In the acute phase of ST-elevation myocardial infarction (STEMI) viability imaging techniques are not validated and/or not available.This study aimed to evaluate the ability of strain parameters assessed in the acute phase of STEMI, to predict myocardial viability after revascularization.Thirty-one STEMI patients whose culprit coronary artery was recanalized and in whom baseline echocardiogram showed an akinesia in the infarcted area, were prospectively included. Bidimensional left ventricular global longitudinal strain (GLS), and territorial longitudinal strain (TLS) in the territory of the infarct related artery were obtained within 24 hours from admission. Delayed enhancement (DE) cardiac magnetic resonance imaging (CMR) was used as a reference test to assess post-revascularization myocardial viability. DE-CMR was performed 3 months after percutaneous coronary intervention. According to myocardial viability, patients were divided into 2 groups; CMR viable myocardium patients with more than half of infarcted segments having a DE <50% (group V) and CMR nonviable myocardium patients with half or more of the infarcted segments having a DE >50% (group NV).P = .002 and −11.0 ± 4.1 vs −3.2 ± 3.1, P = .001). GLS was correlated with DE-CMR  and a cut off value of −13.9% for GLS predicted viability with 86% sensitivity (Se) and 78% specificity (Sp). TLS showed the strongest correlation with DE-CMR . A cut off value of −9.4% for TLS yielded a Se of 78% and a Sp of 95% to predict myocardial viability.GLS and TLS were lower in group V compared to group NV (respectively: −14.4% ± 2.9% vs −10.9% ± 2.4%, GLS and TLS measured in the acute phase of STEMI predicted myocardial viability assessed by 3 months DE-CMR. They are prognostic indicators and they can be used to guide the priority and usefulness of percutaneous coronary intervention in these patients. This strategy aims to restore the coronary flow and myocardial perfusion and, consequently, to recover myocardial contractile function. For prognostic and therapeutic purposes, it is important to predict whether myocardium with severe kinetic dysfunction in the acute phase of STEMI is irreversibly necrotic or reversibly stunned.,2 Delayed enhancement cardiac magnetic resonance imaging (DE-CMR) is currently the criterion standard for myocardial viability assessment. Apart from the problem of its immediate unavailability, DE-CMR was mainly validated in chronic ischemic disease, and its validity in the acute phase of STEMI is not established.Conventional echocardiography with visual assessment of regional and global myocardial function is not able to predict viability.,5 It has been recently suggested that 2D strain in acute coronary syndrome can predict later myocardial viability.Bidimensional (2D) strain is a key predictor of left ventricular (LV) remodeling and prognosis after STEMI. 2D strain also showed a good correlation with DE-CMR in chronic ischemic disease for viability assessment.Our aim was to evaluate the ability of 2D global longitudinal strain (GLS) of the LV and territorial longitudinal strain (TLS) measured in the acute phase of STEMI, to predict later myocardial viability after revascularization assessed by DE-CMR performed at 3 months.2The study was prospective, monocentric conducted in consecutive patients admitted to the intensive care unit of our teaching hospital between January and April 2019. It was approved by the institutional ethics committee.2.1Patients were enrolled after they provided an informed consent. We included adult patients (≥18 years) hospitalized for a first STEMI episode whose echocardiography showed an akinetic myocardial area and whose culprit coronary artery was recanalized. Exclusion criteria were previous (known or identified by baseline echocardiography) STEMI, non-STEMI, or chronic ischemic myocardial disease, the absence of akinesia in the infarcted territory, the absence of recanalization of the culprit artery, a complete left bundle branch block, an atrial fibrillation, and an implanted pacemaker or automated defibrillator device.2.2 Parietal kinetic assessment was performed visually in apical 4, 2, and 3 chamber views and parasternal long-axis and short-axis views. We used a 17 segments LV model and a score was attributed to each analyzed segment; 1 = normal, 2 = hypokinetic, 3 = akinetic and 4 = dyskinetic. The wall motion score index (WMSI) was calculated as the average score of all analyzed segments. Three regional WMSIs were calculated by averaging the scores of segments in each of the 3 coronary artery distribution areas; the left anterior descending (LAD) artery area, the circumflex artery (Cx) area and the right coronary artery (RCA) area.An echocardiography was performed by the same experienced operator in all patients within 24 hours of admission. Echocardiograms were realized on a General Electric Vivid E9 machine equipped with a 2.5 to 5 MHz variable frequency phased array transducer. Cardiac chambers’ quantifications followed the American Society of Echocardiography and the European Association of cardiovascular imaging guidelines.Two-dimensional strain analysis was performed on gray scale acquisitions in 4, 2, and 3 chamber views, centered on the LV with an image rate between 60 and 80 per second. An automated function imaging software, available on the echocardiography machine, allowed the measurement of segmental and GLS. TLS was calculated by averaging manually strain values of segments related to the same coronary artery. By analogy to regional WMSI we obtained three territorial strain values; TLS LAD, TLS Cx and TLS RCA.2.3CMR images analysis were performed concomitantly by two experienced radiologists who were blind to echocardiographic findings. Baseline magnetic resonance images were acquired using a Philips Ingenia 1.5 T system with Intellispace 6 console. For DE-CMR analysis, a 17-segment LV model was used. The protocol included short-axis and 4-chamber cine acquisitions, black blood sequences weighted in T2 and/or short tau inversion recovery in short-axis, first-pass dynamic perfusion sequence or early gadolinium enhancement (within the first 1–3 minutes after contrast infusion) to look for a microvascular obstruction indicating a no reflow, and late gadolinium enhancement (15 min after contrast infusion) using phase-sensitive inversion recovery sequences technique for the determination of transmurality. A myocardial territory was qualified as viable when more than half of its segments had a DE ≤50% and nonviable when half or more of its segments had a DE >50%.The cut off value of 50% of DE was considered to define segmental myocardial viability.2.4 The echocardiographic examination, as described above, was performed in all patients in the acute phase and repeated at 3 months. All patients had a 3 months clinical follow-up. DE-CMR was performed at 3 months after STEMI occurrence.For each patient data were collected prospectively, including clinical, echocardiographic, and angiographic data, as well as percutaneous coronary intervention (PCI) course were recorded. Intrahospital complications were reported. Major cardiovascular events included death, resuscitated cardiac arrest, cardiogenic shock, myocardial infarction, and stroke. PCI results were assessed by the thrombolysis in myocardial infarction score in the culprit vessel.Substudy groups, group V (viable) and group NV (nonviable), were defined according to viability assessment of the myocardial territory related to the culprit coronary artery by DE-CMR.2.5U test, and for correlation assessment we calculated Spearman coefficient. A P value <.05 was considered statistically significant. Sensitivity (Se) and specificity (Sp) for prediction of myocardial viability was determined by performing receiver operating characteristic curve analysis. The value of the variable with the best Se-Sp couple was chosen as the cut-off value, 95% confidence intervals of its Se and Sp were calculated.A statistical software SPSS 22.0 was used. Categorical variables were expressed in numbers and percentages. Quantitative variables were expressed in means and standard deviations. Comparisons of quantitative variables between the 2 groups were made using the Mann-Whitney 33.1Figure Table 3.2P = .008). The early gadolinium enhancement images were assessed in 27 patients, microvascular obstruction (no reflow) was only found in group NV, in 15 patients (P = .001).Among 527 segments evaluated, 94 (17.83%) were nonviable. Nine patients (29%) had a viable myocardium in the territory of the culprit artery (substudy group V) and 22 patients (71%) had a nonviable infarcted myocardial territory (substudy group NV) (Table 3.3P = .02). At 3 months, LVEF remained higher in group V (P = .001). Regional WMSI in the culprit artery territory was lower in group V at baseline and at 3 months. Segmental strain was achieved in 518 (98.3%) segments. Global and Territorial strain measures were obtained in all patients. Strain parameters were better in group V at baseline echocardiography  for GLS and  for TLS. These 2 parameters showed a greater improvement at 3 months in group V, which was for GLS  and for TLS .Table P = .19). Similarly, regional WMSI in the culprit artery territory was not correlated with DE-CMR (P = .08).As shown in Table r = .54, P = .002). A cut off value of −13.9% for GLS predicted viability with 86% Se and 78% Sp . A cut off value of −9.4% for TLS predicted viability with 78% Se and 95% Sp, whereas a cut off value of −5.5% for TLS predicted nonviability with 89% Se and 77% Sp. Extreme values of TLS >−2.5% predicted nonviability with 100% Sp.TLS showed the best correlation with DE-CMR .4.1 and it is currently used as a criterion standard. The use of DE-CMR for viability assessment was on the contrary, very limited during the acute phase of STEMI. In this setting CMR is rarely available and was not validated due to frequent false positives. Indeed, parietal edema in the acute phase of STEMI led to an overestimation of the infarct size by including parts of the area at risk. Gadolinium retention was caused by to a change in extracellular volume due to the rupture of cardiomyocyte membrane and to a slowing of its clearance. All these factors skewed the assessment of myocardial viability and led to inappropriate therapeutic strategies. In our study, DE-CMR was performed 3 months after the STEMI episode to ensure an accurate assessment of myocardial viability.Among CMR techniques of viability assessment in patients with chronic LV dysfunction due to coronary artery disease, DE-CMR had a high sensitivity (95%) and a high negative predictive value,4.2,13 Sciagra et al evaluated 48 patients with STEMI who were treated with primary PCI. The assessment of the viability of the infarcted zone with low-dose dobutamine echocardiography at 3 days allowed prediction of LV function improvement at 6 months. In another cohort of 300 STEMI patients, it was demonstrated that viability assessed by low-dose dobutamine echocardiography performed in the early phase, was associated with a better 9 months survival.Early recognition of viable myocardium has clinical relevance, because only viable segments have the potential of functional recovery with improved clinical outcome.4.3 Several studies demonstrated that, in acute coronary syndromes, LV dysfunction is potentially reversible, related to myocardial stunning, myocardial hibernation, or a combination of these 2 processes; therefore, LV function may improve after revascularization confirming myocardial viability. If this reversibility