Left Ventricular Anterior Wall Research Articles

Genetic mouse models of autism spectrum disorder present subtle heterogenous cardiac abnormalities.

Autism spectrum disorder (ASD) and congenital heart disease (CHD) are linked on a functional and genetic level. Most work has investigated CHD‐related neurodevelopmental abnormalities. Cardiac abnormalities in ASD have been less studied. We investigated the prevalence of cardiac comorbidities relative to ASD genetic contributors. Using high frequency ultrasound imaging, we screened 9 ASD‐related genetic mouse models (Arid1b (+/−), Chd8 (+/−), 16p11.2 (deletion), Sgsh (+/−), Sgsh (−/−), Shank3 Δexon 4–9 (+/−), Shank3 Δexon 4–9 (−/−), Fmr1 (−/−), Vps13b (+/−)), and pooled wild‐type littermates (WTs). We measured heart rate (HR), aorta diameter (AoD), thickness and thickening of the left‐ventricular (LV) anterior and posterior walls, LV chamber diameter, fractional shortening, stroke volume and cardiac output, mitral inflow Peak E and A velocity ratio, ascending aorta velocity time integral (VTI). Mutant groups presented small‐scale alterations in cardiac structure and function compared to WTs (LV anterior wall thickness and thickening, chamber diameter and fractional shortening, HR). A greater number of significant differences was observed among mutant groups than between mutant groups and WTs. Mutant groups differed primarily in structural measures (LV chamber diameter and anterior wall thickness, HR, AoD). The mutant groups with most differences to WTs were 16p11.2 (deletion), Fmr1 (−/−), Arid1b (+/−). The mutant groups with most differences from other mutant groups were 16p11.2 (deletion), Sgsh (+/−), Fmr1 (−/−). Our results recapitulate the associated clinical findings. The characteristic ASD heterogeneity was recapitulated in the cardiac phenotype. The type of abnormal measures (morphological, functional) can highlight common underlying mechanisms. Clinically, knowledge of cardiac abnormalities in ASD can be essential as even non‐lethal abnormalities impact normal development.Lay SummaryAutism spectrum disorder (ASD) and congenital heart disease (CHD) are linked functionally and genetically. ASD cardiac phenotyping is limited. We assessed the cardiac phenotype of 9 ASD‐related mouse models. We found subtle heterogenous cardiac abnormalities compared to controls, with more differences within ASD than between ASD and controls, mirroring clinical findings. Clinically, knowing the cardiac abnormalities in ASD is vital as even non‐lethal cardiac abnormalities can impact development.

Hypertrophic obstructive cardiomyopathy complicated with acute myocardial infarction and diffuse fibrosis: surgery or not?

BackgroundHypertrophic cardiomyopathy with extreme hypertrophy, biventricular obstruction and diffuse myocardial fibrosis complicated by myocardial infarction in the absence of obstructive coronary artery disease (MINOCA) is a rare phenotype. Evidence and guideline recommendations are still lacking for a treatment strategy.Case presentationEmergency coronary angiography was performed in a 38-year-old man with a 2-year history of nonobstructive hypertrophic cardiomyopathy (HCM) presenting with acute myocardial infarction. The coronary angiogram yielded no stenotic lesions but showed a diffusely dilated left descending artery with slow blood flow. All evidence from biomarker analysis, electrocardiography, echocardiography, and imaging supported the diagnosis of acute myocardial infarction in the left ventricular anterior wall. The echocardiogram demonstrated severe interventricular and apical hypertrophy, severe left ventricular outflow tract obstruction and mild right ventricular outflow tract obstruction. Cardiac magnetic resonance imaging showed a concentric morphological subtype of HCM with diffuse late gadolinium enhancement in the left ventricle. Extended septal myectomy was performed 1 month later, and the patient recovered well.ConclusionsHypertrophic obstructive cardiomyopathy with acute myocardial infarction is an indication for coronary angiography. Septal reduction surgery could be performed cautiously in HCM patients with extreme hypertrophy, biventricular obstruction and diffuse myocardial fibrosis complicated by MINOCA to improve the patient’s symptoms.

