The combination of creatine kinase-myocardial band isoenzyme and point-of-care cardiac troponin/contemporary cardiac troponin for the early diagnosis of acute myocardial infarction

BACKGROUND:The early diagnosis of acute myocardial infarction(AMI)remains challenging,especially for institutions without the high-sensitive cardiac troponin(hs-c Tn)assay.Herein,we aim to assess the value of creatine kinase-myocardial band isoenzyme(CK-MB)combined with different cardiac troponin(c Tn)assays in AMI diagnosis.METHODS:This multicenter,observational study included 3,706 patients with acute chest pain from September 1,2015,to September 30,2017.We classified the participants into three groups according to the c Tn assays:the point-of-care c Tn(POC-c Tn)group,the contemporary c Tn(c-c Tn)group,and hs-c Tn group.The diagnostic value was quantified using sensitivity and the area under the curve(AUC).RESULTS:Compared to the single POC-c Tn/c-c Tn assays,combining CK-MB and POC-c Tn/c-c Tn increased the diagnostic sensitivity of AMI(56.1%vs.63.9%,P<0.001;82.7%vs.84.3%,P=0.025).In contrast,combining CK-MB and hs-c Tn did not change the sensitivity compared with hs-c Tn alone(95.0%vs.95.0%,P>0.999).In the subgroup analysis,the sensitivity of combining CKMB and c-c Tn increased with time from symptom onset<6 h compared with c-c Tn alone(72.8%vs.75.0%,P=0.046),while the sensitivity did not increase with time from symptom onset>6 h(97.5%vs.98.3%,P=0.317).The AUC of the combination of CK-MB and POC-c Tn significantly increased compared to the single POC-c Tn assay(0.776 vs.0.750,P=0.002).The AUC of the combined CKMB and c-c Tn/hs-c Tn assays did not significantly decrease compared with that of the single c-c Tn/hs-c Tn assays within 6 h.CONCLUSIONS:The combination of CK-MB and POC-c Tn or c-c Tn may be valuable for the early diagnosis of AMI,especially when hs-c Tn is not available.

Target versus sub-target dose of renin–angiotensin system inhibitors on survival in elderly patients with heart failure with reduced ejection fraction: a systematic review and meta-analysis

BACKGROUND The efficiency of the target versus sub-target dose of renin–angiotensin system inhibitors(RASIs)in elderly patients with heart failure(HF)with reduced ejection fraction(HErEF)remains unclear.METHODS PubMed,Embase,and the Cochrane Central Register of Controlled Trials were searched from database inception through March 2022 for randomized controlled trials(RCTs)and observational studies considering the effect of the target versus sub-target dose of RASIs on survival in elderly patients(≥60 years)with HErEF.The primary outcome was all-cause mortality.The secondary outcomes were cardiac mortality,HF hospitalization,and the composite endpoint of mortality or HF hospitalization.A meta-analysis was conducted to generate combined hazard ratio(HR)and 95%CI.RESULTS Seven studies(two RCTs and five observational studies)enrolling 16,634 patients were included.A pooled analysis suggested that the target versus sub-target dose of RASIs led to lower rates of all-cause mortality(HR=0.92,95%CI:0.87–0.98,I2=21%)and cardiac mortality(HR=0.93,95%CI:0.85–1.00,I2=15%)but not reduced rates of HF hospitalization(HR=0.94,95%CI:0.88–1.01,I2=0)and the composite endpoint(HR=1.03,95%CI:0.91–1.15,I2=51%).However,the target dose of RASIs was associated with a similar primary outcome(HR=0.85,95%CI:0.64–1.14,I2=0)in a subgroup of very elderly patients>75 years of age.CONCLUSIONS Our analysis suggests that the target dose of RASIs has a better survival benefit in elderly patients with HFrEF compared to the sub-target dose of RASIs.However,the sub-target dose of RASIs is associated with a similar mortality rate in very elderly patients>75 years of age.Future high-quality and adequately powered RCTs are warranted.

Chinese consensus on the diagnosis and treatment of immunoglobulin light-chain cardiac amyloidosis

Epidemiology of Amyloid Light-Chain Cardiac Amyloidosis(AL-CA)The annual incidence of amyloid light-chain(AL)amyloidosis is 3-5/million,and the incidence in men is slightly higher than that in women.Approximately,70%of patients with newly diagnosed AL amyloidosis have cardiac involvement.

