Responses between fetal growth restriction (FGR) and appropriate for gestational age infants were compared. Ten infants <28 weeks GA at birth were assessed at ≥36 weeks corrected gestation. Baseline echocardiography1 was performed which was repeated (echocardiography2) after 30 minutes of O2. After a gap of 2–3 hours, iNO was administered for 15 minutes and echocardiography3 was performed, followed by iNO weaning. The gestation and birthweight of the cohort were 25.9 ± 1.6 weeks and 612 ± 175 g. Assessments were performed at 38.7 ± 1.4 weeks corrected gestational age. Baseline time to peak velocity: right ventricular ejection time (TPV/RVETc) increased from 0.24 ± 0.02 to 0.27 ± 0.02  and 0.31 ± 0.03 , indicating a decrease in pulmonary vascular resistance [PVR]. Baseline tricuspid annular plane systolic excursion (TAPSE) increased from 8.1 ± 0.6 mm to 9.3 ± 0.7 mm  and 10.5 ± 1.1 mm , indicating improved ventricular systolic performance. Percentage change for all parameters was greater with iNO. Significant correlations between cardiac performance and PVR were noted. FGR infants noted higher baseline PVR , lower ventricular performance , and lower percentage change with O2 and iNO. A reactive component of pulmonary circulation provides real‐time physiological information, which could rationalize treatment decisions.Pulmonary hypertension (PH) is common in infants with severe bronchopulmonary dysplasia (BPD) and increases the risk of death. The objectives of this preliminary study were to compare responses of pulmonary circulation parameters to 100% oxygen (O Pulmonary vasoreactivity testing with oxygen and inhaled nitric oxide can be performed with echocardiography monitoring. Flow through a patent ductus arteriosus portrays sudden hemodynamic shifts, indicating a reactive pulmonary circulation. The occurrence of pulmonary hypertension (PH) in this cohort influences survival and significantly increases mortality compared to equally preterm infants with BPD but without PH  support, it is a standard approach in many institutions  with inhaled nitric oxide (iNO), as well as between FGR and appropriate for gestational age (AGA) infants. Such assessments with echocardiographic guidance in cohorts of BPD‐associated PH have not been reported earlier.This study aimed to assess the pulmonary circulation with echocardiography monitoring, comparing hemodynamic responses for 100% oxygen (O22). Normal cardiac anatomy and pulmonary venous connections were documented. Infants were assessed at ≥36 weeks’ corrected GA. FGR was defined as birthweight <10th centile for GA and sex with absent/reversed antenatal Doppler's . After approximately 2–3 hours, iNO was administered through continuous positive airway pressure for 15 minutes at 20 ppm (baseline respiratory support settings). iNO was subsequently weaned over 15 minutes. No pharmacologic sedation was used. The same operator using the Vivid E95 Cardiovascular Ultrasound System  performed assessments. Previously studied echocardiography parameters were assessed which represented assessments of PVR and RV systolic performance . After informed written parental consent, 10 infants’ <28 weeks’ GA and severe BPD and PH formed the cohort (severe BPD‐need for positive pressure support and ≥30% O2.12) and echocardiography3 (iNO), followed by comparisons between echocardiography2 and echocardiography3 using Student's two‐tailed t test. Differences were considered significant if p < .05. Pearson product‐moment correlation coefficient, coefficient of determination, the slope of the regression line, and the Y intercept of the regression line were used to describe the relationship between the measures of RV performance and measures of PVR.The data are presented as mean ±standard deviation. Baseline data from echocardiography1 were compared with echocardiography2  (by TPV/RVETc criteria); the same data for PA annular velocity were one and seven, respectively. Comparing baseline data between FGR and AGA infants, PVR was higher and RV systolic performance significantly lower in the former (Table p = .0002). “Percentage change” from baseline was greater in the AGA infants and significantly higher with iNO than O2  and to 2.15 ± 0.4 with iNO (p = .058), respectively. While not an objective of this study, four infants  were later administered sildenafil at the discretion of the medical team. Temporally, this coincided with success in being able to wean respiratory support.Table ow Table . None ofer Table . RV fracO2 Table . All  infants. This was associated with decreased subsequent mortality risk  and global  noted significant changes during pulmonary circulation reactivity testing. This suggests a close inter‐play/ coupling between cardiac contractility and afterload Figure . TPV/RVE4.3Sildenafil administration in infants who demonstrated reactivity led to significant clinical improvements (weaning of respiratory support). Identification of such a subset, where reversible pulmonary vasoconstriction is a significant contributor to BPD pathophysiology, has important therapeutic constructs. Pulmonary vasodilators are in variable use for chronic PH although are not approved by the Food and Drug Administration for use in infants. Sildenafil has been used extensively off‐label for the treatment of PH in neonates, infants as well as children. Clinically, such therapies may be administered for months before/after discharge. Pulmonary vasoreactivity testing prior to long‐term oral pulmonary vasodilator treatment may rationalize therapy. Current guidelines do not use such assessments as a determining factor whether a patient should be placed on sildenafil (or other pulmonary vasodilators) or not. Our results note the useful biological plausibility of such a strategy, based on which a physiologic argument of such non‐invasive, bedside testing could be made. Therapeutics commonly used in adult patients should not be simply extrapolated. Pediatric PH, especially in the neonatal population, has many unique clinical features due to complex maturational influences related to lung vascular development and related factors. Physiologic assessments, including cardiac CATH, echocardiography and serum biomarkers, while associated with clinical outcomes, have not been tested as sufficient endpoints for clinical trials. Bedside echocardiography, using well‐studied parameters, opens up the possibilities of precision medicine and physiology driven approach. This is well placed to potentially personalize the care of patients with pre‐term lung disease, ensuring that treatment decisions are based on underlying, demonstrable pathophysiology, and not in a “one‐size fits all approach.” While ductus arteriosus is mostly closed by 36 weeks corrected GA, patency in one infant provided an immediate visual portrayal of sudden hemodynamic shift.4.4FGR infants stood out (lower baseline RV systolic performance and elevated PVR) as well as reduced vasoreactivity (percentage change). FGR infants made up a substantial part (46%) of a previous CATH assessed cohort. In another study, FGR infants were significantly more likely to have systemic or supra‐systemic baseline RV pressures than AGA infants were. However, the reactivity of this sub‐cohort was not reported separately in either study (Frank et al., 5The limitation of small numbers overall and in each group is acknowledged. Infants were not followed up with subsequent echocardiography. Despite limitations, we identified key knowledge gaps that require further study. Assessment of the pulmonary circulation using echocardiography provided real‐time physiological information of the reactivity in response to pulmonary vasodilators. Such assessments may facilitate physiology‐focussed management and pulmonary vasodilator use, providing additional important information for risk stratification and/or response to therapeutic interventions. A prospective study assessing the clinical/echocardiography impact of ongoing vasodilator therapy comparing the responsive/non‐responsive cohorts is better placed to ascertain its role as a therapeutic target. Follow‐up data of survivors of vasodilator therapies are needed to assess effectiveness and long‐term safety.None.


