, sensitivity, and spatiotemporal signal processing. In this work, we introduce a bioelectronic chemical patch as initially reported and selected cardiac troponin I (cTnI) as the indicator to validate the practicability of DinST-BioC-Patch for in situ spatiotemporal chemical analysis. Excellent bio-adaptability and suitable mechanical property, ensure the feasibility of DinST-BioC-Patch on intricate bio-interfaces. Utilizing a double amplification and fluorinated amino acid-doping strategy, the doped organic electrochemical transistor array biosensors (7 mm x 7 mm with 64 channels), enabled DinST-BioC-Patch to achieve ultrasensitive detection of cTnI down to 8.71 pg/mL. For the spatiotemporal analysis, DinST-BioC-Patch precisely captured cTnI's time-dependent dynamics (T = 0, 15, 30, and 45 min) across time and monitored its spatial distribution on the epicardium of the myocardial infarction area (0.7 cm x 0.7 cm). Notably, the DinST-BioC-Patch platform, in its initial demonstration, the spatiotemporal dynamics of biochemical cTnI in the epicardium of Sprague Dawley (SD) rats after myocardial infarction (MI) can be observed, indicating that biochemical cTnI spreads from the center of the infarction area to its periphery. It is anticipated that the DinST-BioC-Patch not only elucidate valuable insights into comprehensive biomolecular dynamics mechanisms but also serve as a platform for potential advancements in the fields of diagnosis, intervention, and prognostic monitoring of significant diseases.

Background Cardiovascular diseases (CVDs) have the highest mortality worldwide. Human pluripotent stem cells (hPSCs) and their cardiomyocyte derivatives (hPSC-CMs) offer a valuable resource for disease modeling, pharmacological screening, and regenerative therapy. While most CVDs are linked to significant over-production of reactive oxygen species (ROS), the effects of current antioxidants targeting excessive ROS are limited. Nanotechnology is a powerful tool to develop antioxidants with improved selectivity, solubility, and bioavailability to prevent or treat various diseases related to oxidative stress. Cerium oxide nanozymes (CeONZs) can effectively scavenge excessive ROS by mimicking the activity of endogenous antioxidant enzymes. This study aimed to assess the nanotoxicity of CeONZs and their potential antioxidant benefits in stressed human embryonic stem cells (hESCs) and their derived cardiomyocytes (hESC-CMs). Results CeONZs demonstrated reliable nanosafety and biocompatibility in hESCs and hESC-CMs within a broad range of concentrations. CeONZs exhibited protective effects on the cell viability of hESCs and hESC-CMs by alleviating excessive ROS-induced oxidative stress. Moreover, CeONZs protected hESC-CMs from doxorubicin (DOX)-induced cardiotoxicity and partially ameliorated the insults from DOX in neonatal rat cardiomyocytes (NRCMs). Furthermore, during hESCs culture, CeONZs were found to reduce ROS, decrease apoptosis, and enhance cell survival without affecting their self-renewal and differentiation potential. Conclusions CeONZs displayed good safety and biocompatibility, as well as enhanced the cell viability of hESCs and hESC-CMs by shielding them from oxidative damage. These promising results suggest that CeONZs may be crucial, as a safe nanoantioxidant, to potentially improve the therapeutic efficacy of CVDs and be incorporated into regenerative medicine. Graphical Abstract

Cardiac biological pacing (BP) is one of the future directions for bradyarrhythmias intervention. Currently, cardiac pacemaker cells (PCs) used for cardiac BP are mainly derived from pluripotent stem cells (PSCs). However, the production of high-quality cardiac PCs from PSCs remains a challenge. Here, we developed a cardiac PC differentiation strategy by adopting dual PC markers and simulating the developmental route of PCs. First, two PC markers, Shox2 and Hcn4, were selected to establish Shox2:EGFP; Hcn4:mCherry mouse PSC reporter line. Then, by stepwise guiding naïve PSCs to cardiac PCs following naïve to formative pluripotency transition and manipulating signaling pathways during cardiac PCs differentiation, we designed the FSK method that increased the yield of SHOX2+; HCN4+ cells with typical PC characteristics, which was 12 and 42 folds higher than that of the embryoid body (EB) and the monolayer M10 methods respectively. In addition, the in vitro cardiac PCs differentiation trajectory was mapped by single-cell RNA sequencing (scRNA-seq), which resembled in vivo PCs development, and ZFP503 was verified as a key regulator of cardiac PCs differentiation. These PSC-derived cardiac PCs have the potential to drive advances in cardiac BP technology, help with the understanding of PCs (patho)physiology, and benefit drug discovery for PC-related diseases as well.