Trends and challenges of emergency and acute care in Chinese mainland:2005–2017

BACKGROUND:Emergency medical service system(EMSS)is essential in providing acute care services for health conditions.However,trends of emergency and acute care in China haven’t been studied systematically.METHODS:Relevant literature was carefully reviewed,including original and review articles,letters,government reports,yearbooks,both in Chinese and in English.Data on the number of emergency visits,physicians and beds in emergency departments(EDs),and the workforce of prehospital emergency care were summarized and analyzed from China Health and Family Planning Statistical Yearbooks(2006–2018).RESULTS:Over the past decade,the number of ED visits tripled from 51.9 million to 166.5 million;and utilization of pre-hospital emergency care increased from 3.2 million to 6.8 million.In response to rapid increases in demand,the number of licensed emergency physicians raised from 20,058 to 59,409;the beds’number increased from 10,783 to 42,367.For pre-hospital emergency care,the volume of health workforce increased from 3,687 to 8,671,with a 109%increase in the number of physicians from 1,774 to 3,712.However,overcrowding,the long length of stay in EDs,poor work environment,and work exhaustion were still the critical challenges faced by China’s EMSS.CONCLUSIONS:The number of emergency visits has grown with continual capability enhancement during the past decade.However,overcrowding,the long length of stay in EDs,poor work environment,and work exhaustion still need to be solved by China’s EMSS.These fi ndings and comparison with the USA could offer experiences and lessons to EMSS development worldwide,especially for developing countries.

The Efficacy and Safety of Tolvaptan in Heart Failure Patients with Congestive Signs:A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Objective:The aim of this study was to investigate the efficacy and safety of tolvaptan,as well as the impact of its treatment dose and duration in heart failure patients with congestive signs.Methods:The PubMed,Embase,Cochrane Library,and ClinicalTrials.gov databases were searched to collect data from all randomized controlled trials(RCT)examining the efficacy and safety of tolvaptan in heart failure patients with congestive signs compared with placebo or blank control until March 4,2021.Urine volume,change in body weight,improvement in dyspnea,and reduction of edema were evaluated as efficacy indicators.All-cause mortality,worsening heart failure,and adverse events were considered safety indicators.The quality of eligible publications was assessed using the Cochrane risk of bias for RCTs.Results:Ten RCTs with 5,980 patients were included in this analysis.Compared with control,tolvaptan significantly reduced weight in the short term(day 1,7 RCTs,weighted mean difference(WMD):-1.09,95%confidence interval(CI):-1.27 to-0.91;day 2,2 RCTs,WMD:-1.67,95%CI:-3.00 to-0.33;day 7,4 RCTs,WMD:-0.95,95%CI:-1.25 to-0.66),increased urine volume(WMD:1,825.72,95%CI:1,438.38-2,213.07),and relieved dyspnea(risk ratio(RR):1.12,95%CI:1.05-1.19)without increasing the mortality rate(RR:0.96,95%CI:0.87-1.06).Furthermore,the weight loss and increase in urine volume were not dose-dependent effects,and prolonged medication did not lead to sustained weight loss.In addition,there seemed to be more adverse events(RR:1.17,95%CI:1.03-1.32)after treatment with tolvaptan.Further analysis revealed that patients treated with tolvaptan were more likely to report thirst(RR:6.09,95%CI:3.37-11.00)and dry mouth(RR:6.36,95%CI:4.09-9.90),as well as develop hypernatremia(RR:12.76,95%CI:3.52-46.32).Conclusions:The meta-analysis shows that tolvaptan can improve congestion with no increase in mortality rate,but should be used to guard against adverse events.Deserve to be mentioned,the number of RCTs included was limited,suggesting that the observed results should be interpreted with caution.Additional robust clinical studies are warranted to validate the present findings.