is predicted by baseline LVEF is however questionable. In our study, LVEF was not significantly correlated with DE-CMR (P = .19). This result corroborated those of previous studies that did not found a significant relationship between baseline LVEF and 1-year functional recovery.LV function assessed by 2D echocardiography is among the most important determinants of prognosis in STEMI patients and it contributes to therapeutic decisions. In our study, we did not find a significant correlation between WMSI and DE-CMR viability (P = .08). It was previously reported in patients with a first anterior STEMI who were revascularized, that a lower WMSI was a predictor of contractile recovery, but this result was assessed by an echocardiographic follow-up without a reference method for viability assessment.Concerning WMSI, it was found in some studies to be more accurate than LVEF for morbidity and mortality prediction after an ACS.4.4,5 but few studies evaluated the usefulness of 2D strain to predict viability when assessed at the acute phase of STEMI, even if the prognostic value of this parameter was widely demonstrated. In fact, GLS was a strong predictor of LV remodeling and adverse events such as congestive heart failure and death. In chronic ischemic myocardial disease, a cut off value of −13% for TLS, performed 9 months after a first STEMI, identified a transmural infarction assessed by DE-CMR with 80% Se and 83% Sp.Myocardial deformation estimation by either tissue Doppler or speckle tracking 2D strain predicted accurately viability in patients with chronic ischemic LV dysfunctionIn an acute setting, in STEMI patients, we found a correlation between baseline GLS and 3 months DE-CMR and we identified a cut off value of −13.9% to predict viability with 86% Se and 78% Sp, and we found that TLS was a better parameter for viability prediction, a cut off value of −9.4% for TLS predicted viability with a Se of 78% and a Sp of 95%. found also a good correlation between infarct size and GLS in a population of 61 NSTEMI in comparison with 9 ± 3 months DE-CMR and a cut off value of −13.8%, close to our finding, identified patients with a transmural infarction. In a meta-analysis published in 2017 that pooled 11 prospective randomized studies led in patients after a first myocardial infarction (N = 765) either STEMI (6 studies) or non-STEMI (2 studies) or both (3 studies), it was reported a significant correlation between 2D GLS and DE-CMR . GLS predicted an infarct size >12% with a Se of 77% and a Sp of 86%. It should be noticed that in this meta-analysis, only in 3 studies–25 that enrolled respectively 30, 39, and 44 patients, strain assessment was performed in the early phase of STEMI by Doppler imaging or by speckle tracking imaging.,25 The other studies either did not include STEMI patients or reported late assessment of strain, beyond the acute phase. In the 2 more recent and largest studies that used speckle tracking 2D strain,,25 all patients had a primary PCI, and strain was assessed after revascularization. The presence of an akinesia at baseline echocardiogram was not a required inclusion criterium. This can explain the different strain cut off values identified and the more frequent nonviable myocardium in our series. Indeed, our study not only targeted a prognostic assessment but also suggested a guiding of the therapeutic strategy based on strain in patients with borderline indications to PCI. Furthermore, if these 3 studies reported a significant correlation between GLS and 3 or 9 months DE-CMR, in agreement to our findings, none of them reported results with TLS, which had a stronger correlation with DE-CMR in our study.Eek et al GLS provided also an accurate assessment of transmurality, but corroborating our results, they found that the best correlation with DE-CMR was obtained with the regional strain and a cut off value of −12% for TLS identified enhanced areas with 82% Se and 78% Sp.For Cimino et al The cut off value of −13% for GLS, identified large infarct size with 66.7% Se and 88.4% Sp. The authors found also that for TLS, a cut off value of −9.6% predicted viability with a 94% Se and 86% Sp. These results are close and perfectly corroborate our findings.Recently, a study led in 100 patients with anterior STEMI treated with primary PCI demonstrated that baseline GLS could predict infarct size.4.5This prospective cohort study was in favor of a good correlation between early 2D strain and later DE-CMR in STEMI patients. TLS was a strong predictor of myocardial viability. These findings can guide the revascularization strategy in STEMI patients along with a global clinical assessment, this can be important in frail elderly patients, patients with acute renal failure and late revascularizations. Particularly for these patients, we suggest to:-Target by revascularization patients with very likely myocardial viability (TLS <−9.4%)-Discuss revascularization on a case-by-case basis for borderline patients with a TLS between −9.4% and −5.5%.-Avoid unnecessary revascularizations when viability is very unlikely (TLS >−5.5%), and thus avoid potential iatrogenic complications and unnecessary expenditure.4.6First, the number of patients included was not high but despite this our results were statistically significant. Moreover, we did not include patients with ventricular stimulation and left bundle branch block to avoid misinterpretations of strain and visual kinetic assessment. These patients, however, could represent a specific target population of such studies, because STEMI diagnosis and management are more difficult in them. Finally, the calculation of the TLS was based on a theoretical coronary distribution and we did not consider anatomical patients’ particularities, especially the coronary dominance.5In the acute phase of STEMI, 2D strain parameters GLS and TLS can accurately predict post-revascularization myocardial viability, which could help prognosis assessment and therapeutic strategy guiding.The authors acknowledge Pr Zouari Bechir for verifying all the statistical analysis.Dr Mghaieth Zghal was the echocardiography operator, main investigator of the study and main author of the manuscript. Dr Boudiche, Dr Haboubi and Dr Mechri gathered clinical and angiographic data and performed statistics, Dr Ben Halima, Dr Rekik and Dr Ouali performed bibliography research, contributed to the writing of the parts of the manuscript, and helped in language corrections they also gave deep revision remarks. Dr Hantous and Dr Neji performed CMR, and wrote CMR protocol, results ans discussion. Dr Mourali validated the protocol of the research, and gave overall deep revision of the manuscript.


Arrhythmias are common in cardiac amyloidosis and vary based on the amyloidosis type. Conduction defects and atrial arrhythmias are more prevalent in transthyretin amyloidosis compared with light chain amyloidosis, and this difference might be a reflection of the longer survival time in the former. This review summarizes the available literature on arrhythmias in this increasingly recognized form of cardiomyopathy and raises the importance of performing systematic data collection to improve outcomes. Therapy is primarily aimed at managing plasma cell dyscrasia using chemotherapy or stem cell transplantation.Amyloidosis is a collection of diseases characterized by extracellular deposition of the fibrillar proteinaceous material, amyloid, in tissues and organs. Amyloid can be formed from several precursor proteins that misfold into toxic oligomers, which then aggregate with proteoglycan and serum amyloid proteins to form amyloid infiltrates. The vast majority of cardiac amyloidosis (CA) is caused by one of two proteins: light chain or transthyretin (TTR). Light-chain (AL) amyloidosis is a hematological disorder of proliferation of an abnormal plasma cell clone that overproduces lambda or, less commonly, kappa light chains. The abnormal circulating light chains form amyloid that can affect multiple organs.2 There are two types of TTR-related amyloidosis. One is ATTR wild-type (ATTRwt), in which amyloid from normal TTR protein is deposited over a period of decades. ATTRwt has a strong male predilection, and patients typically present between the ages of 60 years and 95 years with carpal tunnel syndrome preceding cardiac involvement. Because of its late presentation, ATTRwt is also referred to as senile amyloidosis. The second type of ATTR is due to mutant TTR (ATTRm) causing familial amyloidosis; patients are generally born with a pathological mutation in the TTR gene, resulting in accelerated breakdown of TTR to amyloid. Over 80 different amyloidogenic missense point mutations have been described. Val-30-Met is the most common pathogenic mutation globally and is the leading cause of familial amyloid polyneuropathy. Another important mutation, Val-122-Ile, is seen in 3% to 4% of African Americans and is the most common mutation leading to familial CA. Patients with ATTRm present at an earlier age (40 to 75 years) than those with ATTRwt and demonstrate a slight male predominance. The clinical manifestation of ATTRm is driven by the specific mutation, with phenotypes ranging from exclusive neurological involvement to CA with overlapping patterns; however, most affected patients have some degree of multisystem involvement.3 Chemotherapy has no role in ATTR. Clinical trials of various therapeutic agents that modify or inhibit amyloid fibril formation are in progress. Prognosis for ATTR is generally better than that for AL amyloidosis.4 CA can also occur in secondary amyloidosis resulting from chronic inflammation, but this is rare, occurring in only 2% of cases .TTR is a pre-albumin produced by the liver and functions as a transporter of thyroxine and retinol in its normal tetrameric form. The monomeric form of TTR tends to misfold to produce amyloid fibrils that are deposited in tissues. Amyloidosis resulting from TTR is termed ATTR.6 Bone-seeking radioisotopes have a high sensitivity for ATTR and are useful for the detection of subclinical CA when the MRI and ECG may still be unrevealing. 