In mammals, specificity protein 1 (SP1) was the first Cys2-His2 zinc finger transcription factor to be isolated within the specificity protein and Krüppel-like factor (Sp/KLF) gene family. SP1 regulates gene expression by binding to Guanine–Cytosine (GC)-rich sequences on promoter regions of target genes, affecting various cellular processes. Additionally, the activity of SP1 is markedly influenced by posttranslational modifications, such as phosphorylation, acetylation, glycosylation, and proteolysis. SP1 is implicated in the regulation of apoptosis, cell hypertrophy, inflammation, oxidative stress, lipid metabolism, plaque stabilization, endothelial dysfunction, fibrosis, calcification, and other pathological processes. These processes impact the onset and progression of numerous cardiovascular disorders, including coronary heart disease, ischemia-reperfusion injury, cardiomyopathy, arrhythmia, and vascular disease. SP1 emerges as a potential target for the prevention and therapeutic intervention of cardiac ailments. In this review, we delve into the biological functions, pathophysiological mechanisms, and potential clinical implications of SP1 in cardiac pathology to offer valuable insights into the regulatory functions of SP1 in heart diseases and unveil novel avenues for the prevention and treatment of cardiovascular conditions.

The spalt (Sal) gene family has four members (Sall1-4) in vertebrates, all of which play pivotal roles in various biological processes and diseases. However, the expression and function of SALL2 in development are still less clear. Here, we first charted SALL2 protein expression pattern during mouse embryo development by immunofluorescence, which revealed its dominant expression in the developing nervous system. With the establishment of Sall2 deficient mouse embryonic stem cells (ESCs), the in vitro neural differentiation system was leveraged to interrogate the function of SALL2, which showed impaired neural differentiation of Sall2 knockout (KO) ESCs. Furthermore, neural stem cells (NSCs) could not be derived from Sall2 KO ESCs and the generation of neural tube organoids (NTOs) was greatly inhibited in the absence of SALL2. Meanwhile, transgenic expression of E1 isoform of SALL2 restored the defects of neural differentiation in Sall2 KO ESCs. By chromatin immunoprecipitation sequencing (ChIP-seq), Tuba1a was identified as downstream target of SALL2, whose function in neural differentiation was confirmed by rescuing neural phenotypes of Sall2 KO ESCs when overexpressed. In sum, by elucidating SALL2 expression dynamics during early mouse development and mechanistically characterizing its indispensable role in neural differentiation, this study offers insights into SALL2’s function in human nervous system development, associated pathologies stemming from its mutations and relevant therapeutic strategy.

Physiologically, the atria contract first, followed by the ventricles, which is the prerequisite for normal blood circulation. The above phenomenon of atrioventricular sequential contraction results from the characteristically slow conduction of electrical excitation of the atrioventricular node (AVN) between the atria and the ventricles. However, it is not clear what controls the conduction of electrical excitation within AVNs. Here, we find that AVN pacemaker cells (AVNPCs) possess an intact intrinsic GABAergic system, which plays a key role in electrical conduction from the atria to the ventricles. First, along with the discovery of abundant GABA-containing vesicles under the surface membranes of AVNPCs, key elements of the GABAergic system, including GABA metabolic enzymes, GABA receptors, and GABA transporters, were identified in AVNPCs. Second, GABA synchronously elicited GABA-gated currents in AVNPCs, which significantly weakened the excitability of AVNPCs. Third, the key molecular elements of the GABAergic system markedly modulated the conductivity of electrical excitation in the AVN. Fourth, GABAA receptor deficiency in AVNPCs accelerated atrioventricular conduction, which impaired the AVN’s protective potential against rapid ventricular frequency responses, increased susceptibility to lethal ventricular arrhythmias, and decreased the cardiac contractile function. Finally, interventions targeting the GABAergic system effectively prevented the occurrence and development of atrioventricular block. In summary, the endogenous GABAergic system in AVNPCs determines the slow conduction of electrical excitation within AVNs, thereby ensuring sequential atrioventricular contraction. The endogenous GABAergic system shows promise as a novel intervention target for cardiac arrhythmias.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is the most prevalent monogenic heart disorder. However, the pathogenesis of HCM, especially its nongenetic mechanisms, remains largely unclear. Transcription factors are known to be involved in various biological processes including cell growth. We hypothesized that SP1 (specificity protein 1), the first purified TF in mammals, plays a role in the cardiomyocyte growth and cardiac hypertrophy of HCM. METHODS: Cardiac -specific conditional knockout of Sp1 mice were constructed to investigate the role of SP1 in the heart. The echocardiography, histochemical experiment, and transmission electron microscope were performed to analyze the cardiac phenotypes of cardiac -specific conditional knockout of Sp1 mice. RNA sequencing, chromatin immunoprecipitation sequencing, and adeno-associated virus experiments in vivo were performed to explore the downstream molecules of SP1. To examine the therapeutic effect of SP1 on HCM, an SP1 overexpression vector was constructed and injected into the mutant allele of Myh6 R404Q/+ (Myh6 c. 1211C>T) HCM mice. The human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) from a patient with HCM were used to detect the potential therapeutic effects of SP1 in human HCM. RESULTS: The cardiac -specific conditional knockout of Sp1 mice developed a typical HCM phenotype, displaying overt myocardial hypertrophy, interstitial fibrosis, and disordered myofilament. In addition, Sp1 knockdown dramatically increased the cell area of hiPSC-CMs and caused intracellular myofibrillar disorganization, which was similar to the hypertrophic cardiomyocytes of HCM. Mechanistically, Tuft1 was identified as the key target gene of SP1. The hypertrophic phenotypes induced by Sp1 knockdown in both hiPSC-CMs and mice could be rescued by TUFT1 (tuftelin 1) overexpression. Furthermore, SP1 overexpression suppressed the development of HCM in the mutant allele of Myh6 R404Q/+ mice and also reversed the hypertrophic phenotype of HCM hiPSC-CMs. CONCLUSIONS: Our study demonstrates that SP1 deficiency leads to HCM. SP1 overexpression exhibits significant therapeutic effects on both HCM mice and HCM hiPSC-CMs, suggesting that SP1 could be a potential intervention target for HCM.