In 2020, cardiovascular diseases (CVDs) remain a leading cause of mortality and morbidity, contributing to the burden of the already overloaded health system. Late or incorrect diagnosis of patients with CVDs compromises treatment efficiency and patient’s outcome. Diagnosis of CVDs could be facilitated by detection of blood-based biomarkers that reliably reflect the current condition of the heart. In the last decade, non-coding RNAs (ncRNAs) present on human biofluids including serum, plasma, and blood have been reported as potential biomarkers for CVDs. This paper reviews recent studies that focus on the use of ncRNAs as biomarkers of CVDs. Cardiovascular diseases (CVDs) including aortic stenosis, hypertension, myocardial infarction, congenital heart diseases, aortic aneurysms, and right ventricle dysfunction can lead to heart failure (HF) and, ultimately, death. CVDs alone are responsible for more than 17.9 million deaths per year, corresponding to 31% of all deaths globally and being the first cause of morbidity and mortality worldwide , data from 2019 [Clinical management of CVDs could be facilitated by detection of blood-based biomarkers that reliably reflect the current condition of the heart. The term biomarker arises from the junction of the words “biological” and “marker”. Biomarkers are defined by WHO as “any substance, structure, or process that can be measured in the body or its products and influence or predict the incidence of outcome or disease”. Later, the definition of a biomarker was extended to “any measurement reflecting an interaction between a biological system and a potential hazard, which may be chemical, physical, or biological” .Ideally, a human biomarker should be of easy access and acquirement, display a high degree of specificity and sensitivity, be stable in its environment , and thus have little or no variability . While iLin-14, by directly binding to lin-14 RNA molecule [In the recent years, a new class of potential biomarkers, including non-coding RNAs (ncRNAs), has received much attention in the cardiovascular field. Representing almost 60% of cell transcriptome, ncRNAs are functional RNA molecules that, despite lacking a protein-coding region, are essential players in gene regulation and, consequently, in cell function and survival . The disMiRNAs are small ncRNA (18–25 nucleotides) that inhibit the expression of their target gene(s) by sequence-specific recognition. The transcript-binding sequence is usually located in the 3′-untranslated region (3’-UTR), whereas the complementary seed sequence is located in the first two to eight nucleotides of the miRNA . The degAlthough miRNAs are established as an important and possibly the most described group of ncRNAs, the largest portion of the ncRNA transcriptome is composed of lncRNAs. LncRNAs are a class of non-coding linear transcripts of more than 200 nucleotides in length, which frequently miss an open reading frame (ORF) and influence gene expression in a variety of manners . NotwithSimilar to miRNAs, lncRNAs can also be found in different cellular compartments such as nucleus, cytoplasm, and extracellular space. In the nucleus, lncRNAs will influence transcription by recruiting regulatory factors and catalytic proteins; alternately, eRNAs drive proteins to enhancer regions, anchoring them to DNA in the right position and organizing chromatin interaction . OppositA newly found class of ncRNAs is circRNAs, which, in contrast with previously reported ncRNAs, are characterized by a circular form that arises as a consequence of back splicing events . CircRNAFurthermore, circRNAs are conserved among species, with some of them displaying cell-type and spatial-temporal specificity . EmerginCircRNAs can also affect gene transcription of the so-called parent gene, the gene that mRNA gives origin to the circRNA after back splicing, through interaction with RNA polymerase II and regulation of its transcriptional activity . As for Here, we will review the literature on the detection of ncRNAs in human samples of blood, plasma, and serum and conclude on their potential as biomarkers of CVDs.A variety of cardiac diseases have different etiologies and specific events that can lead to the expression and circulation of cardiac-derived biomarkersAortic valve stenosis (AS) affects more than 5% of the population above 65 years old. It is defined as a narrowing of the aortic valve that progressively imposes resistance to the blood flow from the left ventricle (LV) to the aorta . UnfortuncRNAs have been studied as prospective biomarkers of AS thanks to their potential to reflect AS pathogenesis and to be detected at an earlier AS stage. Blood-based ncRNA biomarkers could aid in patient’s risk stratification and decision making, such as the timing and type of intervention (SAVR vs. TAVR), as well as in predicting AS progression.Clinically, AS is associated with LV hypertrophy and cardiac fibrosis. In fact, a study measuring the plasma levels of miR-1, miR-133, and miR-378 in AS patients suggested that all three miRNAs were downregulated . Yet, miAnother study showed the presence of myocardial fibrosis in severe AS patients with LV preserved ejection fraction (EF). Interestingly, fibrosis directly associates with miR-21 plasma levels, suggesting that miR-21 levels reflect the degree of myocardial fibrosis . FurtherAnalysis of peripheral blood collected from AS patients demonstrated that serum miR-19b levels are abnormally decreased and inversely correlated with LV stiffness and collagen cross-linking when matched to age and gender healthy controls . PreviouInterestingly, a number of different miRNAs have been related to different phenotypes of AS . For exaDespite certain circRNAs showing aortic valvular tissue specificity, and several associations that have been suggested between lncRNAs and AS pathology, to date, no studies have reported the association of AS with either plasma circRNAs or lncRNAs ,41.Aortic aneurysm (AA) represents an important cause of death. AA is clinically characterized by an enlargement of at least 50% of an aortic segment compared with the same segment in healthy individuals and can be subdivided in thoracic aortic aneurysm (TAA) or abdominal aortic aneurysm (AAA), the latter being the most frequent . AA is aAA incidence and prognosis is associated with patient’s sex and age, typically men and elderly populations are more affected by AA and demonstrate worse outcomes . To dateAn early and correct diagnosis could avoid surgery and improve patient’s outcome. As nearly all patients are asymptomatic, an early diagnosis becomes difficult . Most ofAmong ncRNAs, miRs continue in the front of the biomarkers run as the most well described and studied ncRNAs. Therefore, it is not surprising that most AA related studies on ncRNAs focus on miRs.n = 16) when compared with the control  [In 2020, a small study described seven circulating miRs with an altered expression in AAA condition (iR-1260) . After viR-1260) .Wanhainen et al. analyzed the circulating miRNA profile of 169 AAA patients and contrasted it against the profile of 48 healthy age and sex-matched individuals [A work from ividuals . Of a prividuals . The topividuals . DespiteOn the other hand, lncRNAs were also reported as potential biomarkers for TAA . In factMore promising results were obtained by Tian et al., who investigated the potential role of plasma circMARK3 to identify an advanced stage of aortic aneurysms, such as aortic dissection , particularly acute aortic dissection -Standford type A (AAAD) . The resTogether, the results obtained by Tian et al. are very encouraging and highly suggest serum circMARK3 and miR-1273-3p as potential biomarkers for the AAAD condition.Often viewed as an inflammatory disorder, coronary artery disease (CAD) occurs when vessels that supply blood to the heart (coronary arteries) become damaged . Artery As CAD pathology is directly influenced by endothelial dysfunction, is it feasible to assume that endothelial-related miRNAs could constitute reliable biomarkers of CAD. Accordingly, miR-17 described as a negative regulator of tumor angiogenesis is highly expressed in plasma from patients with severe CAD and is a potential biomarker candidate . Other mNotwithstanding, the levels of circulating miRNAs are not only capable of indicating the presence of CAD lesion, but also can differentiate and correlate with CAD severity, as shown for miR-206 . PatientAnalysis of atherosclerosis- and cardiac-related lncRNAs levels in peripheral blood mononuclear cells (PBMCs) from CAD patients and healthy individuals revealed that three lncRNAs, KCNQ1OT1, HIF1A-AS2, and APO1, are significantly increased in patients when compared with the healthy controls . Of the Vilades and colleagues, who categorize CAD patients according to the levels of plasma circ_0001445 (circSMARCA5), whose expression inversely correlated to coronary atherosclerosis extension and severity [A similar approach was taken by severity . In factseverity . Furtherseverity . After aseverity . Similarseverity . CirZNF6severity . Despiteseverity . Furtherseverity . Whereasseverity .One of the consequences of CAD is the formation of a blood clot that, among other causes, occludes coronary arteries, resulting in ischemia and myocardial infarction . In fact, a correlation between CAD and MI was previously established, namely on how well plasma miRNAs can predict CAD progression towards acute MI. A higher number of stenosed coronary vessels is associated with lower plasma miR-99a levels in MI patients . FollowiData from Centers for Disease Control and Prevention (CDC), a U.S. national public health institute, respective to the U.S. population, reported that, every 40 s, someone dies from a heart attack, and for every five occurrences, one is silent, meaning that no symptoms are recognized by the patient. Commonly, MI is diagnosed by combining an ECG test and analysis of biomarkers such as cardiac troponin I and T levels. However, ECG can only detect 30–70% of MI cases, highlighting the need for more accurate and sensitive biomarkers .Various plasma miRNAs have been described as potential indicators of myocardial infarction, likely the most studied and described event among all cardiovascular diseases. Hence, miR-1, miR-126, miR-30a, miR-195, miR-26a-1, miR-146a, and miR-199a-1 were revealed to be upregulated in individuals diagnosed with acute MI (AMI) ,66,67, wMicroarray analysis in plasma samples of a small group of AMI patients identified 33 differentially expressed miRNAs, from which miR-30d-5p and miR-125-5p were selected for validation in a larger study population composed of 230 AMI patients and 79 healthy controls . DespiteLess promising results were reported for miR-221-3p, which, despite being upregulated by 3.89-fold in AMI , and an Interestingly, even after pharmacological treatment, progression towards maladaptive remodeling occurs in approximately 30% of AMI patients . A totalAs mentioned previously, one mechanism of action of lncRNAs is by competitively binding to miRNAs’ target binding site, which prevents the attachment of mRNA–miRNA, thus inhibiting miRNA action. For example, lncRNA HOTAIR has a sponge like effect on miR-1, an miRNA upregulated in AMI cases . HOTAIR Another myocardial enriched lncRNA is UCA1, which, similar to HOTAIR, is also decreased in the plasma of AMI individuals . By clusOther lncRNAs have been attributed biomarker potential when screening for differentially expressed lncRNAs in plasma of 46 STEMI patients. While aHIF, KCNQ1OT1, and LIPCAR were found to be increased, six others, including HOTAIR, UCA1, MIAT, MALAT1, ANRIL, and CPNE3, were decreased in these patients . The mosDespite the relatively new role of circRNAs as biomarkers of AMI, Deng et al. found 160 circRNAs to be differentially expressed in AMI patients, with 87 of them being increased and 73 decreased when compared with healthy controls . Among tIn the past decade, prenatal testing made crucial advances and increased the survival rate up to 87% in the first year. Currently, neonatal congenital heart defects (CHDs) have an incidence of 4–8 per 1000 births and their manifestations range from minor defects  to severe defects that can even lead to prenatal lethality . The most common include tetralogy of fallot (TOF), atrial septal defect (ASD), ventricular septal defect (VSD) single ventricle (SV), persistent truncus arteriosus (PTA), and bicuspid aortic valve disease (BAV) . A favorBicuspid aortic valve disease (BAV), the most common anomaly of the human heart, results from an anomaly during valvulogenesis that is characterized by no splitting between two adjacent cusps, and it is frequently accompanied by dilation of the ascending aorta . The mosOverall, CHDs can be distinguished from non-CHDs through specific alterations in miRNA expression patterns . Namely,A relatively small study, including 22 pregnant CHD-positive and 17 CHD-free controls, suggested miR-99a to be upregulated in the peripheral blood of the CHD-positive pregnant women when compared with the control group . HoweverYu et al. also suggested that a different group of miRNAs could identify CHDs such as ventricular septal defect (VSD), atrial septal defect (ASD), and tetralogy of fallot (TOF) . The groRegarding lncRNAs in CHDs, HOTAIR was found to be upregulated in both myocardial tissue and plasma samples of ASD, VSD, and patent ductus arteriosus (PDA) patients when compared with healthy subjects, and thus was indicated as a potential biomarker for CHD . HOTAIR From a microarray-based strategy, 17,603 lncRNAs were found to be differentially present in the plasma of fetal CHD pregnant women . From thMore recently, the possible value of circRNAs in the diagnosis of CHD has also been addressed. A study including 40 children with CHD (namely VSD and ASD) and 40 healthy children identified 10 upregulated and 157 downregulated circRNAs in the plasma of the CHD group. Validation by qPCR demonstrated three circRNAs, hsa_circRNA_004183, hsa_circRNA_079265, and hsa_circRNA_105039, to be significantly decreased in the affected group . Hsa_cirThe right ventricle (RV) is responsible for pumping venous blood into the pulmonary vascular bed on the way to the LV, thereby contributing to left ventricular filling and cardiopulmonary function. Its thin walls and the direct connection with low impedance pulmonary circulation make the RV more sensitive to pressure than to volume overload . PulmonaArrhythmogenic cardiomyopathy (ACM) is a life-threating genetic disease where RV myocardial tissue is replaced by fibro-fatty tissue, leading to arrhythmias and, eventually, HF . ACM is PH is a multifactorial disease, with several subgroups being characterized by an increase in RV afterload that can precede (right) HF and, eventually, death. The first report on PH-associated circulating miRNAs analyzed plasma samples from PH patients undergoing right heart catheterization . MiRNAs Another similar study revealed miR-451 as being significantly decreased in PH patients compared with non-PH patients  . AlthougCardiac pathological remodeling associated with the above-mentioned different cardiovascular diseases can lead to HF and, eventually, death. The severity of cardiac pathological remodeling frequently predicts treatment outcome and patient response . In lighUnderstanding the features of cardiac pathological remodeling and the cardiac response to therapy has become a major objective towards better care of CVD patients. In line, biomarkers, and more specifically ncRNAs, are claiming a greater role towards establishing reverse remodeling and predicting patient outcome upon specific therapies.Presently, the only therapy that consistently increases survival of AS patients is AVR surgery. However, the persistence of hypertrophy after AVR surgery is a main limiting factor for patient survival and positive outcomes. Circulating miR-133a levels prior to AVR surgery are a positive predictor of LV mass normalization and subsequent decrease of cardiac hypertrophy up to one year after surgery. When combined with other clinical parameters, miR-133a yielded an AUC of 0.89  and is cA negatively patient outcome after mechanical therapy such as coronary artery bypass graft or AVR due to CAD and AS, respectively, is associated with high levels of serum miR-423-3p . AlthougAnother study collectively addressed miRNA expression in the Pro-BNP Outpatient Tailored CHF Therapy (PROTECT) cohort to predict left ventricle reverse remodeling (LVRR) based on miRNAs that have been involved in human HF phenotypes or known to influence common HF signaling pathways . Only 41Aside from the merit of circulating miRNAs, lncRNAs such as LIPCAR, H19, ANRIL, and MHRT have also emerged as potential biomarkers for LVRR. For example, higher plasma levels of LIPCAR and H19 in CAD patients are associated with chronic HF . In HF pAs previously mentioned, one treatment for CAD is coronary intervention by the use of a stent; however, 12% of patients with stent therapy showed angiographic restenosis, in-sent restenosis (ISR) . ISR is Finally, plasma circRNA MICRA was found to be a strong predictor of LV dysfunction 3 to 4 months after an AMI episode, and lower MICRA levels in MI patients are at higher risk of LV dysfunction .Misdiagnosed CVDs have severe consequences on a patient’s life quality and associated survival rate. The use of standard biomarkers for CVDs as the quantitative assessment of circulating cardiac troponins and natriuretic peptides levels it is still not specific and neither sensitive enough for early detection. Moreover, the complexity of many biological and molecular mechanisms observed on the different CVDs makes the use of a single biomarker insufficient for a correct diagnosis. Currently, circulating ncRNAs display great potential as biomarkers owing to their high abundance and stability in the blood, and ncRNAs can provide a valuable measure of heart health condition. Therefore, ncRNAs have been portrayed as potential non-invasive tools and might help on CVDs’ diagnosis and prognosis, allowing tailored healthcare to each individual and a reduction of the associated societal and economic burden. However, the expression profile of ncRNAs could be influenced by age, sex, and medical drugs, which might add more complexity to our understanding of ncRNAs in CVDs. Furthermore, up to date, only a scarce number of works reported a higher individual diagnostic value of ncRNAs when compared with standard CVD markers; however, frequently, this value is improved when a set of ncRNAs is used or combined with standard CVD markers. The majority of the studies are characterized by a smaller sample size, with some possible cofounders associated , and a short-term follow-up thwarts the hunting for the ideal biomarker. Interestingly, some ncRNAs such as muscle specific miR-1 and lncRNA HOTAIR are reported in several diseases , suggest


Ventricular-arterial coupling plays a key role in the physiologic function of the cardiovascular system. We have previously described a hybrid lumped-finite element (FE) modeling framework of the systemic circulation that couples idealized FE models of the aorta and the left ventricle (LV). Here, we describe an extension of the lumped-FE modeling framework that couples patient-specific FE models of the left and right ventricles, aorta and the large pulmonary arteries in both the systemic and pulmonary circulations. Geometries of the FE models were reconstructed from magnetic resonance (MR) images acquired in a pediatric patient diagnosed with pulmonary arterial hypertension (PAH). The modeling framework was calibrated with pressure waveforms acquired in the heart and arteries by catheterization as well as ventricular volume and arterial diameter waveforms measured from MR images. The calibrated model hemodynamic results match well with the clinically-measured waveforms (volume and pressure) in the LV and right ventricle (RV) as well as with the clinically-measured waveforms (pressure and diameter) in the aorta and main pulmonary artery. The calibrated framework was then used to simulate three cases, namely, (1) an increase in collagen in the large pulmonary arteries, (2) a decrease in RV contractility, and (3) an increase in the total pulmonary arterial resistance, all characteristics of progressive PAH. The key finding from these simulations is that hemodynamics of the pulmonary vasculature and RV wall stress are more sensitive to vasoconstriction with a 10% of reduction in the lumen diameter of the distal vessels than a 67% increase in the proximal vessel's collagen mass. Ventricular-arterial coupling plays a vital role in the physiologic function of the cardiopulmonary circulation as well as in the evolution of cardiovascular diseases, such as pulmonary arterial hypertension (PAH)  modeling framework. In a lumped parameter modeling framework, the ventricular-arterial coupling is described by an electrical analog representation of the cardiovascular system Ursino, . While sin vivo clinical measurements of the anatomy, deformation, and hemodynamics from a PAH pediatric patient. Using the calibrated model, we further investigate how changes associated with the mechanical behavior and microstructure of the microcirculation, large pulmonary arteries, and right ventricle (RV), consequent of PAH progression, affect each other.Here, we describe the extension of our earlier framework , and informed consent was obtained from the parents/guardians of the patient.Clinical data was prospectively acquired in a 11-year-old female patient who was diagnosed with PAH. The patient had an elevated mean pulmonary arterial pressure (mPAP) of 59 mmHg with normal pulmonary capillary wedge pressure (PCWP) of 6 mmHg and elevated pulmonary vascular resistance (PVR) of 13.5 WU, falling within the clinical classification of PAH   to acquire ventricular volume waveforms. Cardiac-gated gradient echo MR images of the vascular anatomy were acquired in the diastolic phase. Luminal area waveforms were also acquired with phase-contrast MR images (PC-MRI) at the ascending aorta and main pulmonary artery. Arterial catheterization was performed to acquire pressure waveforms in the LV, RV, main pulmonary artery (MPA), and aorta. The ventricular volume and pressure waveforms were synchronized to reconstruct pressure-volume (PV) loops  imaging and arterial catheterization. Cine MR images of the short- and long-axis views of the ventricles were acquired at 30 time points in the cardiac cycle. Using the cine MR images, left and right ventricular endocardial surfaces were segmented with the medical image analysis software MeVisLab (www.crimson.software)   were reconstructed from the acquired MR images. The biventricular model was reconstructed from images that correspond to the point in the cardiac cycle where ventricular pressures were lowest during filling  .The biventricular, aorta and pulmonary artery FE models were coupled through a closed loop lumped-parameter circulatory model that describes both systemic and pulmonary circulations . The modVLV, Vsa, Vsv, VRA, VRV, Vpa, Vpv, and VLA are the volumes of the eight compartments with the subscripts denoting the LV, systemic arteries (sa), systemic veins (sv), right atrium (RA), RV, pulmonary arteries (pa), pulmonary veins (pv), and left atrium (LA), respectively. Flow rates at different