99mTc-pyrophosphate for myocardial imaging is readily available and is currently the tracer of choice for the diagnosis of TTR CA. It is also useful for differentiation from AL CA as there is minimal or no myocardial uptake of the tracer in AL CA.7 Endomyocardial biopsy typically shows deposition of amyloid in the extracellular and perivascular spaces that can be specifically stained with sulfated Alcian blue The cardiac manifestations of amyloidosis include marked left ventricular (LV) thickening (due to amyloid fibril deposition) with electrocardiogram (ECG) voltage that is disproportionately low for the degree of LV thickening and associated diastolic (rather than systolic) heart failure. Clinical examination and echocardiography show restrictive cardiomyopathy features. Cardiac arrhythmias are common and are an important cause of morbidity and mortality. Diagnosis is based on imaging studies and biopsy. Cardiac magnetic resonance imaging (MRI) shows increased extracellular volume on T1 imaging, as well as patterns of late gadolinium enhancement in later stages.9Cardiac involvement is invariable in ATTRwt. In the familial TRR amyloidoses , the prevalence of CA varies with the specific mutation. AL amyloidosis may have minimal or severe cardiac involvement, with 50% of patients showing CA. Regardless of the cause of amyloid production, CA is characterized by extracellular amyloid deposition throughout the heart, including the cardiac conduction tissue and valves. The ventricles are non-dilated and thickened, with restrictive filling. Elevated filling pressures result in atrial dilation despite atrial wall thickening from amyloid deposition. Atrial arrhythmias and loss of atrial mechanical function with atrial thrombus formation are important risk factors for cardioembolic stroke.10 Patients with CA occasionally report angina-type chest pains. Persistent cardiac troponin elevation is a feature of AL CA and, to a lesser extent, of ATTR. This increase in troponin may represent myocardial ischemia from small vessel occlusion or direct toxic effects of AL light chains. AL amyloid has been demonstrated to impair myocyte function and calcium release by increasing oxidative stress.11 In a zebrafish model, injecting AL light chains isolated from AL cardiomyopathy patients impaired cardiac function and led to cell death.12 Thus AL amyloidosis is a toxic, infiltrative cardiomyopathy. Inflammatory cell damage and separation of myocytes by amyloid fibrils would explain conduction abnormalities, atrial arrhythmias, and loss of atrial contractility. In the ventricles, non-sustained ventricular tachycardia (VT) is the most common form of arrhythmia. Sustained monomorphic VT is uncommon, as most unexpected lethal ventricular arrhythmias are due to polymorphic VT or ventricular fibrillation (see later).The histology of CA is amyloid infiltration of the extracellular spaces separating and distorting the myocardial cells. Myocardial scarring and patchy fibrosis that are typical of chronic ischemic cardiomyopathy or other non-ischemic cardiomyopathies are not described in CA. Hence, the exact mechanism of arrhythmias in CA is less well defined and is likely to be multifactorial. Small vessel disease due to perivascular amyloid infiltration associated with impaired vasodilation is a likely substrate for myocardial ischemia, especially in AL.13 Conversely, AL amyloidosis has a high mortality rate once cardiac involvement becomes apparent. Several adverse prognostic indicators have been described, including elevated N-terminal pro-brain natriuretic peptide (NT-pro-BNP) and troponin levels, diastolic dysfunction on echocardiography, and the extent of extracellular volume and late gadolinium enhancement on MRI.14 In general, arrhythmia interventions are not likely to be beneficial in cases of severe cardiac involvement, as myocardial dysfunction leads to electromechanical dissociation, the predominant terminal event in patients with CA.TTR amyloidosis, especially ATTRwt, has a protracted course with a median survival of 60 months following presentation with heart failure symptoms.There are few systematic studies of electrophysiological abnormalities and arrhythmias associated with CA and their appropriate management. Most available data are based on case reports or series from single centers. The nature, incidence, and management of arrhythmias differ based on the type of amyloidosis and extent of cardiac involvement.15 An intracardiac electrophysiology (EP) evaluation of sinus node function in 25 patients with AL amyloidosis revealed normal sinus node function in 88% of those examined.16 Sayed et al. reported data from implanted loop recorders in 20 patients with Mayo stage III AL CA who were symptomatic with syncope or presyncope. Persistent sinus bradycardia with pauses requiring cardiac pacing was only detected in one patient.17The conduction system is affected in all forms of CA. Atrioventricular (AV) conduction delay or block is more common than sinus node disease: despite the high frequency of atrial involvement with amyloidosis, sinus node disease appears to be less common and relevant reports are mostly limited to isolated events in patients with ATTRm. In some reports, transient sinus node dysfunction occurred in association with autonomic dysfunction occurring spontaneously or during general anesthesia induction.18 However, the incidence of symptomatic AV block is higher in ATTR, possibly because these patients are older and have better survival. In our series of 18 patients with advanced CA who underwent EP studies primarily for supraventricular arrhythmias, the mean (± standard deviation) HV interval was 87 ± 27 ms, despite a relatively narrow QRS duration (119 ± 32 ms).18 Prolongation of the HV interval with preserved QRS duration is well recognized in CA 16Conduction defects in the His-Purkinje system are more common and are associated with symptomatic AV block. First-degree AV block is often due to a delay in the His-Purkinje system level with preserved conduction at the nodal level. EP studies show an abnormal His bundle–ventricular (HV) interval in most patients with AL and ATTR CA.19 Based on the known pathophysiology of CA and the high incidence of conduction abnormalities, the threshold for pacemaker implantation should be low to prevent recurrent syncope. Prophylactic pacemaker implants have been suggested for all patients with ATTR CA. However, the downside of transvenous pacemakers is the possibility of worsening tricuspid regurgitation due to endocardial leads that cross the valve, impinging on thickened tricuspid leaflets. The advent of leadless pacemakers might partially mitigate this problem.Approximately 25% to 35% of ATTRm and 45% of ATTRwt patients receive pacemaker implants. While cardiac pacing provides symptomatic relief, it does not change the overall prognosis.When the predominant rhythm is sinus, consideration should be given to atrial synchronized ventricular pacing, as maintenance of AV synchrony with atrial synchronized ventricular pacing may be important for maintaining cardiac output in the setting of diastolic dysfunction and preload dependence. A combination of peripheral vasoconstrictors and atrial pacing can be helpful in maintaining an adequate blood pressure in patients with severe autonomic neuropathy and chronotropic incompetence. When ventricular pacing is necessary, there is concern that dysynchrony from right ventricular (RV)-only pacing may cause further deterioration of ventricular function. Observations during echocardiography suggest improved cardiac output from biventricular pacing . However, there are currently no formal studies to support this premise.20 Arrhythmia is more common in ATTRwt due to the older age at presentation and the higher prevalence of age-related AF. In one series, 62% of patients with ATTRwt CA had AF.20 AF or AT is often highly symptomatic and poorly tolerated, mostly due to rapid ventricular rates and an irregular ventricular response that impairs ventricular filling and contractility. Given that atrial contractility is often diminished in CA, the loss of atrial contribution is less likely to be the mechanism for deterioration. Ventricular rate control can be difficult since β-blockers and calcium blockers are not well tolerated due to hypotension and their negative inotropic effects. Although digoxin is known to bind amyloid tissue and increase the risk of toxicity, its use in low doses is usually tolerated, although its role in rate control is limited. Amiodarone provides a good option for AF control and is fairly well tolerated when administered orally. Alternative drugs such as dofetilide can be useful for maintaining sinus rhythm when used cautiously with close monitoring of the QT interval. Anticoagulation is usually well tolerated and should be used for all atrial arrhythmias. If there is evidence for non-contractility of the atria, then there is a case to be made for anticoagulation even in sinus rhythm, as thromboembolism may occur with stasis of blood in the left atrium and appendage.21Atrial fibrillation (AF) or atrial tachycardia (AT) is common in CA, especially as the disease progresses. In a group of patients from Sweden with familial amyloid polyneuropathy, 20% had previously undetected atrial arrhythmias suggesting possible amyloid atriopathy, even in the absence of overt CA.18 This is likely due to amyloid deposition separating out the atrial myocyte bundles and creating a marked delay in intra-atrial conduction. In our series, left atrial voltage mapping revealed significantly lower voltages in amyloid patients compared with an age-matched patient population with persistent AF 18 However, ablation attempts to correct what is often interpreted as left atrial tachycardia on surface ECG often yield only limited success. Despite acute termination and restoration of sinus rhythm with ablation, the recurrence rate is high. In our series, the recurrence rate at one year was 83% for CA patients compared with 25% in the non-CA, persistent AF patient group.18 In addition, procedural complications are higher in CA patients with poor tolerance of fluid shifts and general anesthesia. Acute chronic renal failure and pulmonary congestion are common in the postprocedural period and may require lengthy hospitalization for correction.AF in amyloidosis tends to have longer cycle lengths and may appear organized.22 For ventricular pacing following AV nodal ablation, our practice is to aim for biventricular pacing or placement of the RV lead in the high septal or para-His regions to minimize further depression of ventricular function due to ventricular dysynchrony from RV pacing.When the heart rate is difficult to control, AV nodal ablation with ventricular pacing has the benefits of rate control and rate regularization that improve cardiac output and offer symptomatic improvement.23Isolated atrial amyloidosis due to atrial natriuretic peptide depositing as amyloid fibrils is seen in up to one-third of patients with persistent AF undergoing valve surgery and is unrelated to the atrial arrhythmias of generalized CA. Isolated atrial amyloidosis is a disease of the elderly, with a female preponderance.Postural hypotension resulting from autonomic dysfunction is a common finding in AL amyloidosis and a cause of syncope in this patient population. Diuretics tend to aggravate symptoms. Midodrine, an alpha 1 adrenergic stimulant, is often necessary in high doses to maintain blood pressure. The supine hypertension that is common with midodrine use is not seen in CA, so large doses can be employed without concern. Cardiac arrhythmias such as heart block and ventricular arrhythmias are more important causes of syncope and may be a harbinger of sudden death, but careful history taking and examination can often differentiate one from the other. Ambulatory monitoring and EP studies can be helpful, especially for the detection of infra-Hisian AV block. Atrial arrhythmias with rapid ventricular rates can cause a precipitous drop in cardiac output, resulting in syncope. In advanced CA, another mechanism for syncope is vasodilation with an inability to increase cardiac output due to poor contractility reserve. Patients may present with exertional syncope. Prophylactic midodrine prior to planned exercise can be helpful.24 In this study, mortality was high (88%), suggesting a patient population in a late stage of the disease. The incidence of sudden death was no different between those with and without non-sustained VT, implying little prognostic importance regarding the finding of non-sustained VT alone. In a more recent study with implanted loop monitors in 20 patients with AL CA, non-sustained VT was observed in only one transmission.17 In both studies, recorded sudden deaths were mostly associated with terminal bradycardia followed shortly by pulseless electrical activity.As end-stage heart failure is the major driver of fatality in CA, managing ventricular arrhythmias has assumed a lesser role