Trends in mortality of emergency departments patients in China

BACKGROUND: Emergency medical service system (EMSS) in China is becoming more important. However, studies on mortality of emergency departments (EDs) patients in tertiary hospitals and on the trends in mortality of ED patients all over China are stagnant. The objective of this study was to quantify and describe the trends in mortality of ED patients in China. METHODS: Nine tertiary teaching hospitals were selected from tertiary teaching hospitals in different regions. The annual numbers of ED visits and deaths of these hospitals in 2004, 2009 and 2014 were recorded and analyzed. Chi-square test was used to compare the mortality of the EDs’ visits. Moreover, data on the mortality of ED patients in China from 2005 to 2015 were summarized and analyzed from the China Health and Family Planning Statistical Yearbooks (2006–2016). RESULTS: From 2004 to 2014, the overall annual mortalities in EDs increased among the tertiary hospitals (P<0.001). However, the overall annual mortality in EDs all over China decreased from 0.12% in 2005 to 0.08% in 2015. And the mortalities of EDs patients in the eastern, central and western regions of China all decreased. In addition, the average mortality of EDs patients in northern China was obviously higher than that in southern China (P<0.05). CONCLUSION: The ED mortality was increased in tertiary hospitals while decreased all over China during the past decade, which may be partly caused by some critical challenges faced by China’s EMSS, such as overcrowding and long length of stay in EDs of tertiary hospitals.

Aldehyde dehydrogenase 2 preserves mitochondrial morphology and attenuates hypoxia/reoxygenationinduced cardiomyocyte injury

BACKGROUND:Disturbance of mitochondrial fi ssion and fusion(termed mitochondrial dynamics)is one of the leading causes of ischemia/reperfusion(I/R)-induced myocardial injury.Previous studies showed that mitochondrial aldehyde dehydrogenase 2(ALDH2)conferred cardioprotective effect against myocardial I/R injury and suppressed I/R-induced excessive mitophagy in cardiomyocytes.However,whether ALDH2 participates in the regulation of mitochondrial dynamics during myocardial I/R injury remains unknown.METHODS:In the present study,we investigated the effect of ALDH2 on mitochondrial dynamics and the underlying mechanisms using the H9c2 cells exposed to hypoxia/reoxygenation(H/R)as an in vitro model of myocardial I/R injury.RESULTS:Cardiomyocyte apoptosis was significantly increased after oxygen-glucose deprivation and reoxygenation(OGD/R),and ALDH2 activation largely decreased the cardiomyocyte apoptosis.Additionally,we found that both ALDH2 activation and overexpression significantly inhibited the increased mitochondrial fission after OGD/R.Furthermore,we found that ALDH2 dominantly suppressed dynamin-related protein 1(Drp1)phosphorylation(Ser616)and adenosine monophosphate-activated protein kinase(AMPK)phosphorylation(Thr172)but not interfered with the expression levels of mitochondrial shaping proteins.CONCLUSIONS:We demonstrate the protective effect of ALDH2 against cardiomyocyte H/R injury with a novel mechanism on mitochondrial fission/fusion.

Mendelian randomization studies on atherosclerotic cardiovascular disease: evidence and limitations

Epidemiological research has revealed a galaxy of biomarkers, such as genes, molecules or traits, which are associated with increased risk of atherosclerotic cardiovascular diseases(ASCVD). However, the etiological basis remains poorly characterized.Mendelian randomization(MR) involves the use of observational genetic data to ascertain the roles of disease-associated risk factors and, in particular, differentiate those reflecting the presence or severity of a disease from those contributing causally to a disease. Over the past decade, MR has evolved into a fruitful approach to clarifying the causal relation of a biomarker with ASCVD and to verifying potential therapeutic targets for ASCVD. In this review, we selected high-quality MR studies on ASCVD, examined the causal relationship of a series of biomarkers with ASCVD, and elucidated the role of MR in validating biomarkers as a therapeutic target by comparing the results from MR studies and randomized clinical trials(RCTs) for the treatment of ASCVD. The good agreement between the results derived by MR and RCTs suggests that MR could be performed as a screening process before novel drug development. However, when designing and interpreting a MR study, the assumptions and limitations inherent in this approach should be taken into account. Novel methodological developments, such as sensitivity analysis, will help to strengthen the validity of MR studies.

Angiotensin converting enzyme inhibitors and angiotensin receptor blockers improved the outcome of patients with severe COVID-19 and hypertension

Dear Editor.Hypertension was reportedly the most common coexisting condition of COVID-19 as 15%-31.2%patients with COVID-19 had hypertension,and the incidence of hypertension reached 58.3%in COVID-19 patients requiring ICU care(Wang et al.,2020).However,it remains unclear whether combined hypertension carries an increased risk for a worse outcome in patients with COVID-19 and what clinical factors independently predict death in these patients.