segments of the circulatory model are denoted by qmv, qav, qsa, qsv, qtv, qpvv, qpa, and qpv.In Equation (1), Systemic and pulmonary arteries and veins were modeled using their electrical analogs based on Ohm's law. At each segment, the flow rate depends on the pressure gradient and resistance to the flow as described in the following equationRmv, Rav, Rtv, and Rpvv are the resistances associated with the mitral, aortic, tricuspid, and pulmonary valves, respectively. The valves are each represented by a diode that only permits one-way flow as in previous studies , Vsv,0 and Vpv,0 are the resting volumes and Csv and Cpv are the total compliance of the systemic and pulmonary veins, respectively.where Contraction of the LA and RA was modeled using a time varying elastance function that is given by the following PV relationswhere,k denotes either LA or RA. The volume, end-systolic elastance, and volume-intercept of the end-systolic pressure-volume relationship (ESPVR) of the corresponding atrium are denoted by Vk, Ees,k, and Vk0,, respectively. The parameters Ak and Bk define the atrium curvilinear end-diastolic pressure volume relationship (EDPVR) and the driving function is defined asIn Equation (4), the subscript tmax is the point of maximal chamber elastance and τ is the time constant of relaxation. The time-varying elastance model has been shown to be able to describe atrium contraction well , pulmonary artery and aorta were computed from their corresponding FE models. These relationships can be expressed as non-closed form functions.The weak form associated with the biventricular FE model was derived based on minimization of the following Lagrangian functionalBV0, is the reference configuration of the biventricular unit, uBV is the displacement field, PLV and PRV are, respectively, the Lagrange multipliers that constrain the LV cavity volume VLV, cav(uBV) to a prescribed value VLV and the RV cavity volume VRV, cav(uBV) to a prescribed value VRV . The Lagrange multiplier pBV was used to enforce incompressibility of the tissue . The vectors cBV1, and cBV2, are Lagrange multipliers applied to constrain, respectively, the rigid body translation  and rotation  where Ωinner,k is the volume enclosed by the inner surface Γinner,k of the LV or RV, and n denotes the outward unit normal vector of those surfaces. Taking the first variation of the Lagrangian functional given in Equation (7) leads towhere ΩPBV is the first Piola Kirchhoff stress tensor and FBV is the deformation gradient tensor. The variations of the displacement field, Lagrange multiplier for enforcing incompressibility and volume constraint, zero mean translation, and rotation are denoted by δuBV, δpBV, δPLV, cav, δPRV,cav, δcBV1,, and δcBV2,, respectively. Together with the constraint that the basal deformation at z = 0 is in-plane in the biventricular unit, the solution of the Euler-Lagrange problem was obtained by finding In Equation (9), PLV, cav∈ ℝ, δPRV, cav∈ ℝ, PRV, LVP, VRV, LVV in Equation (6).for all PBV in Equation (9) was additively decomposed into a passive and an active component, i.e.,Mechanical behavior of the myocardial tissue was described by an active stress formulation in which the first Piola-Kirchhoff stress tensor PBV, p is the passive stress tensor, PBV, a is the magnitude of the active stress, whereas ef and ef0 are the local basis vectors that define the cardiac muscle fiber directions in the current and reference configuration, respectively. The passive stress tensor PBV, p is related to the strain energy function WBV, p and deformation gradient tensor FBV byIn Equation (11), A Fung-type transversely-isotropic hyperelastic strain energy function  ϵ  denote the components of the Green-Lagrange strain tensor f, s, n denoting the myofiber, sheet and sheet normal directions, respectively. Material parameters of the Fung-type constitutive model are CBV, bff, bxx, and bfx.was prescribed. In Equation (13b), PBV, a was described byTo describe the active stress behavior, a previously developed active contraction model , and Ea is the stiffness of the serial elastic element. The function lc and is given bywhere T0 is a model parameter that scales the active tension. Both a6 and a7 are model parameters. The time course of the active tension development is controlled bywhere tr is the activation rise time constant, td is the activation decay time constant, b relates activation duration tmax to the sarcomere length ls, and ld is the sarcomere length at the start of the activation time, i.e., when tmax = 0. The time course of the contractile element lc was expressed by an ordinary differential equationIn Equation (16), v0 is the unloaded shortening velocity. The sarcomere length ls was calculated from the myofiber stretch λ and the relaxed sarcomere length ls0 bywhere k = AO denotes the aorta and k = PA denotes the pulmonary artery. Similar to that of the biventricular unit, the finite element formulation of these two arteries can be generalized from the minimization of the following Lagrangian functional, described in the following equationThe pulmonary artery and aorta were modeled as 3D membranes. In the formulation that follows, the subscript k0, is the reference configuration of the arteries, uk is the displacement field and Pk,cav is the Lagrange multiplier that constrains the arterial cavity volume Vk,cav(uk) to a prescribed value Vk. The vectors ck1, and ck2, are Lagrange multipliers applied to constrain rigid body motions. The inlet and outlets of the arteries were constrained to move only in-plane. Therefore, the solution of the Euler-Lagrange problem was obtained by finding where ΩPpa, Vpa, and Psa, saV in Equations (6b) and (6c), respectively.for all Wk in Equation (21), which is given as the sum of the key tissue constituents, namely, elastin-dominated matrix Wk,e, collagen fiber families Wk,c,i and vascular smooth muscle cells (SMC) Wk,m  were oriented in the longitudinal and circumferential directions, whereas the third and fourth families of collagen fibers (i = 3 and 4) were oriented, respectively, at an angle α = 45° and −45° with respect to the longitudinal axis based on a previous study , Wk,m is given byStrain energy function of the SMC Mk,m is the mass per unit volume of the SMC in the tissue, λk,m is the stretch of the SMC, whereas ck,4 and ck,5 are the stiffness parameters. The SMC was assumed to be aligned in the circumferential direction. Mass per unit volume for the different constituents were calculated using following relationsHere, k,e, ϕk,m, ϕk,i denote the mass fraction for elastin, SMC and ith family of collagen fibers, respectively. Twenty percent of the total collagen mass is assumed to be equally distributed in the longitudinal and circumferential fiber families and the remaining 80% was distributed equally to α = 45° and −45° fiber directions. Constitutive parameters, mass fraction of each constituent and other parameters of the pulmonary artery and aorta membrane models are listed in where ϕVLV, Vsa, Vsv, VRA, VRV, Vpa, Vpv, VLA) at each time ti were determined from their respective values and the segmental flow rates  at previous time ti−1 in Equation (2). The computed compartment volumes at ti were used to update the corresponding pressures . Pressures in the atrium  and veins  were computed from Equations (4) and (3), respectively. On the other hand, pressures in the LV (PLV), RV (PRV), were computed from the FE solutions of Equation (10) for the biventricular unit with the volumes  at time ti as input. Similarly, pressures in the aorta (Psa) and pulmonary artery (Ppa) were computed from the FE solutions of Equation (20) with their corresponding volumes  at time ti. We note here that  are scalar Lagrange multipliers in the FE formulation for constraining the cavity volumes to the prescribed values . The computed pressures at time ti were then used to update the segmental flow rates in Equation (2) that will be used to compute the compartment volumes at time ti+1 in the next iteration.An explicit time integration scheme was used to solve the ODEs in Equation (1). Specifically, compartment volumes  and had different values in the RVFW . In the baseline case, model parameters were adjusted to fit the clinically measured LV and RV PV loops, volume and pressure waveforms throughout the cardiac cycle. Specifically, the LV and RV end diastolic pressures were matched by adjusting the passive stiffness parameters CLV and CRV. Stroke volume (SV) of the LV and RV were matched by adjusting the regional contractility parameters . While other model parameters can also affect the SV , the parameters TLV0, and TRV0,, which scale the active stress generated by the myofiber, have a larger effect on the LV and RV SV, respectively. On the other hand, the contraction model parameters tr, td and b were adjusted to match the time course of the volume and pressure waveforms measured in the LV and RV. Parameters tr and td were adjusted to match the time to peak tension and b was adjusted to achieve the desirable relaxation of the myofibers. Circulatory model parameters (resistances and compliances) were also adjusted to match the systolic pressure (afterload), preload and systemic and pulmonary vein pressures. Aortic and PA peripheral resistances  were calibrated to match the systolic pressures of LV and RV. The parameters related to LA and RA time-varying elastance models were prescribed based on a previous study , the septum, and the RV free wall (RVFW). Similar to a previous study  a 50% decrease in RV contractility TRV0,, and (3) a 50% increase in the pulmonary arterial resistance Rpa.Since it is known that key features of the progression of PAH include stiffening of main PA, reduced RV contraction, and increased distal resistance of PA  with a corresponding decrease in the mass fraction of the elastin (from 0.35 to 0.15) and SMC (from 0.23 to 0.15) produced an increase in the PA pressure of 10% (from 71 to 78 mmHg). The RV systolic pressure also increased by 11% (from 68 to 76 mmHg) correspondingly  reduced the RV EF by 5% (from 58 to 53%) (Decreasing the RV contractility  to 53%) . Due to  to 53%) . In addi to 53%) . Because to 53%) . Average to 53%) .Rpa by 50% led to an increase in PA pulse pressure by 36% (from 45 to 61 mmHg), which was also accompanied by an increase in PA systolic and diastolic pressure  that captures detailed bi-directional ventricular-arterial interactions. We have shown that our proposed model describes the cardiopulmonary circulation reasonably well by reproducing patient-specific measurements of (1) LV and RV PV loops, (2) LV and RV volume and pressure waveforms, and (3) aorta and PA pressure and diameter waveforms of a PAH patient.This framework extends our previously developed hybrid lumped-FE model of the systemic circulation  in the model, which reflects the transition to decompensated heart failure, produced an expected decrease in EF and peak systolic pressure that results in a substantial decrease in myofiber stress in the RV. Reducing the RV contractility also reduces the PA peak and pulse pressures, only decreasing the arterial wall stress in the PA slightly. Based on consensus that arterial wall stress is the driver for vascular remodeling  causes ejection to start at a higher pressure and the EF to be slightly reduced in the RV. These results are broadly consistent with the effects on the RV measured in patients under acute hypoxia . Written informed consent to participate in this study was provided by the participants' legal guardian/next of kin.SS, SB, and LL developed the theoretical formulation and computational framework of the model. SS and CT-B carried out the simulations for