in overall outcome. AL amyloid, with its more precipitous downward course after heart failure onset, has a higher incidence of ventricular arrhythmia compared with that of ATTR disease. However, there are few systematic studies on the prevalence of ventricular arrhythmias in CA available to date. In a study of 195 patients with AL amyloidosis, 24-hour Holter recordings revealed non-sustained VT in 27% of patients with advanced AL CA.18 Ventricular fibrillation storm provoked by monomorphic premature ventricular complexes of Purkinje origin was reported in two patients with possible AL amyloidosis, supporting the hypothesis of an inflammatory response to AL amyloid.25 Catheter ablation targeting the Purkinje fibers to trigger fibrillation is helpful in acute arrhythmia control.Monomorphic VT is occasionally inducible during EP study or is noted in patients with an implantable cardioverter-defibrillator (ICD), but it is an infrequent event in CA compared with other cardiomyopathies.24 Even in sudden death, the mechanism is commonly electromechanical dissociation from end-stage heart failure. As a result, there has been very little enthusiasm for the ICD in patients with CA. Arrhythmic sudden death is far more common in AL cardiomyopathy. However, the prognosis of AL amyloidosis with heart failure has historically been dismal, with survival lasting less than 12 months after diagnosis, representing a relative contraindication to ICD implantation. When life expectancy is greater than one year, secondary prevention ICD is a reasonable consideration, following a discussion of the risks and benefits. There is a tendency for a higher defibrillation threshold in patients with CA, but first shock efficacy is generally comparable to that reported in the SCD-Heart Failure Trial study.26 Primary prevention ICD implantation in CA patients is associated with a high rate of appropriate discharges for ventricular arrhythmias in AL patients  but does not translate to improved survivial.28 With improved treatment options for AL amyloidosis, it is time to revisit the issue of primary prevention ICDs. However, the prediction of risk for arrhythmic sudden death does not follow the available guidelines for other forms of heart disease. An ICD would be a reasonable consideration for unexplained syncope or recurrent episodes of non-sustained VT in the early stages of AL amyloidosis, when the levels of biomarkers such as troponin and NT-pro-BNP are low. Primary prevention ICD may also have a role in patients being considered for cardiac transplantation.The most frequent documented terminal event in CA is pulseless electrical activity or agonal bradycardia.http://www.arci.org). Early pacemaker implantation in patients at high risk for heart block may also serve as arrhythmia monitoring with respect to data gathering. With the high rate of pacemaker implantation in ATTR amyloidosis, a trial of biventricular pacing in patients with heart block is feasible and important to clarify the role of ventricular synchrony in this unique form of cardiomyopathy. In the more malignant AL amyloidosis, the role of ICDs has thus far been assessed largely in the later stages, when severe heart failure negates any benefit from defibrillation. ICD should be evaluated in the earlier stages of AL CA, when arrhythmic sudden death is likely to be a greater risk.A combined multicenter effort to define the cardiac arrhythmias associated with CA is essential to gauge the survival benefits from early antiarrhythmic prophylaxis in CA. The formation of the Amyloid Research Consortium is an encouraging move in this direction (There has been considerable progress in our understanding of amyloidosis pathophysiology and treatment in recent years. Drugs aimed at preventing new amyloid formation achieve very favorable responses in some patients, and formal trial results are awaited. Early diagnosis and management by experts are key to improving outcomes in CA. The disease can no longer be dismissed as a terminal illness with limited therapeutic options.


Hyperlipidemia is a common metabolic disorder and one of risk factors for cardiovascular disease. Clinical studies have shown that hyperlipidemia increases the risk of non-ischemic heart failure, while decreasing serum lipids can reverse heart dysfunction. Apart from indirectly affecting the function of the heart by promoting the development of atherosclerosis, hyperlipidemia also affects the systolic function and cardiac electrophysiological response of the heart directly, which may be related to gradual accumulation of cardiac lipids and consequent systemic oxidative stress, proinflammatory state and mitochondrial dysfunction. However, the mechanism underlying direct effects of hyperlipidemia on the heart are not fully understood. In this review, we provide an updated summary of recent experimental and clinical studies that focus on elucidating the mechanisms of the action of hyperlipidemia on cardiac function, the relationship between heart failure and serum lipids, and protective effects of lipid-lowering drugs on the heart. The exciting progress in this field supports the prospect of guiding early protection of the heart to benefit the patients with chronic hyperlipidemia and familial hyperlipidemia. Hyperlipidemia indicates abnormally elevated levels of lipids or lipoproteins in the blood due to abnormal fat metabolism or function, and it is caused by dietary disorders, obesity, genetic diseases such as familial hypercholesterolemia (FH) or other diseases such as diabetes . PatientA number of studies have shown that hyperlipidemia, in addition to well-known role in promoting atherosclerosis in the blood vessels, may directly affect the heart, leading to increased ischemia/reperfusion injury and weakened response to cardiac protective interventions such as ischemic preconditioning and post conditioning . In the Therefore, this review aimed to provide an updated summary of recent experimental and clinical studies that focus on elucidating the mechanisms of the action of hyperlipidemia on cardiac function, the relationship between heart failure and serum lipids, and protective effects of lipid-lowering drugs on the heart.2+-ATPase (SERCA), ryanodine receptors (RyR) and Na+/Ca2+ exchangers [A variety of lipids such as triglycerides (TG) and total cholesterol (TC), and high and low density lipoproteins  are involved in the regulation of microvascular function. Hypercholesterolemia decreases coronary blood flow reserve and capillary density, induces apoptosis of capillary endothelial cells and ultimately leads to impaired left ventricular (LV) function. It is advocated that hypercholesterolemia may have an impact on the change of membrane lipid bilayer, the regulation of intracellular calcium ions and isoform expression patterns of myosin heavy chain, making the myocardium more sensitive to exogenous damage  . In partchangers . Inhibitchangers . Converschangers . Uncouplchangers . Overexpchangers .Moreover, hypercholesterolemia may result in myocardial ultrastructure changes through several mechanisms Fig. . First, In FH patients, endocardial longitudinal strain (LS), myocardial LS, average LV LS and circumferential strain (CS) decreased significantly, and LDL-c levels were negatively correlated with LS and CS . In addiIn animal models of hyperlipidemia, HFHC diet induced cardiac fibrosis and LV diastolic dysfunction in SHRSP5/Dmcr rats . In miceIn conclusion, obesity and hyperlipidemia affect LV structure and function at early stage, and these effects are unrelated to myocardial ischemia and hypoxia caused by coronary heart disease, suggesting that serum lipids affect cardiac function independently of the vascular system, which partly explains high cardiovascular morbidity and mortality resulting from myocardial dysfunction in obesity and hyperlipidemia patients.2+ current, along with abnormal expression of gap junction protein and prolonged action potential duration (APD) and QTc interval [Obesity has been proven as an independent risk factor for arrhythmias in both clinical and experimental studies. Mice with dystrophemia had increased susceptibility to atrioventricular arrhythmia, sympathetic innervation, repolarization dispersion and Cainterval , 25. In interval . Taken t2+/calmodulin-dependent protein kinase II (CaMK II) not only regulates cardiac electrophysiology and structure, but also plays an important role in various types of arrhythmias [PPARγ is a crucial transcription factor that regulates lipid metabolism. PPARγ accelerates cellular fat absorption and is upregulated in the heart of patients with metabolic syndrome. Increased lipids and abnormal mitochondrial morphology were observed in the heart of PPARγ transgenic mice . Joseph hythmias . In parthythmias  .FH and high level of non-fasting triglycerides were reported to increase the risk of heart failure . HoweverP-oxyphosphatase 1 (PON1) can inhibit the oxidation of lipids such as LDL . InteresWhile statins are the most widely used lipid-lowering drugs, the positive effects of statins on the heart go far beyond reducing blood lipids. Furthermore, exploring pharmacological effects of lipid-lowering drugs on the heart may provide important insights into the mechanisms by which hyperlipidemia directly affect the heart. A recent large scale study confirmed that early initiation of lipid-lowering therapy could reduce the incidence of cardiovascular events . In factAtorvastatin improved cardiac function and inhibited LV remodeling in rats with heart failure, via the downregulation of the expression and enzyme activity of matrix metalloproteinase 2 and 9 . In addiFibrates are fibric acid derivatives that lower blood triglyceride levels and have been used for treating hypertriglyceridemia. Fenofibrate effectively prevented ischemia/reperfusion induced ventricular premature beats, ventricular tachycardia, and ventricular fibrillation in isolated rat hearts . BezafibRecently, medicinal plants have attracted more attention in order to screen active compounds with antioxidant and beneficial effects , 49. ForHyperlipidemia is a complex disease that affects heart structure and function even before atherosclerosis occurs. For a long time, the direct effects of serum lipids on cardiac function independent of atherosclerosis are not acknowledged. However, accumulating evidence from recent studies indicates that serum lipids could accumulate in the heart, induce oxidative stress and inflammatory cardiac fibrosis, decrease autophagy and microvascular density, and change the mitochondrial function of cardiomyocytes, making the myocardium vulnerable to damage and leading to cardiac dysfunction and electrophysiological changes. Notably, lowering serum lipid could effectively reverse early ventricular dysfunction and provide heart protection.However, lipid-lowering drugs have various effects and further studies are needed to focus on the direct effects of these drugs on the myocardium. In addition, the detailed mechanisms and signaling pathways by which lipids induce structural and functional disruption in the myocardium remain to be fully understood. In the clinical, people with hyperlipidemia have no obvious signs or symptoms, but cardiac structure and function may have begun to be damaged. Therefore, powerful diagnosis techniques should be developed to detect these changes at very early stage. Nevertheless, the exciting progress in this field supports the prospect of guiding early protection of the heart to benefit the patients with chronic hyperlipidemia and FH.


