A novel mouse model of calcific aortic valve stenosis

Background:Calcific aortic valve stenosis(CAVS)is one of the most challenging heart diseases in clinical with rapidly increasing prevalence.However,study of the mecha-nism and treatment of CAVS is hampered by the lack of suitable,robust and efficient models that develop hemodynamically significant stenosis and typical calcium deposi-tion.Here,we aim to establish a mouse model to mimic the development and features of CAVS.Methods:The model was established via aortic valve wire injury(AVWI)combined with vitamin D subcutaneous injected in wild type C57/BL6 mice.Serial transthoracic echocardiography was applied to evaluate aortic jet peak velocity and mean gradi-ent.Histopathological specimens were collected and examined in respect of valve thickening,calcium deposition,collagen accumulation,osteogenic differentiation and inflammation.Results:Serial transthoracic echocardiography revealed that aortic jet peak velocity and mean gradient increased from 7 days post model establishment in a time depend-ent manner and tended to be stable at 28 days.Compared with the sham group,sim-ple AVWI or the vitamin D group,the hybrid model group showed typical pathological features of CAVS,including hemodynamic alterations,increased aortic valve thicken-ing,calcium deposition,collagen accumulation at 28 days.In addition,osteogenic dif-ferentiation,fibrosis and inflammation,which play critical roles in the development of CAVS,were observed in the hybrid model.Conclusions:We established a novel mouse model of CAVS that could be induced efficiently,robustly and economically,and without genetic intervention.It provides a fast track to explore the underlying mechanisms of CAVS and to identify more effec-tive pharmacological targets.

Emergency Hybrid Correction in a Newborn with Critical Aortic Valve Stenosis with Acute Pulmonary Edema in the First Hour after Birth

Critical aortic valve stenosis in newborns is the cause of a severe clinical condition with the onset of symptoms during first hours after birth.We present a clinical case of a successful surgical correction of a critical aortic stenosis using a hybrid method applied in a newborn during the first day of life.The infant was diagnosed with a hypoplastic left heart complex with an intact atrial septum(aortic and mitral valves stenosis variant),that led to the cardiogenic shock and acute pulmonary edema.The procedure included bilateral banding of the pulmonary artery branches and atrioseptostomy with stenting of the interatrial septum.The surgery was performed through a median sternotomy.

Aortic valve stenosis： treatments options in elderly high-risk patients

In the last decades, a trend towards a worldwide aging has been reported and diseases which are common in the elderly people would have important implications in clinical practice. Aortic stenosis （AS） is perhaps the most common and most often cause of sudden death among valvular heart diseases. Its prevalence is low among adults aged 〈 60 years, but increases to almost 10% in adults ≥ 80 years.[2] Since the degenerative calcific disease represents the lead- ing cause of AS in developed countries, the improved understanding on its pathogenesis （atherosclerotic processes and/or skeleton key） may offer potentially new targets for preventing and inhibiting AS development and progres- sion.[3] Patients with AS are generally asymptomatic for a prolonged period and the development of symptoms is a critical point in the natural history. Indeed, the prognosis changes dramatically with the onset of symptoms of angina,

Animal Model of Aortic Valve Calcification: Their Methodology Helps Us Understand Aortic Valve Calcification

Aortic valve calcification disease (CAVD) is the most prevalent degenerative valve disease in humans, leading to significant morbidity and mortality. Despite its common occurrence, our understanding of the underlying mechanisms remains incomplete, and available treatment options are limited and risky. A more comprehensive understanding of the biology of CAVD is essential to identify new therapeutic strategies. Animal models have played a crucial role in advancing our knowledge of CAVD and exploring potential treatments. However, these models have inherent limitations as they cannot fully replicate the complex physiological mechanisms of human CAVD. In this review, we examine various CAVD models ranging from pigs to mice, highlighting the unique characteristics of each model to enhance our understanding of CAVD. While these models offer valuable insights, they also have limitations and shortcomings. We propose that the guide wire model shows promise for future CAVD research, and streamlining the methodology could enhance our understanding and expand the research scope in this field.