Background Transcription factors HAND1 and HAND2 (HAND1/2) play significant roles in cardiac organogenesis. Abnormal expression and deficiency of HAND1 / 2 result in severe cardiac defects. However, the function and mechanism of HAND1 / 2 in regulating human early cardiac lineage commitment and differentiation are still unclear. Methods With NKX2.5 eGFP H9 human embryonic stem cells (hESCs), we established single and double knockout cell lines for HAND1 and HAND2 , respectively, whose cardiomyocyte differentiation efficiency could be monitored by assessing NKX2.5-eGFP + cells with flow cytometry. The expression of specific markers for heart fields and cardiomyocyte subtypes was examined by quantitative PCR, western blot and immunofluorescence staining. Microelectrode array and whole-cell patch clamp were performed to determine the electrophysiological characteristics of differentiated cardiomyocytes. The transcriptomic changes of HAND knockout cells were revealed by RNA sequencing. The HAND1/2 target genes were identified and validated experimentally by integrating with HAND1/2 chromatin immunoprecipitation sequencing data. Results Either HAND1 or HAND2 knockout did not affect the cardiomyocyte differentiation kinetics, whereas depletion of HAND1 / 2 resulted in delayed differentiation onset. HAND1 knockout biased cardiac mesoderm toward second heart field progenitors at the expense of first heart field progenitors, leading to increased expression of atrial and outflow tract cardiomyocyte markers, which was further confirmed by the appearance of atrial-like action potentials. By contrast, HAND2 knockout cardiomyocytes had reduced expression of atrial cardiomyocyte markers and displayed ventricular-like action potentials. HAND1 / 2 -deficient hESCs were more inclined to second heart field lineage and its derived cardiomyocytes with atrial-like action potentials than HAND1 single knockout during differentiation. Further mechanistic investigations suggested TBX5 as one of the downstream targets of HAND1/2, whose overexpression partially restored the abnormal cardiomyocyte differentiation in HAND1 / 2 -deficient hESCs. Conclusions HAND1 / 2 have specific and redundant roles in cardiac lineage commitment and differentiation. These findings not only reveal the essential function of HAND1/2 in cardiac organogenesis, but also provide important information on the pathogenesis of HAND1 / 2 deficiency-related congenital heart diseases, which could potentially lead to new therapeutic strategies.

INTRODUCTION:Cell fate determination and transition are of paramount importance in biology and medicine. Naive pluripotency could be achieved by reprogramming differentiated cells. However, the mechanism is less clear. Osmolarity is an essential physical factor that acts on living cells, especially for pluripotent cells, but its significance in cell fate transition remains unexplored. OBJECTIVES:To investigate the role of osmolarity in cell fate transition and its underlying mechanism. METHODS:Flow cytometry, quantitative real-time PCR, teratoma and chimeric mice assays were performed to assess reprogramming efficiency and characterize iPSCs. TEM, immunofluorescence staining, western blot, chemical treatment and genetic modification were utilized to evaluate cell morphology, signaling pathways, cytoskeleton and nuclear structure. Multiomic sequencings were applied to unveil the transcriptome, histone markers and chromatin accessibility of EpiSCs in hypo-osmotic condition. RESULTS:In hypo-osmotic condition, the reprogramming efficiency of hypo-osmotic EpiSCs increased over 60-fold than that of iso-osmotic cells (1100 vs 18 colonies per 3 × 105 cells), whereas no colony formed in hyper-osmotic cells. As expected, the converted cells displayed naive pluripotency. The hypo-osmotic EpiSCs exhibited larger cell size, nuclear area and less heterochromatin; ATAC-seq and ChIP-seq confirmed the increased accessibility of naive pluripotent gene loci with more H3K27ac. Mechanistically, hypo-osmolarity activated PI3K-AKT-SP1 signaling in EpiSCs, which reshaped cytoskeleton and nucleoskeleton, resulting in genome reorganization and pluripotent gene expression. In contrast, hypo-osmolarity delayed the ESCs' exit from naive pluripotency. Moreover, in MEFs reprograming, hypo-osmolarity promoted the conversion to naive pluripotency. CONCLUSION:Hypo-osmolarity promotes cell fate transition by remodeling cytoskeleton, nucleoskeleton and genome via PI3K-AKT-SP1 pathway.