Moreover, baseline HR was negatively correlated with HA exposure-induced changes in HR  and CI . Following HA exposure, subjects with lowest tertile of baseline HR showed an increased HR , left ventricular ejection fraction (LVEF)  and mitral S′ velocity . However, subjects with highest tertile of baseline HR showed an unchanged HR, LVEF and mitral S′ velocity, but a decreased E′ velocity . Our findings indicate that baseline HR at sea level could determine cardiac responses to HA exposure; these responses were characterized by enhanced LV function in subjects with a low baseline HR and by reduced LV myocardial velocity in early diastole in subjects with a high baseline HR.High-altitude (HA) exposure has been widely considered as a cardiac stress, and associated with altered cardiac function. However, the characteristics of cardiac responses to HA exposure are unclear. In total, 240 healthy men were enrolled and ascended to 4100 m by bus within 7 days. Standard echocardiography and color tissue Doppler imaging were performed at sea level and at 4100 m. In all subjects, HA exposure increased HR  but decreased the stroke volume index (SVi) [35.5  vs. 32.9  ml/mThe online version of this article (10.1007/s10554-020-01769-w) contains supplementary material, which is available to authorized users. High-altitude (HA) exposure has been widely considered as a cardiac stress during short-term or prolonged periods at HA for the purposes of recreation, sports, work or military training. Well-adapted cardiac performance may facilitate oxygen delivery to tissues when no oxygen therapy is available. It has been well documented that the global systolic left ventricular (LV) and right ventricular (RV) functions are well preserved, but both ventricles show altered filling patterns, subendocardial systolic dysfunction, and the increase in mean pulmonary arterial pressure (mPAP) –3. NotabThe initial cardiac responses to acute HA exposure include the increase in heart rate (HR) and cardiac output (CO) but with no change in stroke volume (SV). However, after a few days of acclimatization (3–5 days), the CO begins to decrease and returns to baseline level with a higher HR and a lower SV . The incConsidering that tissue Doppler imaging (TDI) allows for the noninvasive determination of myocardial velocity in a shape-independent manner and may provide an exact evaluation for cardiac function , we condhttps://www.chictr.org.cn). All procedures and protocols were approved by the Clinical Research Ethics Board at the Army Medical University  (NO: 2012014) and conformed to the standards set by the Declaration of Helsinki. All subjects volunteered to participate in this study and gave written informed consent.A total of 240 healthy men who were born or permanently live at sea level  were recruited in Chongqing, China, and ascended to HA in succession from Yanggongqiao  to Litang  by bus with a stair-like journey within 7 days and finally arrived on July 9, 10, 11 and 12, 2013, respectively. Data collections were performed at SL and within 5 ± 2 h after arriving at 4100 m. Exclusion criteria were known malignant tumors, cardiovascular diseases, any chronic cardiovascular therapy, pulmonary diseases, liver and kidney dysfunction, hematologic diseases, history of HA exposure in the recent 6 months, history of angioedema, and psychiatric disorders. This study was registered under the Chinese Clinical Trial Registration  was calculated as 0.0061 × height (cm) + 0.0128 × weight (kg) − 0.1529). Resting HR was from electrocardiogram. Systolic blood pressure (SBP) and diastolic blood pressure (DBP) were measured with an Omron HEM-6200 (Japan) with the subject resting in a sitting position for at least 5 min. The oxygen saturation (SaO2) values were obtained from warmed hands from the fingertips with a pulse oximeter  after at least 10 min of rest.Age, height, body weight and smoking history were recorded. Body mass index (BMI) was calculated as weight (kg)/[height (m)]Two-dimensional, Doppler and tissue Doppler echocardiography were performed by registered sonographers by using CX50 ultrasound systems  as previously described . All ima2 + 10.The measurements were conducted according to the current guideline . The LV Tissue velocities were measured from the apical 4-chamber view in a standard manner through color TDI analysis in 147 randomly selected subjects as a subgroup. The systolic (S′) positive wave and early diastolic (E′) tissue velocities were measured at the center of the lateral walls from the mitral or tricuspid annulus from the average of three cardiac cycles Fig. . The E/eObserver reliability of main echocardiographic measurements was assessed in 20 randomly selected subjects. Interobserver variability was performed by two separate observers, and intraobserver variability was performed by the same observer at least 1 month apart. Both the intraobserver and interobserver variabilities were tested using the intraclass correlation coefficient (ICC) by Cronbach’s α.2 test. Statistical power calculations were evaluated , and more than 80% statistical power was achieved for detect significant differences between subgroups using a two-sided alpha of 0.05. All statistical tests were two-sided, and a p-value < 0.05 was statistically significant and was presented in bold in Tables.Statistical analyses were performed using SPSS 22.0 for Windows . Continuous variables were presented as either the mean ± standard deviation (SD) or median  according to their normality results from the Kolmogorov–Smirnov test. The differences between parameters at sea level and at HA were compared with paired t-tests or Wilcoxon rank–sum tests. Correlations were performed using linear regression. Trend tests were used for cross-group comparisons of continuous variables. Categorical variables were expressed as counts and percentages and analyzed using the χ2 level was decreased compared with the values at SL. The EDVi, and ESVi and the calculated SVi  were significantly reduced. Consequently, CI was unaltered. However, the LVEF was improved . Moreover, there were significant reductions in the mitral peak E-wave velocity, peak A-wave velocity and the E/A ratio. Furthermore, the mitral E′ was significantly reduced  but the mitral S′ was comparable before and after HA exposure. Therefore, the LV MPI was significantly increased but the LV filling index  was also decreased after HA exposure.The basic information of the participants, including age, height, weight, BSA, BMI, ethnicity, and smoking history is shown in Supplemental Table S1. As shown in Table Following HA exposure, the decrease in RV EDAi and the unchanged RV ESAi resulted in a significant reduction in RV FAC . Furthermore, there were significant reductions in tricuspid peak E-wave velocity, peak A-wave velocity and the E/A ratio, although the tricuspid S′ and tricuspid E′ remained unchanged. Consequently, the tricuspid E/E′ ratio was decreased. Nevertheless, the RV MPI and mPAP were significantly increased, and the percentage of subjects with functional TR increased from 56.3% to 80.0%. The calculated SPAP from TRV was also increased  , middle tertile HR (MT) and highest tertile HR (HT), and their baseline characteristics were summarized in Supplemental Table S1, which showed no significant differences. However, following HA exposure, the HR was significantly increased in the LT  and MT groups but not in the HT group; the ΔEDVi and ΔESVi, although the EDVi and ESVi for subjects at SL gradually decreased with increasing baseline HR. However, the calculated SVi, which was decreased in total subjects, was unchanged in the LT group but decreased in the MT and HT groups, and the CI increased in the LT group but decreased in the HT group  of the main cardiac structural and functional parameters for the intra- and inter-observer measurements are shown in Supplemental Table S2. All the measurements showed excellent or good agreements.In this study, we demonstrated that the baseline HR of subjects at SL was associated with the changes in HR and CI after HA exposure. The HR increased in the LT and MT groups but not in the HT group, and the SVi decreased in the MT and HT groups but not in the LT group; this resulted in an increase in CI in the LT group, an unchanged CI in the MT group and a decreased CI in the HT group. Furthermore, after acute HA exposure, the global LV systolic function and myocardial contractility were enhanced, and the LV myocardial velocity in early diastole was unchanged for subjects in the LT group; however, while the global LV systolic function and myocardial contractility were unaltered, there was a decline in LV myocardial velocity in early diastole for subjects in the HT group. Our findings indicated that the baseline HR of subjects at sea level could determine the cardiac responses to acute HA exposure, which are characterized by enhanced LV function in subjects with a low baseline HR and by reduced LV myocardial velocity in early diastole in subjects with a high baseline HR Fig. .Fig. 4CeThe reasons for the decline in SVi have been continuously debated for over 40 years, but the exact mechanisms involved are still not completely understood. Undoubtedly, HR, preload, afterload and ventricular function are the main determinants of SV . In this2 consumption during HA exposure, the elevated HR observed in patients with metabolic syndromes resulted in a deterioration of LV function via impaired LV filling and relaxation [2; however, an abnormal HR response in patients with nonobstructive coronary artery disease was usually associated with impaired cardiac function [Due to the shortening of the diastolic period, subjects with a high baseline HR showed lower ventricular filling at sea level than at HA, as described in the present study and by previous data . Howeverlaxation . In contlaxation . Indeed,function .HR, which is the most important determinant of myocardial oxygen consumption, plays a central role in the cardiac adaptation to sources of metabolic stress, such as hypoxia. The results from the Framingham heart study demonstrated that all-cause mortality increased by 14% for every increase of 10 bpm in the baseline HR, and subjects with a baseline HR > 80 bpm were significantly associated with a high risk of heart failure . In addiThe present observational study has some limitations. First, the enrolled participants were healthy young men, and whether the established results could be generalized to other types of individuals or circumstances  is still unknown. Second, due to its complex anatomy, imaging the right ventricle with echocardiography is not an ideal approach. However, the evaluations of the right ventricle in our study were based on the guidelines published by the American Society of Echocardiography , and magFor the first time, we demonstrated that the baseline HR of subjects at sea level could determine the cardiac responses to acute HA exposure, which were characterized by enhanced LV function in subjects with a low baseline HR and by reduced LV myocardial velocity in early diastole in subjects with a high baseline HR. Our findings provide novel insights into the cardiac responses to acute HA exposure, which could improve our understanding of the cardiac adaptations to acute HA hypoxia and guide our decision making for HA travels or work. Further investigations need to be performed to identify these effects in a larger population or in other types of subjects, such as patients with cardiovascular diseases.Supplementary file1 (DOC 47 kb)Supplementary file2 (DOC 59 kb)Below is the link to the electronic supplementary material.