Biomechanical assessment of aortic valve stenosis:Advantages and limitations

Aortic valve stenosis(AS)is a frequent and potentially severe disease of the heart.Accurate assessment of AS is a critical factor in determining prognosis and treatment.This paper describes the advantages and limitations of AS assessment from a biomechanical engineering perspective,by contrasting the non-invasive AS diagnostic methods of echocardiography(Echo),computed tomography(CT),magnetic resonance imaging(MRI),computational analysis(CA)including the invasive technique of cardiac catheterization.The findings illustrated that current methods of AS evaluation,with assumptions of an ideal fluid,geometry and governing equations may not apply well to the aortic valve pathology and could increase the uncertainty of the degree of stenosis and valve area.This review suggests an alternative method using CA,which could potentially overcome the pitfalls of other AS assessments that incorporate geometry,pressure recovery and aorta wall compliance,based on the accurate conversion of AS imaging to the numerical modelling.Further,this review highlights the importance of CA boundary conditions,and the role of verification and validation to produce reliable computational results.

Transcatheter aortic valve replacement(TAVR) for severe aortic valve stenosis with left main artery disease:A case report

Introduction: This is the first case of Transcatheter Aortic Valve Replacement(TAVR) in the prefecture level hospital of Xinjiang Province in China. It also proves that severe left main coronary artery disease(LM)is not the contraindication to this operation of TAVR. Patient concerns:The patient had dyspnea for two years, with the 4/6 spurious murmur at the aortic valve. The cardiac ultrasound revealed a severe aortic valve stenosis(AS) and severe mitral regurgitation(MR). Coronary angiography(CAG)showed 80% stenosis of the left main artery. Diagnosis: The severe aortic valve stenosis(AS). Interventions: He received the TAVR, which also is the first case in the First People's Hospital of Kashi Prefecture. Outcomes: The patient's symptoms were significantly improved. The cardiac ultrasound showed that no obvious regurgitation was found in the implanted artificial aortic valve and the MR was significantly reduced. So far, the patient has recovered well for five months after TAVR. Conclusion:TAVR is an effective method for the severe AS patients with serve LM and loss of surgical opportunity.

The effects of severe aortic stenosis and high pulmonary artery pressure on aortic valve replacement

Background: Pulmonary hypertension development in pure severe aortic stenosis is a situation that affects mortality and morbidity. Material and Methods: Data from files of 31 patients with systolic pulmonary artery pressure over 50 mm Hg and with pure severe aortic stenosis, and underwent aortic valve replacement in our clinic were examined retrospectively. Results: Preoperative effort capacities of the patients were evaluated as follows according to NYHA;4 patients class 1-2, 16 patients class 3, and 11 patients class 4. Twenty-five metal, and 6 biologic aortic valves were used. Postoperative hospital mortality was recorded as 12% with 4 patients. Patients were reevaluated on the postoperative 2nd and 12th months. Pulmonary arterial pressure of the patients was measured using echocardiography. Preoperative average pulmonary artery systolic pressure was measured as 55 ± 3 mmHg. The average pressure was measured as 41 ± 3 mmHg on the 2nd, and as 37.8 ± 4 mmHg on the 12th month. The effort capacity evaluation in the postoperative 2nd month was as follows: 11 patients class 1-2, 12 patients class 3, and 4 patients class 4. The effort capacity evaluation conducted in the 12th month was: 14 patients were class 1-2, 10 patients were class 3, and 2 patients were class 4. During the follow-up 1 year, survival rate of the patients was determined as 83.8% average, 5 year survival rate was determined as 61.5%. Conclusion: We believe that AVR may be performed in severe aortic stenosis cases with high pulmonary pressure with acceptable ortality, leading to a better quality and longer life.

Prognostic value of the ratio between prosthesis area and indexed annulus area measured by MultiSlice-CT for transcatheter aortic valve implantation procedures