different cases and prepared the results. CT-B and CF acquired the clinical data. LL, SB, and CF planned and supervised the work. All authors helped in interpretation of the results and contributed to the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Our study aimed to determine whether layer-specific strain (LSS) could reflect regional myocardial impairment in patients with hypertrophic cardiomyopathy (HCM). The study enrolled 50 patients with HCM and 30 age-matched healthy controls. Transmural gradient of longitudinal strain (TGLS), defined as the difference between the longitudinal strain of the endocardium and epicardium in a left ventricular segment, was used to reflect layer-specific myocardial impairment. Negative TGLS was consistently observed in healthy controls. The TGLS was relatively consistent within the basal, middle, and apical levels in healthy controls,but showed a significant gradient from the base towards the apex. In patients with HCM, the hypertrophic segments had significantly higher TGLS than the relatively normal segments or healthy controls at all 3 levels . Abnormal TGLS, defined as positive TGLS, in patients with HCM was associated with chest pain. In receiver operating characteristic curve analysis, a large area of abnormal TGLS (> 4 segments) had moderate accuracy for predicting chest pain . TGLS, a novel LSS derived parameter, may reflect regional myocardial impairment in patients with HCM. Patients with hypertrophic cardiomyopathy (HCM) could develop layer-specific myocardial impairment because of subendocardial microvascular dysfunction and focal cardiac fibrosis, however, this phenomenon has not received significant attention due to the lack of a feasible examination method.The hypertrophic left ventricular segments had significantly higher TGLS, defined as the difference between territorial longitudinal strain of the endocardium and the epicardium, than the relatively normal segments of HCM patients or healthy controls.Positive TGLS, which was consistently negative in healthy controls, was associated with chest pain in HCM patients, and may reflect endocardium-specific impairment of regional heart function in patients with HCM.Two-dimensional 2-D) speckle-tracking echocardiography is widely acknowledged as a sensitive method for evaluating global and regional left ventricular (LV) function. The ventricular wall consists of 3 layers, namely, the epicardium, mid-myocardium, and endocardium. Conventionally, assessment of the ventricular wall has not taken into account the different layers of the myocardium but has considered them as a single functional unit. This simplification generally works well. However, in patients with hypertrophic cardiomyopathy (HCM), this could be problematic. Previous studies have demonstrated that patients with HCM could develop subendocardial microvascular dysfunction  and foca-D specklImprovements in the temporal and spatial resolution of 2-D echocardiography and strain analysis software have enabled layer-specific strain (LSS) analysis . SeveralThis study prospectively recruited 67 consecutive patients with HCM according to the definition of the European Society of Cardiology Guidelines on diagnosis and management of HCM  at West E/e′– the ratio of mitral inflow early diastolic velocity (E) to the septal mitral annular spectral tissue Doppler early diastolic velocity (e’) – was also obtained in the apical 4-chamber view. Other parameters, such as maximum wall thickness, LV outflow tract gradient, and the phenomenon of systolic anterior motion, were also evaluated in accordance with the recommendations of the American Society of Echocardiography [All echocardiographic data assessments and image acquisitions were performed by an experienced sonographer by using an E9 ultrasonography system . Routine 2D images were acquired at a frame rate of 40–80 fps. LVEF was measured using the Simpson biplane method. The mitral iography .The 18-segment model, including posterior , anteroseptal , septal , lateral , inferior , and anterior  segments, was used in the segmental analysis. The LV segmental thickness in patients with HCM was measured to identify the hypertrophic (> 12 mm) and normal (≤ 12 mm) segments, and dynamic images were observed. Three consecutive measurements were conducted to find the average value. Images in the apical 4-, 2-, and 3-chamber views from 3 consecutive cycles were stored digitally and analyzed offline.The 2-D multilayer global strain in the LV myocardium was analyzed using ECHOPAC version 201 software . Aortic valve closing was automatically confirmed by software combined with manual adjustment. The border of the endocardium and the width of the target myocardium were manually traced and adjusted. The poorly traced segments  were also excluded. The software automatically calculated segmental strain of the endocardial, middle, and epicardial myocardial layers , adding or up-titration of non-dihydropyridine calcium channel blockers (3 patients) and other changes in regimens (3 patients). Both patients and healthy controls received another echocardiography examination at the end of the follow-up, or before any invasive treatment if invasive strategies including open surgery, septal alcohol ablation or pace-maker implantation were planned.The intra-observer and inter-observer reproducibility of TGLS was measured successively in 10 randomly selected patients with HCM. To test the intra-observer variability, a single observer analyzed the data twice on separate occasions at an interval of 1 month. To test the inter-observer variability, a second observer who was blinded to the first observer’s measurements analyzed the same data.t tests or the Wilcoxon test. Categorical variables were described as counts and percentages, and were compared using the Pearson chi-square test. Comparisons between the different segments, the 3 segmental levels in the controls, and the different subgroups were performed using analysis of variance. Multivariate ordinal logistic regression was used to assess association of different parameters with the grade of severity of abnormal TGLS segments. A receiver operating characteristic (ROC) curve was constructed for the completed model, and a probability threshold was selected for the likelihood of predicting chest pain based on the number of segments with abnormal TGLS. The resulting sensitivity and specificity were also estimated. The intra-observer and inter-observer variability values were analyzed using Bland-Altman bias plots, and by intraclass correlation coefficients (ICC). All tests were 2-sided, and p < 0.05 was considered significant.All statistical analyses were conducted using SPSS version 19.0 . The Shapiro-Wilk test was used to estimate the normality of the distributions of continuous data. Continuous variables with normal distributions are presented as mean ± standard deviation, whereas those with skewed distributions are expressed as median (interquartile range). Baseline characteristics were compared between the HCM and control groups using independent-samples 2 in HCM group and 68.5 ± 10.4 g/m2 in the control group. 64 % of the HCM patients had left ventricular outflow tract (LVOT) obstruction, with a mean resting gradient of 56 mmHg.The baseline characteristics and clinical findings of the study participants are listed in Table The layer specific longitudinal strain of healthy volunteers and HCM patients were listed in Table Abnormal TGLS, defined as a positive TGLS, was observed in 1.1 % 6 of 540) of the normal LV segments in healthy controls. In patients with HCM, 11.3 % (61 of 542) of the non-hypertrophic segments and 45.3 % (156 of 344) of the hypertrophic segments had abnormal TGLS . The presence of LVOT obstruction was also strongly correlated with the severity of abnormal TGLS . Other parameters including age, sex, body mass index, width of pulmonary artery, and E/e’ were not significantly associated with the level of abnormal TGLS segments  was assessed in a multivariate ordinal logistic regression. The results demonstrated that LV mass index positively correlated with the severity of abnormal TGLS. In particular, with the increase in LV mass index for every 1 g/mTo further elucidate the clinical significance of abnormal TGLS, patients with HCM were further divided into 2 groups according to symptom. Patients with chest pain generally had more LV segments with abnormal TGLS than those without chest pain . In the ROC curve analysis, a large area of abnormal TGLS (> 4 segments) had moderate accuracy for predicting chest pain   TGLS is a reproducible echocardiographic parameter. A negative TGLS was consistently observed in healthy controls. TGLS was significantly decreased from the base toward the apex but was relatively consistent within the basal, middle, and apical levels. (2) In patients with HCM, the hypertrophic LV segments had significantly higher TGLS than the relatively normal segments and healthy controls. (3) The abnormal TGLS in patients with HCM could be associated with subendocardial ischemia and LVOT pressure gradient.Previous studies have demonstrated that strain imaging was helpful in diagnosis and prognosis prediction in HCM patients , 12. A sAlthough changes in transmural gradient of strain was observed in hypertrophic segments of HCM, its clinical significance has not been clearly elucidated yet. Recent echocardiography studies have reported that endocardial function was more affected in patients with ischemia , 6. A veFurthermore, a recent study reported improvement of subendocardial strain in patients with hypertrophic obstructive cardiomyopathy after alcohol septal ablation , suggestAnother difficulty in interpreting the abnormal transmural strain gradient was the lack of universal measurement and normal reference value. Nagata et al.  attempteAs for the normal reference value, we simply used 0.0 % as the cutoff value for abnormal TGLS in the present study. This cutoff value had relatively high specificity. Healthy controls generally had a negative TGLS. The false-positive rate of TGLS was only 1.1 % in healthy controls. In HCM patients, positive TGLS was found mainly in the hypertrophic segments. However, a significant change of TGLS from the basal toward the apical segments was observed in our study. This trend was also observed by other investigators. In the study by Nagata et al. , the aveThis study has several limitations. Firstly, the major limitation of the present study is the relatively small sample size. Secondly, the possibility that some patients with HCM might also have coronary artery disease but was not totally excluded. Most of the study subjects underwent coronary angiography or coronary computed tomography to rule out potential coronary artery disease. However, in some young and asymptomatic patients, it is unethical to perform invasive coronary angiography or coronary computed tomography. Thirdly, TGLS may be also affected by the presence of microvascular dysfunction in HCM patients. Thus, comparison of echocardiography derived strain with more sensitive perfusion techniques, such as nuclear imaging and CMR, could provide more information. However, only a small portion of our patients received CMR or nuclide myocardial imaging. Thus, comparison of these techniques was not possible in this article. Further studies will be helpful to elucidate the mechanism underlying the layer specific impairment of myocardial strain.A novel LSS-derived parameter named TGLS, defined as the difference between the territorial longitudinal strains of the endocardium and epicardium, could reflect the endocardium-specific impairment of regional heart function in patients with HCM.