Trimetazidine is a metabolic anti-ischemic agent, which increases the tolerance of cardiomyocytes to ischemia. However, few studies have explored the effect of trimetazidine on ventricular remodeling in coronary artery disease (CAD) patients undergoing percutaneous coronary intervention (PCI) with left ventricular hypertrophy (LVH).It is a randomized, placebo-controlled trial, and we propose to recruit one hundred and twenty-four CAD patients undergoing PCI with LVH during a 12-month period. They will be randomized to receive either trimetazidine (35 mg twice a day) or placebo in the following 12 months after PCI. Blood tests, echocardiography, symptom of angina and major adverse cardiovascular events (MACEs) will be collected at follow-up visit at 3 and 12 months. The primary end point will be the left ventricular remodeling measured by left ventricular mass index (LVMI) at 3- and 12-month follow-up compared with the baseline. The secondary end points will be the symptom of angina assessed by Seattle Angina Questionnaire, myocardial ischemia measured by 6-min walk test and exercise electrocardiography test, as well as MACEs .This study aims to demonstrate the effect of trimetazidine on left ventricular remodeling and myocardial ischemia in CAD patients undergoing PCI with LVH. Trimetazidine treatment is likely to improve the left ventricular remodeling, symptoms of angina and myocardial ischemia. It might also reduce the risk of MACEs in CAD patients undergoing PCI with LVH.ChiCTR1800017876). Registered on 19 Aug 2018.http://www.chictr.org.cn, Chinese Clinical Trial Registry ( Coronary artery disease (CAD) has become the second leading cause of death after malignant tumor in China, with the prevalence of 6.46% , 2. LeftBesides, microvascular dysfunction is a recognized feature of hypertrophic cardiomyopathy and it may exacerbate myocardial ischemia in CAD patients . AlthougThis prospective randomized trial is therefore designed to explore whether trimetazidine can improve ventricular remodeling in CAD patients with LVH, as well as trying to investigate whether trimetazidine treatment can reduce major adverse cardiovascular events (MACEs). This study is to provide evidence for further clinical application of trimetazidine in CAD patients undergoing PCI with LVH.It is the first prospective, placebo-controlled study to explore the relationship between trimetazidine and ventricular remodeling. CAD patients undergoing PCI with LVH will be randomized to receive trimetazidine (35 mg twice a day) or placebo for 12 months after PCI. Coronary intervention and other medication therapy will be performed according to current guidelines, and no difference in the use of angiotensin-converting enzyme inhibitor (ACEI), angiotensin receptor blocker (ARB) and aldosterone antagonist should be ensured between the two groups. The web-based randomization will be used for a 1:1 ratio grouping to either trimetazidine or placebo. Secretary of department of cardiology accesses the website via account password and is responsible for randomization. Block randomization will be stratified by concomitant medications , sex and family history and it is blind to those who enroll participants or assign interventions. Blood biochemistry, echocardiography, Seattle Angina Questionnaire, 6-min walk test (6-MWT), exercise electrocardiography test and MACEs will be collected at the 3- and 12-smonth clinical follow-ups. All personal information will be converted to the new subject number. The attending physicians are responsible for data entry. Data monitoring committee is responsible for data security and accuracy. Committee members  have access to the final dataset and periodically range check for data values.The primary end point is the change of ventricular remodeling assessed by left ventricular mass index (LVMI) at 3- and 12-month follow-up after PCI compared with the baseline. The secondary end points will be the symptom of angina assessed by Seattle Angina Questionnaire, myocardial ischemia measured by 6-MWT and exercise electrocardiography test, as well as MACEs . Details of the proposed study, including enrollment and follow-up visits, are outlined in Table Chinese Clinical Trial Registry (ChiCTR1800017876). All patients will provide written informed consents before randomization.The trial protocol has been approved by the Institutional Ethics Committee of Sir Run Run Shaw Hospital of Zhejiang University (KY20180508–25) and has been registered in at The trial has been designed to investigate the hypothesis that trimetazidine treatment  could significantly improve the left ventricular remodeling, reduce the incidence of MACEs and effectively improve myocardial ischemia in CAD patients undergoing PCI with LVH. The primary objective is to validate that trimetazidine treatment could reduce LVMI and improve ventricular remodeling. The secondary objective is to validate that trimetazidine treatment could reduce the risk of MACEs, as well as improve the symptom of angina and myocardial ischemia.2 for men and women, respectively) at Sir Run Run Shaw Hospital of Zhejiang University will be enrolled in the trial. The enrollment period is expected to be finished in 2020. Detailed inclusion and exclusion criteria are listed in Table One hundred and twenty-four CAD patients undergoing PCI with LVH (LVMI > 120 and 100 g/mPatients’ demand to withdraw the informed consent.Study protocol violation (including poor compliance).Lost to follow-up.Pregnancy or new-onset malignant tumor during the follow-up.Detrimental to the patient’s well-being.Every participant will have the right to withdraw from the study without restriction, and participants may be removed ifEvery withdrawal will be recorded in the CRFs, and a visit will be arranged if possible.The study protocol is shown in Fig. 3-LVEDd3]-13.6 g.The primary end point in this study is the change between baseline and follow-up LVMI / body surface area). Two-dimensional and Doppler echocardiography will be performed to quantify left ventricular function and structure  . VentricThe secondary end points are the change the symptom of angina and myocardial ischemia, and the 3- and 12-month incidence of MACEs. The symptom of angina will be assessed at baseline, 3- and 12-month follow-up period by Seattle Angina Questionnaire. The improvement of myocardial ischemia and exercise capacity will be measured using exercise electrocardiography test and 6-MWT. The 6-MWT is a sample, low-cost method for estimating exercise capacity and will be performed according to standard procedures . ClinicaWenbin Zhang guides the research team and provides overall supervision for the trial. The data monitoring committee  is responsible for reviewing and monitoring data safety. Investigators have the right to reveal a participant’s allocated intervention or terminate the study in advance after discussion with Wenbin Zhang in the event of safety issues during the study as well as notify the ethics committee.According to previous study , we hypop-value < 0.05 will be considered significant. All statistical analyses will be performed using the Statistical Package for Social Sciences (SPSS), version 20.0 . The results will be published by chief investigator and major contributors.The final results will be presented on an intention-to-treat (ITT) basis. All data will be presented as percentages or mean ± standard deviation (SD). The comparison of data will be performed using the Chi-squared test  or Student’s t test (continuous variables). Cumulative incidences of end points in 12 months after PCI will be calculated using Kaplan-Meier methods. Log-rank tests will be used for comparisons between groups. Possible covariables will be incorporated in the analysis if certain important baseline levels are still not matched after randomization. Mean imputation will be used to handle missing data. A The study is the first investigator-initiated, prospective study to evaluate the treatment effect of trimetazidine on ventricular remodeling in CAD patients undergoing PCI with LVH. The result of the study will confirm whether trimetazidine improves ventricular remodeling, angina and myocardial ischemia.Cardiac hypertrophy is a common pathological change in cardiovascular diseases. In the early stage, it is an adaptive response of the heart to the overload. With the development of the disease, the myocardial structure will be disordered and the compliance will be decreased. The mechanism of CAD associated with LVH is a complex process involving multiple factors, such as blood pressure, catecholamine and renin-angiotensin-aldosterone system. It is characterized by hypertrophy of cardiomyocytes and changes in coronary microcirculation. Coronary microcirculation networks are the metabolic site of myocardium, and their lesions can cause the decline of coronary reserve function and the changes of myocardial ultrastructure, which are closely related to the maintenance of myocardial energy metabolism.Myocardial energy metabolism disorders occur prior to typical morphological changes in ventricular hypertrophy . During p = 0.046 at 1 month; and 4% vs. 16%, p = 0.017 at 3 months). A significant improvement in regional wall motion was noted after treatment with trimetazidine compared with placebo. Three months after PCI, inferior left ventricular wall hypokinesia had improved in 66.7% trimetazidine recipients and in 42.9% placebo recipients (p = 0.05), and anterior wall hypokinesia had improved in 72.7% in trimetazidine group and in 33.3% in placebo group (p = 0.04). However, the researchers only focused on the improvements for 3 months, long-term impact of trimetazidine on left ventricular remodeling in CAD patients undergoing PCI is still unclear. Subsequent Korean study suggested that trimetazidine treatment in non-ST segment elevation myocardial infarction (NSTEMI) patients provided improvements in left ventricular end diastolic volume [Previous study has showed trimetazidine minimizes myocardial reperfusion injury during PCI and improves global and regional wall motion at one and 3 months after PCI . In thisc volume . The adjc volume . NonetheThere were also studies in recent years exploring possible molecular mechanisms. The rat model of aortic constriction was established to induce myocardial metabolic disorder within 7 days, and it was found that trimetazidine pretreatment could improve the myocardial energy metabolism by reducing serum levels of oxidative stress markers, attenuating the induction of genes related to myocardial hypertrophy, inhibiting the up-regulation of serum neuropeptide Y (NPY) levels, and further increasing the expression of myocardial NPY receptors . This noOther researchers verified in vivo and in vitro that trimetazidine could effectively inhibit myocardial fibrosis through nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-reactive oxygen species (ROS)-connective tissue growth factor (CTGF) signaling pathway . Howeverp < 0.05) will be adjusted. But in addition to statistical considerations, we will also assess the relationship between the adjusted covariates and the end points, rather than unselectively adjust them.In our study, stratified randomization will be used to reduce the possibility of variable imbalance. Thus, no difference will exist in the use of ACEI, ARB and aldosterone antagonist between groups. Nonetheless, it is possible that some baseline levels are still not matched after randomization. In this case, we believe that it occurs “by chance” and is a small probability event. Those variables  on the ventricular remodeling in CAD patients with LVH. We expect that the study results will confirm whether trimetazidine treatment can significantly improve ventricular remodeling.


Background Paradoxical low-flow (LF) severe aortic stenosis (AS) with preserved left ventricular ejection fraction (LVEF) may have poorer prognosis than normal-flow (NF) AS, though its pathophysiology remained unclear. In particular, LV stiffness has not been compared between LF vs NF. We used a novel echocardiography-derived index of LV stiffness to compare between these groups. Consecutive patients with medically-managed isolated severe AS  and preserved LVEF (>50%) were studied. Echocardiographic LV stiffness index was measured by a method previously validated against cardiac catheterization. We compared LF  and NF severe AS. Of the 352 patients, 121 (34%) were LF. Both LF and NF groups had similar demographics, valve areas and indices. Compared to NF, LF severe AS had higher LV stiffness indices . Increased LV stiffness was associated with concentric remodelling and more severe diastolic dysfunction, especially in LF AS. An LV stiffness index of > 0.11 ml−1 was independently associated with increased mortality, after adjusting for age, clinical and echocardiographic parameters . Non-invasive echocardiographic-derived index of LV stiffness may be important in LF AS. Increased LV stiffness was related to LV concentric remodelling and diastolic dysfunction, and associated with poorer clinical outcomes in medically-managed AS. This is impractical for routine serial evaluation in AS as it requires invasive cardiac catheterization3.Significant differences in echocardiographic profiles exist between paradoxical low-flow (LF) and normal-flow (NF) severe aortic stenosis (AS). This may be due to differences in pathophysiological processes in the natural history of LF compared to NF AS. Of note, left ventricular (LV) stiffness has not been evaluated in AS. Conventional measurement of LV stiffness involves using invasive cardiac catheterization and determination of the end-diastolic pressure-volume relationship by pressure-volume loop analysis5. LF AS (LV stroke volume index (SVI) < 35 mL/m2) despite preserved left ventricular ejection fraction (LVEF), termed “paradoxical low-flow”, has been increasingly recognised as a subgroup of severe AS that portends a worse prognosis compared to normal-flow6. However, the differential effects of the aortic valve pathology on the LV in LF compared to NF AS, particularly LV stiffness, remains to be elucidated9.AS remains an important disease because of its high prevalence. It affects approximately 5% of patients over 75 years of age, and is associated with reduced survival12. These studies examined clinical, biochemical, and echocardiographic parameters14. For example, global longitudinal strain, valvuloarterial impedance, stroke work loss, aortic valve resistance, and systemic arterial compliance have been shown to be important prognostic markers of clinical outcomes in severe NF AS that predicted mortality18. However, these have not been demonstrated to be useful in paradoxical LF AS6.In addition, several studies have identified predictors of poor prognosis and outcomes in patients with severe ASLV stiffness remained to be evaluated to LF compared with NF AS, and prognostic markers in this subgroup of patients were poorly understood. We thus aimed to evaluate the role of an echocardiography-derived measure of LV stiffness in medically-managed LF versus NF severe AS.2) from 2000–2011 with preserved LVEF (>50%) that were on medical therapy. Patients who had concomitant valvular pathology involving other valves of at least moderate severity, and patients who underwent valve replacement  were excluded from our study. These patients may be asymptomatic or have either declined valve replacement or were deemed to be medically unfit for the procedures. The patients were then stratified into low-flow (SVI < 35 mL/m2) and normal-flow groups. This classification of AS severity was in accordance with the American Society of Echocardiography/European Association of Cardiovascular Imaging guidelines20. The LV outflow track (OT) diameter was measured at the parasternal long-axis view from inner edge to inner edge. The LVOT velocity was measured with pulsed Doppler from the apical view. The LVOT diameter and LVOT velocity measurements were performed at the same annular level19. All echocardiographic measurements were made by independent and certified cardiologists.We examined the index echocardiographic studies of consecutive patients with severe AS , early (E’) and late (A’) diastolic velocities was performed. Severity of diastolic function was graded according to the American Society of Echocardiography/European Association of Cardiovascular Imaging guidelines22. Important prognostic markers of severe AS that were previously identified were also assessed.All echocardiographic parameters were measured in accordance with the guidelines and standards of the American Society of Echocardiography/European Association of Cardiovascular Imaging3:LV stiffness was measured by means of a novel echocardiographic index, derived from the following equation2 for males and 104 g/m2 for females. The cut-off for RWT was 0.43 for both sexes. If RWT and LVMI were both below the cut-off points, then the patient had normal LV geometry. Patients with high LVMI but RWT < 0.43 were defined as eccentric hypertrophy. Patients with high RWT but LVMI below the cut-off were defined as having concentric remodelling. If both LVMI and RWT were above the cut-offs, then the patient was identified as concentric hypertrophy24.Patients were grouped based on four categories of LV geometry; determined by left ventricular mass index (LVMI) and relative wall thickness (RWT). The cut-off for LVMI was 116 g/mDifferences in continuous variables between groups were compared using Student’s t-tests. The association between LV stiffness index and diastolic function grade was assessed using Spearman’s rank correlation. Multivariable logistic regression was used to compare differences between LF versus NF AS. We entered baseline clinical and echocardiographic parameters that were statistically significant on univariate analyses (p < 0.05) into the multivariable model. Parameters that were collinear with SVI and the LV stiffness index were excluded.The optimized cut-off value for LV stiffness index for predicting all-cause mortality in the entire study population was determined by Youden index using receiver operating characteristic curve analysis. Differences in all-cause mortality between patients with low versus high LV stiffness were assessed using Kaplan-Meier curves and calculating the log-rank test statistic. A multivariate Cox regression model was then constructed to evaluate the effect of increased stiffness in predicting mortality and to adjust for other confounding parameters associated with mortality. We included all baseline clinical and echocardiographic parameters that were statistically significant on univariate analysis (p < 0.05), but excluded parameters that were collinear with the LV stiffness index. All statistical analyses were performed with SPSS for Windows, Version 20.0, SPSS Inc, Chicago, IL. A p-value of less than 0.05 was considered to be statistically significant.Ethics approval for this study was obtained from National Healthcare Group Domain Specific Review Board (DSRB) prior to the conduct of this study. The study was in compliance with all DSRB requirements based on the Declaration of Helsinki, ethical principles in the Belmont report and the guidelines stipulated by the Bioethics Advisory Committee. No patient identifiers were collected and a waiver for the need for informed consent was obtained from the DSRB.2) were significantly lower in the LF group  were low-flow, while the remaining 231 (66%) were normal-flow. The patients in the LF group were older (73.5 ± 13.8 vs 69.9 ± 13.5 years), but otherwise similar in terms of demographic background  compared to patients with normal-flow AS   was associated with older age, higher body mass index, lower left ventricular mass index and lower end-systolic wall stress. Prevalence of cardiovascular risk factors and comorbidities as well as degree of AS severity were similar  compared with low stiffness, patients with increased LV stiffness had significantly higher mortality  was demonstrated to be independently associated with increased mortality  after adjusting for age, body mass index, LV mass index and cardiovascular risk factors such as diabetes mellitus, hypertension and hyperlipidaemia  with high LV stiffness  patients