Background Postprocedural aortic regurgitations following transcatheter aortic valve implantation （TAVI） procedures remain an is- sue. Benefit of oversizing strategies to prevent them isn＇t well established. We compared different level of oversizing in our cohort of con- secutive patients to address if severe oversizing compared to normal sizing had an impact on post-procedural outcomes. Methods From January 2010 to August 2013, consecutive patients were referred for TAVI with preoperative Multislice-CT （MSCT） and the procedures were achieved using Edwards Sapien~ or Corevalve devices~. Retrospectively, according to pre-procedural MSCT and the valve size, pa- tients were classified into three groups： normal, moderate and severe oversizing; depending on the ratio between the prosthesis area and the annulus area indexed and measured on MSCT. Main endpoint was mid-term mortality and secondary endpoints were the Valve Academic Research Consortium （VARC-2） endpoints. Results Two hundred and sixty eight patients had a MSCT and underwent TAVI procedure, with mainly Corevalve~. While all-cause and cardiovascular mortality rates were similar in all groups, post-procedural new pacemaker （PM） implantation rate was significantly higher in the severe oversizing group （P = 0.03）, while we observed more in-hospital congestive heart-failure （P = 0.02） in the normal sizing group. There was a trend toward more moderate to severe aortic regurgitation （AR） in the normal sizing group （P = 0.07）. Conclusions Despite a higher rate of PM implantation, oversizing based on this ratio reduces aortic leak with lower rates of post-procedural complications and a similar mid-term survival.

Balloon aortic valvuloplasty as a bridge-to-decision in high risk patients with aortic stenosis： a new paradigm for the heart team decision making

Background Whilst the majority of the patients with severe aortic stenosis can be directly addressed to surgical aortic valve replace- ment （AVR） or transcatheter aortic valve implantation （TAVI）, in some instances additional information may be needed to complete the diagnostic workout. We evaluated the role of balloon aortic valvuloplasty （BAV） as a bridge-to-decision （BTD） in selected high-risk patients. Methods Between 2007 and 2012, the heart team in our Institution required BTD BAV in 202 patients. Very low left ventricular ejection fraction, mitral regurgitation grade 〉 3, frailty, hemodynamic instability, serious comorbidity, or a combination of these factors were the main drivers for this strategy. We evaluated how BAV influenced the final treatment strategy in the whole patient group and in each specific subgroup. Results Mean logistic European System for Cardiac Operative Risk Evaluation （EuroSCORE） was 23.5%±15.3%, age 81 ± 7 years. In-hospital mortality was 4.5%, cerebrovascular accident 1% and overall vascular complications 4% （0.5% major; 3.5% minor）. Of the 193 patients with BTD BAV who survived and received a second heart team evaluation, 72.6% were finally deemed eligible for definitive treatment （25.4% for AVR; 47.2% for TAVI）： 96.7% of patients with left ventricular ejection fraction recovery; 70.5% of patients with mitral regurgitation reduction; 75.7% of patients who underwent BAV in clinical hemodynamic instability; 69.2% of frail patients and 68% of patients who presented serious comorbidities. Conclusions Balloon aortic valvuloplasty can be considered as bridge-to- decision in high-risk patients with severe aortic stenosis who cannot be immediate candidates for definitive transcatheter or surgical treatment.

Minimally invasive aortic valve surgery

Aortic valve disease is a prevalent disorder that affects approximately 2% of the general adult population. Surgical aortic valve replacement is the gold standard treatment for symptomatic patients. This treatment has demonstrably proven to be both safe and effective. Over the last few decades, in an attempt to reduce surgical trauma, different minimally invasive approaches for aortic valve replacement have been developed and are now being increasingly utilized. A narrative review of the literature was carried out to describe the surgical techniques for minimally invasive aortic valve surgery and report the results from different experienced centers. Minimally invasive aortic valve replace- ment is associated with low perioperative morbidity, mortality and a low conversion rate to full sternotomy. Long-term survival appears to be at least comparable to that reported for conventional full sternotomy. Minimally invasive aortic valve surgery, either with a partial upper stemotomy or a right anterior minithoracotomy provides early- and long-term benefits. Given these benefits, it may be considered the standard of care for isolated aortic valve disease.

What are the benefits of a minimally invasive approach in frail octogenarian patients undergoing aortic valve replacement？

A best evidence topic was devised in light of a structured protocol. What is the advantage of （minl＂mally invasive） approach in （frail patients） undergoing （aortic valve replacement）？ In cardiac outpatient clinic you review an 85-year old male with severe aortic valve stenosis, low left ventricular ejection fraction and creatinine clearance of less than 50 mL/min. Other comorbidities include treated pulmonary hypertension, mild cognitive impairment, marked limitation of ordinary physical activity and depression. You resolve to determine whether to recommend mim＇mally invasive or conventional aortic valve replacement （AVR） or transcathe- ter aortic valve implantation （TAVI）, however you are not sure of the differences of the impact of frailty on preopera- tive risk for each approach; hence you investigate the best evidence on the topic.