The optimal anticoagulation strategy for COVID-19,prophylactic or therapeutic?:a meta-analysis,trial sequential analysis,and meta-regression of more than 27,000 participants

Background:Anticoagulants are promising regimens for treating coronavirus disease 2019(COVID-19).However,whether prophylactic or intermediate-to-therapeutic dosage is optimal remains under active discussion.Methods:We comprehensively searched PubMed,Embase,Scopus,Web of Science,Cochrane Library,ClinicalTrials,and MedRxiv databases on April 26,2022.Two independent researchers conducted literature selection and data extraction separately according to predetermined criteria.Notably,this is the first meta-analysis on COVID-19,taking serious consideration regarding the dosage overlap between the 2 comparison groups of prophylactic anticoagulation(PA)and intermediate-to-therapeutic anticoagulation(I-TA).Results:We included 11 randomized controlled trials(RCTs)and 36 cohort studies with 27,051 COVID-19 patients.By analyzing all the RCTs,there was no significant difference in mortality between the PA and I-TA groups,which was further confirmed by trial sequential analysis(TSA)(odds ratio[OR]:0.93;95%confidence interval[CI]:0.71–1.22;P=0.61;TSA adjusted CI:0.71–1.26).The rate of major bleeding was remarkably higher in the I-TA group than in the PA group,despite adjusting for TSA(OR:1.73;95%CI:1.15–2.60;P=0.009;TSA adjusted CI:1.09–2.58).RCTs have supported the beneficial effect of I-TA in reducing thrombotic events.After including all studies,mortality in the I-TA group was significantly higher than in the PA group(OR:1.38;95%CI:1.15–1.66;P=0.0005).The rate of major bleeding was similar to the analysis from RCTs(OR:2.24;95%CI:1.86–2.69;P<0.00001).There was no distinct difference in the rate of thrombotic events between the 2 regimen groups.In addition,in both critical and noncritical subgroups,I-TA failed to reduce mortality but increased major bleeding rate compared with PA,as shown in meta-analysis of all studies,as well as RCTs only.Meta-regression of all studies suggested that there was no relationship between the treatment effect and the overall risk of mortality or major bleeding(P=0.14,P=0.09,respectively).Conclusion:I-TA is not superior to PA for treating COVID-19 because it fails to lower the mortality rate but increases the major bleeding rate in both critical and noncritical patients.

Plasma biomarkers and plaque strain predict long-term cardiovascular events in patients with acute coronary syndrome

To test whether circulating and intracoronary biomarkers and coronary plaque strain have additive values to Global Registry of Acute Coronary Events(GRACE) score for predicting long-term cardiovascular events in ACS patients. One hundred ACS patients were enrolled and the GRACE score and plasma levels and intracoronary gradients of a number of biomarkers were measured. Coronary plaque burden and morphology in non-critical stenotic plaques were determined by intravascular ultrasound(IVUS) technique, and the maximal shear strain(SSmax) and maximal area strain(ASmax) were determined by intravascular ultrasound elastography(IVUSE) technique. Patients were followed for cardiovascular events and the predictive values of clinical characteristics, plasma biomarkers and plaque parameters were compared with GRACE score, and the incremental values of these measurements to the GRACE score were assessed. GRACE score, plasma biomarkers and plaque strain were independent predictors of cardiovascular events. Combination of GRACE score, plasma biomarkers and plaque strains significantly improved the predictive value of the GRACE score alone with the receiver-operating characteristic area increased from0.457 to 0.667(P=0.014). The combination of circulating and intracoronary biomarkers, plaque strain and GRACE score provides a better predictive tool than GRACE score alone in patients with ACS.