with LF AS had higher LV stiffness than those with normal-flow AS, (2) increasing LV stiffness is related to concentric remodeling and hypertrophy, as well as more advanced diastolic dysfunction; and (3) AS subjects with increased LV stiffness had higher mortality than those with lower LV stiffness.13. Patients with LF AS tended to be older and have increased cardiovascular risk factors such as diabetes mellitus and hyperlipidemia. Understanding this subgroup of patients would therefore be important in the management of AS.Paradoxical LF AS has been shown to form a significant proportion (up to 30%) of Asian cohorts3. This parameter indexed the tissue Doppler assessment of diastolic function against the measured end-diastolic volume as a surrogate measure of LV stiffness. It has previously been employed to study patients with heart failure with preserved ejection fraction (HFpEF)2. Though LV stiffness has not been validated in the setting of LV pressure overload, this study proposes that the findings and application may be extrapolated to the AS population. A published study has shown that E/e’ ratio correlates with filling pressures in AS. The study demonstrated that E/e’ ratio was found to be the best single Doppler predictor of elevated filling pressures in patients with severe AS. The E/e’ ratio correlated significantly with LV pre-A pressures , and the LV end-diastolic pressure 23.This novel echocardiographic index to estimate LV stiffness has been evaluated and validated against the gold standard of cardiac catheterization with pressure-volume loop analysis25. In HFpEF, increased LV stiffness has been shown to be associated with symptoms of dyspnea and reduced exercise tolerance, and correlated with disease progression28.Indeed, for patients with AS, the high chronic afterload may lead to LV remodelling and fibrosis, resulting in increased stiffness and diastolic dysfunction. Increased LV stiffness from increased afterload had been previously shown in patients with essential hypertension as well as in HFpEF29. LV diastolic dysfunction, and subsequently indices of LV myocardial and chamber stiffness had been associated with symptomatic AS, especially dyspnea30. These findings had suggested that heart failure symptoms in severe AS were driven by high LV filling pressures consequent to LV hypertrophy and diastolic dysfunction31. The actual relationship between LV remodeling and diastolic filling however is highly complex, where both early relaxation and passive LV filling later in diastole have demonstrated important roles in the development of heart failure symptoms32.LV diastolic dysfunction has also been shown to be of increasing importance in severe AS. Prior studies had established the relationship between diastolic dysfunction and patients with severe AS with preserved LVEF35. True enough, we found increased LV stiffness in patients with LF compared to NF severe AS. As LV stiffness appeared to be a prominent feature in patients with LF AS, it may also be related to the development of symptoms such as dyspnea and reduced effort tolerance. In the context of severe AS, the development of such symptoms would be a Class I indication for aortic valve replacement36. Classically, patients with severe AS who develop dyspnea would have a median survival of 2 years, although whether this holds true for patients with LF severe AS remained unclear3. By comparison, patients with NF tended to have lower LV stiffness, and the correlation between increasing LV stiffness and increasing degree of diastolic dysfunction was not demonstrated in the NF group.We therefore postulated that a similar phenomenon described in HFpEF may also be observed in our population of patients with LF compared to NF severe AS38. This suggested that targeted therapy against LV remodeling in the form of beta-blockade (as used in heart failure) or renin-angiotensin blockade may be beneficial in LF AS to reduce harmful LV remodeling39.In our study, we observed that increasing LV stiffness is predominantly related to concentric remodeling and hypertrophy. This trend was most prominent in patients with LF AS. Furthermore, increasing LV stiffness was also associated with increasing diastolic dysfunction in LF AS. We postulate that LV stiffness in LF AS may be secondary to chronic sympathetic stimulation of the beta-adrenoreceptor, associated with higher plasma concentrations of brain natriuretic peptide (BNP), as evidenced by significant LV remodelling and diastolic dysfunction15 and thus had a limited role in prognosis for patients with LF severe AS with preserved LVEF16. The LV stiffness index appeared to be more useful for prognosis in the LF subgroup.The LV stiffness index also appeared to have prognostic value. Even after adjusting for age, body mass index, LV mass index and cardiovascular risk factors such as hypertension, hyperlipidaemia and diabetes, increased LV stiffness index remained independently associated with increased mortality. Regardless of flow-category, patients with higher stiffness showed significant higher mortality on subsequent follow-up. Other parameters conventionally used to predict outcomes in severe AS such as valvuloarterial impedance and systemic arterial impedance had been criticized to be highly flow-dependentWe therefore found that an echocardiographic parameter of LV stiffness has the potential to guide prognostication and management of patients with LF severe AS. This index may be more useful compared to other more flow-dependent indices and predictors which may be less reliable in LF AS. The pathophysiological process in LF AS with preserved LVEF may parallel that of HFpEF and other disease processes where increasing LV stiffness and diastolic dysfunction results in morbidity and mortality.39. Nevertheless, our findings remained hypothesis-generating, and the role of medical therapy in improving LV stiffness may be an important subject for future prospective studies with serial echocardiographic analyses.This study was retrospective and examined a moderately-sized cohort of index echocardiographic studies for patients diagnosed with isolated severe AS. It was however prospective in terms of clinical outcomes. As this was a cross-sectional study, there may have been lead-time bias as subjects were studied at different time points of the natural progression of AS. There was also no follow-up echocardiographic data, which may be useful in evaluating the progression of AS severity over time. Specific biomarkers such as brain natriuretic peptide could have been compared to the LV stiffness estimation, however this was not investigated in the present study. In addition, we did not evaluate the prognostic significance of LV stiffness in surgical management of severe AS. Although we did not examine the role of medical therapy on LV stiffness, renin-angiotensin blockade had previously been described to be associated with a lower prevalence of pathological LV remodelling in severe ASLV stiffness was demonstrated to be significantly higher in patients with LF AS, and this was related to the development of LV concentric remodelling, concentric hypertrophy and diastolic dysfunction. An increased LV stiffness index was associated with poorer mortality outcomes in medically-managed severe AS. This novel non-invasive echocardiographic estimation of LV stiffness may be an important prognostic tool in medically-managed AS.


Prophylactic implantation of a cardioverter/defibrillator (ICD) has been shown to reduce mortality in patients with chronic myocardial infarction (CMI) and an increased risk for life threatening ventricular arrhythmia (VA). The use of ICDs in this large patient population is still limited by high costs and possible adverse events including inappropriate discharges and progression of heart failure. VA is related to infarct size and seems to be related to infarct morphology. Contrast enhanced cardiovascular magnetic resonance imaging (ceCMR) can detect and quantify myocardial fibrosis in the setting of CMI and might therefore be a valuable tool for a more accurate risk stratification in this setting.ceCMR can identify the subgroup developing VA in patients with prophylactic ICD implantation following MADIT criteria.©, Germany) to assess left ventricular function (LVEF), LV end-diastolic volume (LVEDV) and LV mass . For quantitative assessment of infarct morphology late gadolinium enhancement (LGE) was performed including measurement of total and relative infarct mass (related to LV mass) and the degree of transmurality (DT) as defined by the percentage of transmurality in each scar. . MRI images were analysed using dedicated software . LGE was defined as myocardial areas with signal intensity above the average plus 5 SD of the remote myocardium. After implantation, patients were followed up including ICD readout after 3 and than every 6 months for a mean of 945 ± 344 days. ICD data were evaluated by an experienced electrophysiologist. Primary endpoint was the occurrence of an appropriate discharge (DC), antitachycard pacing (ATP) or death from cardiac cause.We prospectively enrolled 52 patients  with CMI and clinical indication for ICD therapy following MADIT criteria. Prior to implantation (36 ± 78 days) patients were investigated on a 1.5 T clinical scanner . These patients had a higher relative infarct mass  as well as high degree of transmurality . Their LVEF , LV mass , LVEDV  or total infarct mass  were however not significant from the group with no events. In a cox proportional hazards regression model including LVEF, LVEDV, LV mass, DT and age, only degree of transmurality and relative infarct mass emerged as independent predictors of the primary end point (p = 0.009)In CMI-patients fulfilling MADIT criteria ceCMR could show that the extent and transmurality of myocardial scarring are independent predictors for life threatening ventricular arrhythmia or death. This additional information could lead to more precise risk stratification and might reduce adverse events and cost of ICD therapy in this patient population. Larger trials are needed to confirm this finding.