Aortic Valve Replacement for Patients with Heyde Syndrome:A Literature Review

Objective To explore the characteristics and clinical outcomes of patients with Heyde syndrome(HS)who undergo aortic valve replacement(AVR).Methods Electronic databases including Pub Med,Embase,Ovid,WANFANG,VIP and CNKI were searched to identify all case reports of HS patients undergoing AVR surgery,using different combinations of search terms"Heyde syndrome","gastrointestinal bleeding","aortic stenosis",and"surgery".Three authors independently extracted the clinical data including the patients’characteristics,aortic stenosis severity,gastrointestinal bleeding sites,surgical treatments and prognosis.Results Finally,46 case reports with 55 patients aging from 46 to 87 years,were determined eligible and included.Of them,1 patient had mild aortic stenosis,1 had moderate aortic stenosis,42 had severe aortic stenosis,and 11 were not mentioned.Gastrointestinal bleeding was detected in colon(n=8),jejunum(n=6),ileum(n=4),cecum(n=3),duodenal(n=3)and multiple sites(n=8).No specific bleeding site was identified in 23 patients.Preoperative hemoglobin level ranged from 43 to 117 g/L.All but one of 16 patients showed decreased level of high molecule weight von Willebrand factor.Of the 55 patients,43 underwent AVR,and 12 received transcatheter AVR.Aortic valves of 14 cases were replaced by mechanical valves,and 33 cases by biological valves.All patients recovered well during the follow-up,except 5 patients.One patient who had perivalvular leakage and gastrointestinal bleeding after AVR underwent the second AVR.Two patients had recurrent gastrointestinal bleeding.Two patients died of life-threatening acute subdural hematoma and multiple organ failure,respectively.Conclusions HS is a rare syndrome characterized by aortic stenosis and gastrointestinal bleeding.AVR is an effective treatment for HS.

Validation of methods for effective orifice area measurement of prosthetic valves by two-dimensional and Doppler echocardiography following transcatheter self-expanding aortic valve implantation

Background The effective orifice area(EOA)is utilized to characterize the hemodynamic performance of the transcatheter heart valve(THV).However,there is no consensus on EOA measurement of self-expanding THV.We aimed to compare two echocardiographic methods for EOA measurement following transcatheter self-expanding aortic valve implantation.Methods EOA was calculated according to the continuity equation.Two methods were constructed.In Method 1 and Method 2,the left ventricular outflow tract diameter(LVOTd)was measured at the entry of the prosthesis(from trailing-to-leading edge)and proximal to the prosthetic valve leaflets(from trailing-toleading edge),respectively.The velocity-time integral(VTI)of the LVOT(VTILVOT)was recorded by pulsed-wave Doppler(PW)from apical windows.The region of the PW sampling should match that of the LVOTd measurement with precise localization.The mean transvalvular pressure gradient(MG)and VTI of THV was measured by Continuous wave Doppler.Results A total of 113 consecutive patients were recruited.The mean age was 77.2±5.5 years,and 72 patients(63.7%)were male.EOA1 with the use of Method 1 was larger than EOA2(1.56±0.39 cm2 vs.1.48±0.41 cm2,P=0.001).MG correlated better with the indexed EOA1(EOAI1)(r=-0.701,P<0.001)than EOAI2(r=-0.645,P<0.001).According to EOAI(EOAI≤0.65 cm2/m2,respectively),the proportion of sever prosthesis-patient mismatch with the use of EOA1 was lower than EOA2(12.4%vs.21.2%,P<0.05).Compared with EOA2,EOA1 had lower interobserver and intra-observer variability(intra:0.5%±17%vs.3.8%±22%,P<0.001;inter:1.0%±9%vs.3.5%±11%,P<0.001).Conclusions For transcatheter self-expanding valve EOA measurement,LVOTd should be measured in the entry of the prosthesis stent(from trailing-to-leading edge),and VTILVOT should match that of the LVOTd measurement with precise localization.