Cardiomyocyte-specific knockout of ADAM17 ameliorates left ventricular remodeling and function in diabetic cardiomyopathy of mice

Angiotensin-converting enzyme 2(ACE2)has proven beneficial in attenuating diabetic cardiomyopathy(DCM)but has been found to be a substrate of a disintegrin and metalloprotease protein-17(ADAM17).However,whether ADAM17 plays a role in the pathogenesis and intervention of DCM is obscure.In this study,we created cardiomyocyte-specific knockout of ADAM17(A17^(α-MHCKO))mice,and left ventricular dimension,function,pathology and molecular biology were assessed in ADAM17^(fl/fl) control,A17^(α-MHCKO) control,ADAM17^(fl/fl) diabetic and A17^(α-MHCKO) diabetic mice.Both differentiated H9c2 cells and neonatal rat cardiomyocytes(NRCMs)were used to explore the molecular mechanisms underlying the effect of ADAM17 on DCM.The results showed that protein expression and activity of ADAM17 were upregulated whereas the protein expression of ACE2 was downregulated in the myocardium of diabetic mice.Cardiomyocyte-specific knockout of ADAM17 mitigated cardiac fibrosis and cardiomyocyte apoptosis and ameliorated cardiac dysfunction in mice with DCM.Bioinformatic analyses detected a number of genes enriched in metabolic pathways,in particular the AMPK signaling pathway,expressed differentially between the hearts of A17^(α-MHCKO)and ADAM17^(fl/fl)diabetic mice.The mechanism may involve activated AMPK pathway,increased autophagosome formation and improved autophagic flux,which reduced the apoptotic response in cardiomyocytes.In addition,hypoxia-inducible factor-1α(HIF-1α)might act as an upstream mediator of upregulated ADAM17 and ADAM17 might affect AMPK signaling viaα1 A-adrenergic receptor(ADRA1A).These results indicated that ADAM17 activity and ACE2 shedding were enhanced in DCM,which was reversed by cardiomyocyte-specific ADAM17 knockout.Thus,inhibition of ADAM17 may provide a promising approach to the treatment of DCM.

An intersegmental single-cell profile reveals aortic heterogeneity and identifies a novel Malat1+vascular smooth muscle subtype involved in abdominal aortic aneurysm formation

The developmental origin,anatomical location,and other factors contribute to aortic heterogeneity in a physiological state.On this basis,vascular diseases occur at different ratios based on position specificity,even with the same risk factor.However,the continuous intersegmental aortic profile has been rarely reported at the single-cell level.To reveal aortic heterogeneity,we identified 15 cell subtypes from five continuous aortic segments by marker genes and functional definitions.

Vascular macrophages sense octanal and drive athero-inflammation

In a recent paper in Science,Orecchioni et al.identified the expression of olfactory receptor 2(OLFR2)and its human ortholog olfactory receptor 6A2(OR6A2)in vascular macrophages,which detects the compound octanal and activates the NLRP3 inflammasome,driving vascular inflammation and atherosclerosis progression[1].Their work provides new insights into the pathogenesis of atherosclerosis and suggests that inhibiting OR6A2 may represent a promising anti-inflammatory strategy to preventand treatat herosclerosis(Fig.1).

Amylin:new insight into pathogenesis,diagnosis,and prognosis of non-insulin-dependent diabetesmellitus-related cardiomyopathy

Co-secretion with insulin,highly amyloidogenic human amylin is considered to contribute to the initiation and progression of diabetic heart complications,despite other situations such as hypertension and atherosclerosis.In response to insulin resistance,hyperinsulinemia,and consequently hyperamylinemia,is common in prediabetic patients,where highly concentrated amylin is prone to form amylin oligomers,which further assemble into fibrils and amyloids with high b-sheet content.The infusion and deposition of oligomeric amylin in myocytes cause a series of consequences,including cytosolic Ca^(2+)dysregulation,calmodulin activation,myocyte hypertrophy,and ventricular stiffness,eventually leading to heart failure.In this review,we present the latest reports of amylin-related heart complications,provide new insights,and state the underlying pathogenesis,diagnosis,possible treatment,and prevention of diabetic cardiomyopathy.

Anti-inflammatory Therapy in Atherosclerosis:The Past and the Future

Since 1847 when Vogel,an eminent German pathologist,first observed that cholesterol was present in arterial plaques,[1]atherosclerosis(AS)has been regarded as a cholesterol storage disease characterized by a passive deposition of cholesterol in the artery wall.One decade later,Virchow,[2]a renowned pathologist,stated that AS is not really“a consequence of a fatty process but a direct product of inflammation”.