A genetic system, ProTracer, has been recently developed to record cell proliferation in vivo. However, the ProTracer is initiated by an infrequently used recombinase Dre, which limits its broad application for functional studies employing floxed gene alleles. Here we generated Cre-activated functional ProTracer (fProTracer) mice, which enable simultaneous recording of cell proliferation and tissue-specific gene deletion, facilitating broad functional analysis of cell proliferation by any Cre driver.

The growth and maturation of the ventricular chamber require spatiotemporally precise synergy between diverse cell types. Alternative splicing deeply affects the processes. However, the functional properties of alternative splicing in cardiac development are largely unknown. Our study reveals that an alternative splicing factor polypyrimidine tract-binding protein 1 (PTBP1) plays a key role in ventricular chamber morphogenesis. During heart development, PTBP1 colocalizes with endothelial cells but is almost undetectable in cardiomyocytes. The endothelial-specific knockout of Ptbp1 , in either endocardial cells or pan-endothelial cells, leads to a typical phenotype of left ventricular noncompaction (LVNC). Mechanistically, the deletion of Ptbp1 reduces the migration of endothelial cells, disrupting cardiomyocyte proliferation and ultimately leading to the LVNC. Further study shows that Ptbp1 deficiency changes the alternative splicing of β-arrestin-1 ( Arrb1 ), which affects endothelial cell migration. In conclusion, as an alternative splicing factor, PTBP1 is essential during ventricular chamber development, and its deficiency can lead to congenital heart disease.

Kinase-catalyzed phosphorylation plays a crucial role in pathological cardiac hypertrophy. Here, we show that CDC-like kinase 4 (CLK4) is a critical regulator of cardiomyocyte hypertrophy and heart failure. Knockdown of Clk4 leads to pathological cardiomyocyte hypertrophy, while overexpression of Clk4 confers resistance to phenylephrine-induced cardiomyocyte hypertrophy. Cardiac-specific Clk4 -knockout mice manifest pathological myocardial hypertrophy with progressive left ventricular systolic dysfunction and heart dilation. Further investigation identifies nexilin (NEXN) as the direct substrate of CLK4, and overexpression of a phosphorylation-mimic mutant of NEXN is sufficient to reverse the hypertrophic growth of cardiomyocytes induced by Clk4 knockdown. Importantly, restoring phosphorylation of NEXN ameliorates myocardial hypertrophy in mice with cardiac-specific Clk4 deletion. We conclude that CLK4 regulates cardiac function through phosphorylation of NEXN, and its deficiency may lead to pathological cardiac hypertrophy. CLK4 is a potential intervention target for the prevention and treatment of heart failure.

近四百年来,心脏病学领域取得了突飞猛进的发展.1628年,英国医生兼生理学家威廉·哈维(William Harvey)提出了血液循环的理论,奠定了近代生理科学的基础,做出了划时代的贡献,他也因此成为与哥白尼和牛顿等齐名的科学巨匠.1903年,荷兰医生兼生理学家威廉·爱因托芬(Willem Einthoven)发明了最早的心电图量测装置,确立了心电图的标准测量单位;1912年,他提出了心电活动的"爱因托芬三角"理论;1924年,他获得诺贝尔生理学或医学奖,被后世誉为"心电图之父".1938年,美国外科医生罗伯特·格罗斯(Robert Gross)首次通过手术成功治疗了动脉导管未闭,开创了心血管外科手术的先河,挑战了当时认为人类心脏无法修补的教条,完成了心脏手术从实验室到临床的伟大转化.此外,还有心脏起搏传导系统的发现、心脏病预防医学的诞生、动作电位的记录、超声心动图技术的发明、起搏器和植入式除颤器的诞生、重大心血管疾病药物的研发成功、射频消融术的诞生和人工心脏的研发等这些里程碑式的发现和发明.遗憾的是,21世纪以来,世界心脏病学领域鲜有根本性的理论突破和颠覆性的技术革命.