Elevated deoxyhaemoglobin seen downstream in a territory subtended by a stenotic coronary artery can be assessed by blood oxygen level-dependent (BOLD) MRI. Deoxyhemoglobin is paramagnetic and acts as an intrinsic contrast agent leading to signal loss in T2- and T2*-weighted sequences. Previous animal and human BOLD studies at 1.5 Tesla using T2*-weighted sequences were fundamentally limited by the relatively small signal differences between normal and de-oxygenated myocardial regions. A new T2-prepared steady-state free precession (SSFP) BOLD sequence gave promising results in animal models at 1.5 Tesla.[Twenty-two patients  with CAD (at least 1 stenosis > 50% on quantitative coronary angiography-QCA) and 10 normal volunteers  underwent 3 T BOLD MRI and PET. For BOLD-CMR, a single mid-ventricular slice was acquired at mid-diastole using a T2-prepared SSFP pulse sequence with the following parameters: T2 preparation weighting 40 ms, matrix 168 × 192, slice thickness 8 mm, flip angle 44°. A set of 6 images was acquired at rest and at peak adenosine (140 μg/kg/min) stress. Using PET with oxygen-15 labeled water, myocardial blood flow (MBF) was measured at baseline and during adenosine hyperemia. The BOLD short-axis view was divided into 6 segments, according to the mid-ventricular segments of the 17-AHA segment model, and mean signal intensities (SI) were calculated using QMass (Medis) software. SI values were corrected for differences in T1-weighting owing to heart rate changes at stress and rest. PET images were analyzed with home-built software under MATLAB (MathWorks Inc.) and registered with the BOLD short-axis image using anatomical landmarks.Based on the coronary anatomy, 59 myocardial segments were supplied by significantly stenosed vessels (stenosed segments) and 73 segments were supplied by vessels with minimal or no disease (remote to ischemia segments). A third group of myocardial segments (n = 60) from normal volunteers were labeled as 'normal' segments. Rest MBF, stress MBF, coronary flow reserve and BOLD-SI change of stenosed, remote to ischemia and normal segments are shown in Table T2-prepared SSFP 3 T BOLD imaging is feasible in the clinical setting and has good agreement with PET perfusion measurements for the detection of myocardial ischemia.


P = 0.068). Compared with the healthy controls, the uncontrolled blood glucose group showed an impaired GLS . Nevertheless, PSD was appreciably increased in the controlled blood glucose group  and uncontrolled blood glucose group . Multivariate linear regression analysis showed that HbA1c was closely related to PSD lesion in the LV in the T2DM group . PSD plays an important role in evaluating the coordination and synchronization of myocardial movement and provides a more accurate and sensitive index assessment of early LV systolic function in T2DM patients. In addition, HbA1c levels were related to LV dysfunction.Cardiovascular disease is one of the main causes of death in diabetes mellitus (DM) patients. The aim of the current study was to explore the value of peak strain dispersion (PSD) for discovering early-stage left ventricular (LV) dysfunction in type 2 diabetes mellitus (T2DM) patients. One hundred and one T2DM patients and sixty healthy subjects were selected for this study. T2DM patients were further divided into controlled blood glucose  and uncontrolled blood glucose  subgroups. All participants underwent conventional echocardiography and two-dimensional speckle-tracking echocardiography. Our results showed that an obvious difference was not observed in global longitudinal strain (GLS) between the controlled blood glucose group and the control group (− 20.34% vs − 21.22%,  In addition, large-sample and multicentre studies have confirmed that compared with nondiabetic patients, diabetic patients have a two- to threefold increase in the risk of congestive heart failure and cardiovascular disease mortality2. Furthermore, there are many mechanisms that may lead to myocardial lesion in diabetes, such as myocardial cell metabolism disorder, myocardial fibrosis, myocardial cell apoptosis, microvascular disease, oxidative stress, and inflammatory response4. Patients with T2DM may have heart function damage to different degrees. Therefore, early detection of cardiac dysfunction and treatment intervention are necessary to reduce the risk and mortality of cardiovascular disease. Left ventricular ejection fraction (LVEF) is the most commonly used index to evaluate left ventricular (LV) systolic function, but a decrease in LVEF often appears in advanced periods of diabetes.In recent years, the incidence of type 2 diabetes mellitus (T2DM) has gradually increased. Epidemiological studies show that approximately 70–80% of diabetic patients die of cardiovascular disease, making cardiovascular complications the main cause of death of diabetic patients6. Accumulating evidence has shown that GLS is the most commonly used strain and can be used to detect early subclinical LV dysfunction in patients with normal LVEF. GLS is significantly reduced in some diseases, such as hypertension7 and valvular disease8. However, GLS has an inherent shortcoming, ignoring the change in myocardial movement sequence or peak time parameters10.With the rapid development of echocardiography in recent years, the technology can also be used to evaluate early LV systolic dysfunction with myocardial strain index, such as global longitudinal strain(GLS), and global circumferential strain(GCS), obtained by two-dimensional speckle-tracking echocardiography (2DSTE)12. PSD is used to evaluate the early systolic dysfunction of LV by combining the coordination and synchronization of cardiac mechanical movement, and this index has been applied to assess early LV systolic dysfunction in some diseases, such as mitral valve prolapse13, aortic stenosis14 and hypertrophic cardiomyopathy15. In the current study, we aimed to explore the value of PSD for discovering early-stage LV dysfunction in T2DM patients.The emerging study of peak strain dispersion (PSD) identifies whether the peak time of long axis strain of LV myocardium is consistent, which can directly reflect the effective work of the heart and make up for the deficiency of GLS in evaluating LV systolic function16. Exclusion criteria included coexisting poorly controlled high blood pressure (BP), coronary artery disease, hyperlipidaemia, pericardial disease, cardiac arrhythmia , damage to valves  regurgitation (mild and above) and any degree of valve stenosis), structural heart diseases or poor acoustic windows. Finally, one hundred and one patients were selected for the case group. The hemoglobin A1c (HbA1c) level is regarded as the most valuable index to judge the state of blood glucose control in patients with T2DM17. To evaluate whether controlled blood glucose levels and uncontrolled blood glucose levels may lead to different myocardial lesions in patients with T2DM, the case group was further divided into a controlled blood glucose  group , 6 cases with obesity, and 6 cases with hypertension  and obesity) and an uncontrolled blood glucose  group , 5 cases with obesity, and 8 cases with hypertension  and obesity ) on the basis of HbA1c levels tested in the past two weeks. Sixty subjects with good ultrasound image quality were also included in the control group in this study. Twenty-eight healthy subjects, 19 controls with hypertension , 9 controls with obesity and 4 controls with hypertension  and obesity were included in the control group. All of the subjects of the study provided written informed consent.This study included one hundred and eighteen T2DM patients with New York Heart Association functional classifications of class I or II. All T2DM patients met the diagnostic criteria of diabetes mellitus (DM) according to the 2010 guidelines of the American Diabetes AssociationAge, body surface area (BSA), body mass index (BMI), sex, heart rate (HR), systolic blood pressure (SBP) and diastolic blood pressure (DBP) were recorded for all subjects. Blood samples were obtained from all participants, and the following laboratory tests were performed: high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, total cholesterol, and triglycerides. HbA1c was also tested, and the duration of T2DM was recorded in patients with T2DM.m, and Am were measured in all subjects. LV mass index (LVMI) was assessed by LV mass, which was calculated using the Devereux formula divided by BSA. LVEF was calculated by the biplane Simpson’s method after images were obtained from the 4-chamber and 2-chamber sections of apical views. The E/A ratio, Em/Am ratio and E/Em ratio were calculated.All subjects received routine echocardiography examination. All subjects were in sinus rhythm at the time of echocardiography. Routine echocardiography image acquisition and data measurement were performed using the GE VividE9 ultrasound diagnostic system and M5Sc probe, whose frame rates were adjusted to the range of 1.5–4.6 MHz. LV end diastolic diameter (LVEDD), LV end diastolic volume (LVEDV), peak E, peak A, isovolumetric relaxation time (IVRT), EImages from 2DSTE were obtained using an M5Sc transducer (Vivid E9) in the four-chamber, three-chamber and two-chamber of apical views for all subjects. All participants were told to