SUPER Score Contributes to Warning and Management in Early-Stage COVID-19

Background:Some COVID-19 patients deteriorate to severe cases with relatively higher case-fatality rates,which increases the medical burden.This necessitates identification of patients at risk of severe disease.Early assessment plays a crucial role in identifying patients at risk of severe disease.This study is to assess the effectiveness of SUPER score as a predictor of severe COVID-19 cases.Methods:We consecutively enrolled COVID-19 patients admitted to a comprehensive medical center in Wuhan,China,and recorded clinical characteristics and laboratory indexes.The SUPER score was calculated using pa-rameters including oxygen saturation,urine volume,pulse,emotional state,and respiratory rate.In addition,the area under the receiver operating characteristic curve(AUC),specificity,and sensitivity of the SUPER score for the diagnosis of severe COVID-19 were calculated and compared with the National Early Warning Score 2(NEWS2).Results:The SUPER score at admission,with a threshold of 4,exhibited good predictive performance for early identification of severe COVID-19 cases,yielding an AUC of 0.985(95%confidence interval[CI]0.897-1.000),sensitivity of 1.00(95%CI 0.715-1.000),and specificity of 0.92(95%CI 0.775-0.982),similar to NEWS2(AUC 0.984;95%CI 0.895-1.000,sensitivity 0.91;95%CI 0.587-0.998,specificity 0.97;95%CI 0.858-0.999).Com-pared with patients with a SUPER score<4,patients in the high-risk group exhibited lower lymphocyte counts,interleukin-2,interleukin-4 and higher fibrinogen,C-reactive protein,aspartate aminotransferase,and lactate dehydrogenase levels.Conclusions:In conclusion,the SUPER score demonstrated equivalent accuracy to the NEWS2 score in predicting severe COVID-19.Its application in prognostic assessment therefore offers an effective early warning system for critical management and facilitating efficient allocation of health resources.

Measurement of left ventricular fluid dynamic parameters in healthy Chinese adults based on echocardiographic vector flow mapping

To the Editor:As we concerdered that there was barely any widely representative,recognized,and standardized echocardiographic vector flow mapping(VFM)method has been established for the observation and measurement of the blood flow in cardiac cavities in clinical practice,and there were no commonly accepted normal reference values for Chinese adults have been obtained till now,hindering the further promotion and application of this technology in clinical practice.Establishing normal reference values for echocardiographic VFM that can be widely accepted in clinical practice is of great significance for determining the normal or abnormal fluid dynamic status in the left ventricle(LV)chamber.

Vaspin alleviates pathological cardiac hypertrophy by regulating autophagy-dependent myocardial senescence

Background:Visceral adipose tissue-derived serine protease inhibitor(vaspin),a secretory adipokine,protects against insulin resistance.Recent studies have demonstrated that serum vaspin levels are decreased in patients with coronary artery disease and that vaspin protects against myocardial ischemia-reperfusion injury and atherosclerosis.However,it remains unclear whether vaspin exerts specific effects on pathological cardiac hypertrophy.Methods:An in vivo study was conducted using a cardiac hypertrophy model established by subcutaneous injection of isoproterenol(ISO)in C57BL/6 and vaspin-ko mice.Rapamycin was administered intraperitoneally to mice,for further study.H9c2 cells and neonatal rat ventricular myocytes(NRVMs)were treated with ISO to induce hypertrophy.Human vaspin fusion protein,the proteasome inhibitor MG132,and chloroquine diphosphate were used for further mechanistic studies.Results:Here,we provide the first evidence that vaspin knockdown results in markedly exaggerated cardiac hypertrophy,fibrosis,and cardiomyocyte senescence in mice treated with ISO.Conversely,the administration of exogenous recombinant human vaspin protected NRVMs in vitro against ISO-induced hypertrophy and senescence.Furthermore,vaspin significantly potentiated the ISO-induced decrease in autophagy.Both rapamycin and chloroquine diphosphate regulated autophagy in vivo and in vitro,respectively,and participated in vaspin-mediated cardioprotection.Moreover,the PI3K-AKT-mTOR pathway plays a critical role in vaspin-mediated autophagy in cardiac tissues and NRVMs.Our data showed that vaspin downregulated the p85 and p110 subunits of PI3K by linking p85 and p110 to NEDD4L-mediated ubiquitination degradation.Conclusion:Our results show,for the first time,that vaspin functions as a critical regulator that alleviates pathological cardiac hypertrophy by regulating autophagy-dependent myocardial senescence,providing potential preventive and therapeutic targets for pathological cardiac hypertrophy.