Transcatheter Aortic Valve Dislocation in Left Ventricular Outflow Tract with Successful Repositioning Using “Double Snare” Technique

Background: Transcatheter aortic valve implantation (TAVI) is a widely used treatment of severe aortic stenosis. Implantation of a self-expanding valve into a dense calcified aortic annulus can be challenging and may result in device malposition and malfunction. Aim: The aim of our case report is to present a novel technique of transcatheter aortic valve dislocation treatment. Case presentation: An 86-year-old woman with severely calcified aortic valve underwent TAVI using a 27-mm self-expanding Portico valve (Abbott Vasc, USA). In the last phase of implantation, the valve dislocated deep into the left ventricular outflow tract resulting in significant paravalvular regurgitation and patient instability. Repositioning of the valve with a single snare was ineffective because of severe aortic ring calcifications. A novel “double snare” technique was applied and the valve was successfully repositioned upward with an excellent anatomic and haemodynamic result. Conclusion: “Double snare” technique can be an effective strategy for repositioning of deeply implanted self-expanding transcatheter aortic valves. It represents an efficient bailout strategy in case of single snare approach failure, especially in cases of severe aortic ring calcifications.

Paradoxical Low Flow Low Gradient Severe Aortic Stenosis—An Under-Recognized Entity

Some patients with severe aortic stenosis (AS), due to restrictive cardiac physiology, paradoxically have relatively low flow and low gradients across stenotic aortic valves despite preserved left ventricular (LV) systolic function. It results in symptoms and reduced quality of life and carries a high mortality. Whilst this form of severe AS, termed paradoxical low flow low gradient (pLFLG), is well reported, patients with this diagnosis experience inappropriate barriers to aortic valve replacement (AVR), the only efficacious treatment. We present the case of an 88-year-old female with 12 months of exertional dyspnoea on a background of hypothyroidism and hypercholesterolemia. Transthoracic echocardiogram (TTE) revealed LV hypertrophy, with a small LV cavity size and reduced stroke volume, yet normal systolic function. A heavily calcified aortic valve was identified with severe aortic stenosis, based on valve area, yet with incongruous mean transvalvular gradient of 25 mmHg (severe ≥ 50 mmHg). Following exclusion of other differential diagnoses, her symptoms were attributed to paradoxical LFLG severe AS. She was however declined definitive transcatheter aortic valve implantation (TAVI) due to her paradoxically low mean aortic gradient. Following further deterioration in her symptoms and supportive quantification of poor exercise performance, she was ultimately re-referred, accepted, and underwent TAVI. Following her AVR, the patient experiences significant improvement in both symptoms and quality of life after only one month. Paradoxical LFLG severe AS remains a well-documented yet under recognized disease. It carries high morbidity and mortality if untreated, yet is significantly less likely to be referred and accepted for intervention. With its prevalence expected to rise with an ageing population, this case serves as a timely reminder for clinicians to address the under recognition of important pathology.

Emergency Treatment of Acute Decompensated Severe Aortic Stenosis with Transcatheter Aortic Valve implantation under the Coplane View Using J-Tipped Wires Fluoroscopy

Patients experiencing severe aortic stenosis with acute decompensation often face elevated surgical aortic valve replacement risks,leading to high postoperative mortality rates.However,for some patients eligible for transcatheter aortic valve implantation(TAVI),computed tomography angiography for assessing the aortic root and coronary artery might be challenging before the TAVI procedure.This case highlights a patient who underwent emergency TAVI guided by coplane view generated using J-tipped wires fluoroscopy without computed tomography evaluation before the TAVl.This approach reduces contrast usage during the TAVI procedure,significantly mitigating the risks of renal injury and heart function deterioration.

Preoperative echocardiographic predictors for 1-year mortality in patients treated with standard endovascular aneurysm repair for abdominal aortic aneurysm

Background: Abdominal aortic aneurysm (AAA) and cardiovascular disease are intimately associated, the latter representing the most common cause of death in Sweden. Cardiac complications are held responsible for the majority of perioperative morbidity and mortality in patients undergoing repair of AAA. The importance of preoperative thorough cardiac assessment is therefore obvious. The aim of this study was to evaluate the prognostic significance of preoperative echocardiographic findings for 1-year mortality after elective endovascular aneurysm repair (EVAR) of infrarenal AAA. Design: Retrospective analysis. Methods: The 505 patients were identified in a prospective database for endovascular interventions between 1998 and 2011, and data were retrieved from patient records. Preoperative echocardiography reports in 380 patients were reviewed and findings were notified according to a predefined protocol. Results: The 1-year mortality rate was 6.7%. Severe valve disease was present in 8.7% of the patients, aortic valve stenosis being the leading cause of valve pathology. Severe valve disease (OR 3.5, 95% CI [1.2 - 10.7];p = 0.025) and chronic kidney disease grade ≥ 3 (OR 7.5, 95% CI [2.1 - 26.1];p = 0.002) were the only independent risk factors for increased mortality rate at 1-year. Conclusion: Echocardiography should be a part of the preoperative workup in AAA patients. Finding of severe valve disease should be further evaluated by a cardiologist prior to EVAR.