hold their breath while images were obtained so that high-quality images could be acquired. When we take images, each patient is connected to an electrocardiograph. All images were collected in 3–5 complete cardiac cycles. The frame rate of the image was fixed in the range of 40–80 frames/s. An advanced quantitative analysis EchoPAC workstation (version 201) was used for 2DSTE analyses. The endocardium of the LV was tracked point by point in the apical four-chamber, apical three-chamber and apical two-chamber views. After 17 segments of the LV were successfully tracked, GLS and LV PSD were automatically abtained. The analysis procedure of GLS and PSD is exhibited in Fig. All statistical analyses were conducted using SPSS version 23.0 . Independent-sample T tests or Mann–Whitney nonparametric tests were applied to compare the clinical and echocardiographic parameters between the case group and the control group. One-way analysis of variance or the Kruskal–Wallis and Mann–Whitney nonparametric tests were employed for comparisons among groups. The normality of continuous data was tested by the Kolmogorov–Smirnov test. Data conforming to a normal distribution are shown as the mean ± SD or as the median (25th and 75th percentiles). The chi-square test was applied to compare categorical data.m ratio), multivariate linear regression analysis was used to test the risk of the abovementioned factors on GLS and PSD in LV for the case group. P values < 0.05 were considered statistically significant for all analyses.To evaluate whether LV dysfunction is affected by multiple factors . Written informed consent was obtained from all participants. All methods were performed in accordance with relevant guidelines and regulations.All authors give their consent for publication.1c . There were no considerable differences for age, BSA, BMI, sex, HR, SBP, DBP, HDL, LDL cholesterol, total cholesterol and triglycerides among the groups (P > 0.05). Arterial hypertension  and obesity were equally distributed in the control group and T2DM subgroups.Table 2 vs 93.55 g/m2, P = 0.002) and E/Em ratio  and an apparently lower E/A ratio , Em , and Em/Am ratio . A mild descending peak E  and a mild increasing peak A  were also observed in the T2DM group matched with the control group. The T2DM and control groups were well matched for IVRT and Am. In the comparison among subgroups, we found that, compared with the control group, impaired LVMI and Em were found in the controlled blood glucose group  and uncontrolled blood glucose group , but the greatest alteration was found in the uncontrolled blood glucose group. Slightly damaged peak E , peak A , E/A ratio , IVRT , Am , Em/Am ratio  and E/Em ratio  were observed in the uncontrolled blood glucose group. LVEDD, LVEDV and LVEF were comparable among those groups , and PSD  were significantly damaged in the T2DM group. Different changes in GLS and PSD in the controlled blood glucose group and uncontrolled blood glucose group are also displayed in Table P = 0.068). Compared with the healthy controls, the uncontrolled blood glucose group showed an evident impaired GLS . Nevertheless, PSD was appreciably increased in the controlled blood glucose group  and uncontrolled blood glucose group . Moreover, a large difference was observed in the uncontrolled blood glucose group , LVMI  and the E/Em ratio . HbA1c , LVMI  and E/Em ratio  were correlated with impaired PSD in the LV in the T2DM group. T2DM duration, age, SBP and LDL were not affected by GLS or PSD in the LV. In general, LVMI had an obvious impact on GLS destruction in the LV, and HbA1c was closely related to PSD lesions in the LV in the case group.  and inter-observer (GLS for − 5.73 to 5.67% and PSD for − 4.99–5.07 ms) measurements was good  GLS and PSD may be used to detect early LV systolic dysfunction in T2DM patients with preserved LVEF, (2) the LV myocardium is damaged, and the coordination and synchronization of myocardial movement are poor in T2DM patients, (3) subclinical LV diastolic and systolic function were impaired in patients with T2DM, and (4) LV remodelling and hypertrophy may occur in patients with T2DM. These phenomena may be explained by the following reasons. Various pathogeneses, such as metabolic disorders, cardiomyocyte apoptosis, microvascular disease, oxidative stress, and mitochondrial structural disorders, may be involved in myocardial hypertrophy and compliance reduction, LV remodelling and ventricular wall rigidity22, which may lead to damage to LV systolic and/or diastolic function. Therefore, PSD by 2DSTE may be used to estimate subclinical LV dysfunction, which is consistent with previous studies23.In this study, we found that LVEF was comparable between the control group and the T2DM group. The LVMI and E/E17. Therefore, to explore the relationship between blood glucose level and LV dysfunction, we divided T2DM patients into two subgroups (including the controlled blood glucose group and uncontrolled blood glucose group) based on HbA1c level. The outcomes of the present study showed that there was no difference in LVEF among those groups. Damaged LVMI and Em were observed in the two subgroups compared with the control group, but the most obvious change was seen in the uncontrolled blood glucose group. Impaired peak E, peak A, E/A ratio, IVRT, Am, Em/Am ratio and E/Em ratio were rarely observed in the uncontrolled blood glucose group. In addition, we also observed that GLS was not different between the controlled blood glucose group and the control group. The uncontrolled blood glucose group matched with healthy controls had a significantly impaired GLS. However, PSD was evident in the two subgroups. A noticeable difference was found in the uncontrolled blood glucose group. Our results showed that (1) PSD is a more sensitive and accurate indicator than GLS in the detection of early LV systolic dysfunction. PSD estimates whether the peak time of long axis strain of the LV myocardium is consistent 12. Recent paper has also shown that PSD is associated with an elevated risk of fatal arrhythmias and sudden cardiac death in patients with coronary artery disease and hypertension23. Thus, compared with GLS, PSD may be used to evaluate early LV dysfunction more comprehensively by combining the coordination and synchronization of cardiac mechanical movement. (2) There are still inconsistencies in the synchrony and coordination of myocardial movement in patients with T2DM with well-controlled blood glucose. (3) Cardiac dysfunction was more obvious in the poor blood glucose control group with T2DM.HbA1c is the most valuable index to judge the state of blood glucose control. The index is stable and can be used to reflect the average blood glucose level in the two months before blood samplingm ratio were related to GLS lesions and PSD in the LV in the case group. The LVMI has an evident influence on impaired GLS in the LV, and HbA1c is closely correlated with destroyed PSD in the LV. These results indicated that the more hypertrophic the LV and the higher the level of HbA1c, the more serious the damage to LV function, which corresponds to previous reports. The reasons may be as follows: (1) Hyperglycaemia may generate excessive reactive oxygen species through the electron transport chain, which may result in myocyte apoptosis24. (2) Hyperglycaemia may induce other biochemical cascade reactions of myocardial injury, stimulate the expression and accumulation of collagen and promote the cross connection of collagen25, which may lead to increased myocardial fibrosis and decreased myocardial compliance. (3) Increased glucose uptake of myocardial cells may affect their energy metabolism, which may lead to the occurrence of diabetic cardiomyopathy and obvious damage to myocardial function26. (4) Myocardial compensatory hypertrophy may occur after myocardial damage, which may result in limitations of myocardial movement and damage to myocardial deformation4.In addition, the results of this study also showed that HbA1c, LVMI and the E/Em were all related to damaged LV function. The higher the level of blood sugar is, the greater the damage to heart function. Therefore, early monitoring of cardiac function and active control of blood glucose are of great clinical significance for improving prognosis and reducing mortality for T2DM patients.Overall, PSD plays an important role in evaluating the coordination and synchronization of myocardial movement and provides a more accurate and sensitive index assessment of early LV systolic function in T2DM patients. Lesions of GLS appear more frequently in T2DM patients with poor blood glucose control. PSD is more susceptible to early estimation of LV systolic dysfunction in T2DM patients with well-controlled blood glucose. In addition, HbA1c level, LVMI and E/EThe limitations of this study include the following. First, the study was a cross-sectional study, lacked follow-up data, and failed to evaluate the prognostic significance of damaged GLS and PSD in T2DM patients; Second, the study was a single-centre study with a small sample size. Third, the study evaluated GLS in the LV, and layer-specific analysis should be considered in future studies. Finally, 2DSTE requires high image quality, and some patients were not included because of poor image quality.