Evaluation of the safety and efficacy of transcatheter aortic valve implantation in patients with a severe stenotic bicuspid aortic valve in a Chinese population

Objective： The purpose of this study is to evaluate the safety and efficacy of transcatheter aortic valve implantation （TAVI） in patients with a severe stenotic bicuspid aortic valve （BAV） in a Chinese population. While several groups have reported the feasibility, efficacy, and safety of TAVI for patients with a BAV, worldwide experience of the technique is still limited, especially in China. Methods： From March 2013 to November 2014, high surgical risk or inoperable patients with symptomatic severe aortic stenosis （AS） who had undergone TAVI at our institution were selected for inclusion in our study. Results were compared between a BAV group and a tricuspid aortic valve （TAV） group. Results： Forty patients were included in this study, 15 （37.5%） of whom were identified as having a BAV. In the BAV group, the aortic valve area was smaller （（0.47±0.13） vs. （0.59±0.14） cm2）, the ascending aortic diameter was larger （（40.4±4.4） vs. （36.4±4.3） mm）, and the concomitant aortic regurgitation was lower. No significant differences were found between the groups in the other baseline characteristics. No differences were observed either in the choice of access or valve size. The procedural success achieved in this study was 100%. There were no differences between groups in device success （86.7% vs. 88.0%）, 30-d mortality （6.7% vs. 8.0%）, or 30-d combined end point （13.3% vs. 12.0%）. The incidences of new pacemaker implantation, paravalvular regurgitation and other complications, recovery of left ventricle ejection fraction and heart function were similar in both groups. Conclusions： Patients with a severely stenotic BAV can be treated with TAVI, and their condition after treatment should be similar to that of people with a TAV.

Near-infrared spectroscopy in adult cardiac surgery： between conflicting results and unexpected uses

Neurological complications after cardiac surgery, rang- ing from permanent stroke to transient dysfunction, repre- sent a key issue in the management of geriatric patients. Many patients aged 70 or more have history of neurological dysfunctions, which increases the risk of complications and sequelae, Severe neurologic diseases, such as strokes, occur in up to 6% of patients undergoing cardiac surgery. Therefore, in the setting of fragile patients, prevention is more important than treatment. There are several intraop- erative mechanisms of neurological injury, such as embo- lism, inflammation, intraoperative anemia,

Oxidized phospholipids and lipoprotein-associated phospholipase A_2 as important determinants of Lp(a) functionality and pathophysiological role

Lipoprotein（a） [Lp（a）] is composed of a low density lipoprotein（LDL）-like particle to which apolipoprotein（a）[apo（a）] is linked by a single disulfide bridge. Lp（a） is considered a causal risk factor for ischemic cardiovascular disease（CVD） and calcific aortic valve stenosis（CAVS）. The evidence for a causal role of Lp（a） in CVD and CAVS is based on data from large epidemiological databases, mendelian randomization studies, and genome-wide association studies. Despite the well-established role of Lp（a） as a causal risk factor for CVD and CAVS, the underlying mechanisms are not well understood. A key role in the Lp（a） functionality may be played by its oxidized phospholipids（OxPL） content. Importantly, most of circulating OxPL are associated with Lp（a）; however, the underlying mechanisms leading to this preferential sequestration of OxPL on Lp（a） over the other lipoproteins,are mostly unknown. Several studies support the hypothesis that the risk of Lp（a） is primarily driven by its OxPL content.An important role in Lp（a） functionality may be played by the lipoprotein-associated phospholipase A_2（Lp-PLA_2）,an enzyme that catalyzes the degradation of OxPL and is bound to plasma lipoproteins including Lp（a）. The present review article discusses new data on the pathophysiological role of Lp（a） and particularly focuses on the functional role of OxPL and Lp-PLA_2 associated with Lp（a）.