In univariate analysis, hypertension (HTN) (β = −0.294 (−0.313–0.047), p = 0.009, smoking β = −0.244 (−0.289–0.015) =0.03, WMA β = −0.317 (−0.284–0.014), p = 0.004 and the number of diseased vessels β = −0.256 (−0.188– 0.054) p=0.03 were predictors of delta global SR. In multivariate analysis, only HTN β = 0.263 (0.005–3.159) and the number of diseased vessels β =0.263 (0.005 - 3.159), p=0.04) predicted delta global SR. In ACS, the echocardiographic regional myocardial deformation is accurate in detecting early recovery of LV myocardial function after culprit lesion revascularization. Also, the findings of this study support the current practice regarding the crucial importance of proximal epicardial vessel PCI treatment on LV function compared to more distal lesions. The aim of this study was to assess the accuracy of echocardiographic techniques in detecting the early recovery of left ventricular (LV) function after revascularization in acute coronary syndrome (ACS). In 80 consecutive patients with ACS , an echocardiographic examination of left ventricle regional wall motion abnormalities (LV RWMA), peak systolic strain rate (PSSR), peak systolic strain (PSS) and end systolic strain (ESS) was performed before and after percutaneous intervention (PCI). Of the 80 patients, one vessel stenosis (>70%) was present in 53 (66%), two vessel disease in 12 (15%) and multivessel disease in 15 patients (19%). In total, 51% of patients had hypertension, 40% diabetes and 23% dyslipidemia. After PCI, regional PSS, ESS and PSSR of their segments subtended by the culprit vessel improved; left anterior descending-LAD, circumflex-LCx and right coronary-RCA  as well as global S and SR ( Acute coronary syndrome (ACS) remains a major cause of death and morbidity worldwide , despiteThe evaluation of cardiac function, in particular left ventricular (LV) function before PCI, adds to the accurate design of treatment strategy. Recently, beyond the assessment of ejection fraction (EF) as a global marker of LV function, the evaluation of myocardial deformation by regional or global strain and strain rate (SR) has been introduced in routine clinical practice  and in aThe aim of this study was to assess the early effect of coronary revascularization by PCI for ACS on the recovery of segmental and regional LV function as well as the impact of the proximity of the targeted lesion on cavity function recovery.Eighty consecutive patients presenting to the emergency room of the International Cardiac Centre (ICC), Alexandria, Egypt from January 2018 to October 2018 were included in this study. ACS was defined and patients were managed according to the European Guidelines . PatientAll patients with previous myocardial infarction, PCI, coronary artery bypass graft surgery (CABG), more than mild valve disease, atrial fibrillation on admission, LV ejection fraction (EF) <35% or hemodynamic instability were excluded from the study. On admission, all patients had a preliminary ECG, a blood sample withdrawn for troponin and creatine kinase-MB (CK-MB) in addition to other routine laboratory investigations including hematology and biochemistry. The patients also underwent a full echocardiographic examination by the clinician on call, including tissue Doppler imaging (TDI) (first 30 patients) and speckle tracking echocardiography (STE) (the remaining 50 patients). The echocardiographic examination was performed using a Philips system equipped with an adult 1.5–4.3 MHz phased array transducer. The standard views from the parasternal long and short axis and the apical four-chamber views were acquired. The LV end-diastolic dimension (LVDd) and end-systolic dimension (LVDs) were measured in the parasternal LV long-axis view, and the fractional shortening was calculated. The interventricular septal thickness and LV posterior wall thickness were measured at the end-diastole and end-systole in the LV short-axis view at the basal level. The LV EF was calculated using the biplane method . −1 with a superimposed ECG (lead II), and the measurements were taken as means of three consecutive cardiac cycles. Speckle tracking images were obtained with the patient in the left lateral decubitus position, from the parasternal short axis  and from apical 4-, 3- and 2-chamber views, at rest. Two-dimensional grey scale images were obtained at a frame rate of 70–80 Hz during three cardiac cycles and were then digitally stored for off-line analysis. The off-line analysis of the TDI and STE cine loops was performed by two investigators using commercially available software . After manually outlining a clear myocardial border at the end-systole, the region of interest (ROI), generated automatically by the software, was manually adjusted and the peak systolic strain (PSS), peak systolic strain rate (PSSR), and peak end systolic strain rate (PESSR) at the basal, middle, and apical levels were all measured [The tissue Doppler segmental myocardial velocities were measured at the basal segments of the longitudinal segments according to the conventional guidelines of the American Society of Echocardiography and European Association of Cardiovascular Imaging . All Dopmeasured . The strain analysis through the entire cardiac cycle provided continuous values of global and segmental strain for all segments simultaneously. The regional strain was calculated by combining the values of the segments subtended by each of the three main epicardial coronary arteries, the left anterior descending (LAD), circumflex (LCx) and right coronary artery (RCA). The regional values for the basal and apical segments were also combined based on the respective arterial blood supply. In addition, the improvement of myocardial deformation after PCI was calculated as delta strain.According to clinical presentation, the patients underwent either a primary PCI (for STEMI) or elective PCI within the first 48 hours of admission (for non-STEMI) . Before Troponin was measured at admission using Rosh diagnostics highly sensitive troponin (T) with a normal cutoff value of 0.014 ng/dL. CK-MB was also measured using Rosh Diagnostics with a normal range of 1.72–4.78 ng/dL for males and 1.39–3.61 ng/dL for females .All patients underwent a diagnostic coronary angiogram using the Judkins procedure and an onsite Toshiba lab and the conventional protocol. The culprit lesion was identified and stented. Other lesions were also treated in another setting according to the patient’s hemodynamic status. This study conformed with the Helsinki convention guidelines, the protocol was approved by the local Ethics Committee  and all patients gave informed consent to participate in the study. p value <0.05 (2-tailed). The statistical analysis was performed with SPSS Software Package  version 22.0.The data are summarized using frequencies (percentages) for categorical variables and mean ± standard deviation for continuous variables or median interquartile (IRQ) ranges, when appropriate. The differences between the data before and after PCI were compared using the dependent t-test. The correlations were tested with Pearson coefficients. The predictors of delta Global SR were identified with univariate analysis, and multivariate logistic regression was performed using the stepwise method. The receiver operational characteristic (ROC) analyses were performed and the best cut-off value was determined and, at that point, sensitivity and specificity were determined. A significant difference was defined as The patients’ mean age was 55.7 ± 9.4 years, 23% were females, 51% had hypertension where hypertension was defined as office SBP values ≥140 mmHg and/or diastolic BP (DBP) values ≥90 mmHg , 40.1% hFollowing successful PCI, which was defined according to the ACC/AHA as the achievement of <30% residual diameter stenosis of all the treated lesions assessed visually or using QCA, without an in-hospital major adverse cardiac event  , the LV p < 0.05 for all) as did PSSR, PSS and ESS for the territories supplied by LCx and RCA . Delta regional SR of the territories correlated with the successful corresponding LAD PCI , territories of LCx  and those of the RCA . Delta regional PSS also correlated with delta ESS,  except delta ESS for LCx and PSS for LAD  in predicting successful PCI of culprit LAD stenosis. A delta regional SR of <-0.02 was 67% sensitive and 70% specific  in predicting LCx PCI. A mean SR of <−0.03 was 73% sensitive and 67% specific  in predicting RCA treated stenosis   . p = 0.001) and a delta SR < 0.31 predicted two vessel disease with 75% sensitivity and 63% specificity . The respective values for predicting one vessel disease were delta global SR < 0.29, with 67% sensitivity and 65% specificity    . Delta gfor all) .p < 0.001, p = 0.69 respectively)  . Also, wctively) .p = 0.04, respectively), as did the apical delta SR . A similar pattern was seen in the LCx territories, with respective values  and  compared with mid/distal occlusion. Likewise, those of the RCA territories  and apical  as well as for the RCA territories , but the LCx territories did not show a significant difference ), compared with a SR TDI <−0.02 ), in predicting successful LAD PCI. The delta global SR STE strongly predicted the presence of multivessel disease compared with the delta global SR TDI  vs.  =0.03, WMA β= −0.317 (−0.284–0.014), p = 0.004 and the number of diseased vessels β = −0.256 (−0.188–0.054), p = 0.03 predicted the delta global rise of SR. In the multivariate analysis, only HTN β = 0.263 (0.005–3.159) and the number of diseased vessels β = 0.263 (0.005–3.159), p = 0.04) independently predicted a delta global rise of SR after PCI  (β = −0.294 (−0.313–0.047), fter PCI .Findings: In a group of patients with ACS found to have significant culprit lesions treated by conventional PCI, the revascularization procedure did not affect the conventional global marker of systolic LV function, i.e., the ejection fraction. It was associated however with a significant improvement in the segmental and regional myocardial function, which are shown be deformation parameters. Irrespective of the branch PCI, the regional strain and SR increased within 3 days of PCI and the delta regional increase correlated with the revascularized artery, with an average sensitivity and specificity of 70%. The highest accuracy of PCI associated with an increased global SR <−35% was seen in patients with multivessel CAD, with an accuracy of 77%. Also, PCI to proximal branch culprit lesions, of the three epicardial arteries, resulted in greater improvement of basal and apical regional deformation. The basal improvement of the deformation function was more profound than the apical region in LAD and RCA PCI but not in LCx PCI. Of note, the STE-based function assessment was more accurate than those obtained from the one third of patients who underwent TDI deformation. Finally, hypertension and multivessel disease were the only independent predictors of recovery of LV function in this group of patients.Data interpretation: PCI is known to result in early segmental LV improvement of function in patients with disturbed function under controlled conditions, irrespective of the acuity of presentation. Although the conventional LV ejection fraction does not significantly change, the assessment of segmental performance has been shown to improve within hours of successful revascularization ,16. OverLimitations: Our study has obvious limitations, mainly related to the relatively small sample volume and the potential impact on statistical analysis, despite that the significant level of PCI-related change in segmental and regional LV function suggests that it is robust, irrespective of the sample volume. Although the induced acute ischemia might have also affected our results, this would have only strengthened our conclusion. We did not have longer term data on these patients to assess potential further improvements of LV function, whether segmental or global. Speckle tracking echocardiography remains a research vehicle; its daily use in clinical practice should optimize operators’ skills and the technique’s accuracy in serving such patients.Clinical implication: PCI of the culprit lesion in acute coronary syndrome is associated with a significant improvement of segmental and regional LV function assessed by myocardial deformation techniques, particularly STE over and above that obtained using tissue Doppler technique. These findings strengthen the clinical application of STE as an accurate technique for monitoring CAD patients, obtaining baseline values and following them up, particularly when they develop symptoms.In ACS, the echocardiographic regional myocardial deformation is very accurate in detecting early recovery of LV myocardial function after culprit lesion revascularization. Also, the findings of this study support the current practice regarding the crucial importance of proximal epicardial vessel PCI treatment on LV function compared to more distal lesions. Finally, they also support the fundamental importance of preserving basal LV regional function by optimum revascularization.