Ubiquitin Carboxyl-Terminal Hydrolase L1 of Cardiomyocytes Promotes Macroautophagy and Proteostasis and Protects Against Post-myocardial Infarction Cardiac Remodeling and Heart Failure.

Ubiquitin carboxyl-terminal hydrolase L1 (UCHL1) is a deubiquitinase known to play essential roles in the nervous tissue. Myocardial upregulation of UCHL1 was observed in human dilated cardiomyopathy and several animal models of heart disease, but the (patho)physiological significance of UCHL1 in cardiomyocytes remains undefined. Hence, we conducted this study to fill this critical gap. We produced cardiomyocyte-restricted Uchl1 knockout (CKO) by coupling the Uchl1-floxed allele with transgenic Myh6-Cre in C57B/6J inbred mice. Mice transgenic for Myh6-Cre were used as controls (CTL). Myocardial Uchl1 proteins were markedly reduced in CKO mice but they did not display discernible abnormal phenotype. Ten-week old CTL or CKO mice were subjected to left anterior descending artery ligation (myocardial infarction, MI) or sham surgery (Sham) and characterized at 7- and 28-day after surgery. Compared with Sham mice, significant increases in myocardial UCHL1 proteins were detected in CTL MI but not in CKO MI mice. MI-induced left ventricular (LV) chamber dilation, reduction of ejection fraction (EF) and fractional shortening (FS), and LV anterior wall thinning detected by echocardiography were comparable between the CTL MI and CKO MI groups 7-day post-MI. However, by 28-day post-MI, MI-induced LV chamber dilatation, EF and FS reduction, increases of myocardial ubiquitin conjugates, and increases in the heart weight to body weight ratio and the ventricular weight to body weight ratio were significantly more pronounced in CKO MI than CTL MI mice. As further revealed by LV pressure-volume relationship analyses, CKO MI mice but not CTL MI mice displayed significant decreases in stroke volume, cardiac output, and the maximum rates of LV pressure rising or declining and of LV volume declining, as well as significant increases in LV end-diastolic pressure and Tau, compared with their respective Sham controls. LC3-II flux assays reveal that autophagic flux is decreased in CKO mouse myocardium as well as in cultured Uchl1-deficient cardiomyocytes. In conclusion, UCHL1 of cardiomyocytes is dispensable for development but promotes macroautophagy in cardiomyocytes. Upregulation of UCHL1 in post-MI hearts occurs primarily in the cardiomyocytes and protects against post-MI cardiac remodeling and malfunction likely through supporting autophagic flux and proteostasis during a stress condition.

Effect of Yanshiqiangxin Decoction on Cardiomyocyte Apoptosis in Heart Failure Rats Based on PI3K/Akt/Caspase-9 Signaling Pathway

<bold>Objective</bold> To detect the effect of Yanshiqiangxin decoction on apoptosis of cardiomyocytes in rats with heart failure based on PI3K/Akt/Caspase-9 signalling pathway and to explore the possible mechanism of Yanshiqiangxin decoction in the treatment of heart failure. <bold>Methods</bold> A total of 60 Wistar male rats were randomly divided into the normal group, the model group, the low dose Yanshiqiangxin decoction group, the medium dose Yanshiqiangxin decoction group,the high dose Yanshiqiangxin decoction group and the Perindopril group according to the random number table method, with 10 cases in each group. Except for the normal group, the remaining five groups were modelled by injecting adriamycin solution to induce myocardial injury and to establish the rat model of heart failure. In the low, medium and high dose Yanshiqiangxin decoction groups, 4.325, 8.65 and 17.3 g/(kg·d) of raw drug were administered by gavage respectively; the Perindopril group was given perindopril solution by gavage at the dose of 4 mg/(kg·d). The gavage dose was calculated as 10 mL/(kg·d) ,the normal group and the model group were given the same volume of distilled water. One day after the last gavage, M-mode echocardiography [left ventricular ejection fraction (LVEF), left ventricular short-axis shortening (LVFS), left ventricular internal dimension diastole (LVIDd) and left ventricular internal dimension systole (LVIDs)] was performed through an ultra-high resolution small animal ultrasound imaging system; B-type natriuretic peptide (BNP) was measured by ELISA method; the apoptosis of cardiomyocytes was observed through laser confocal microscopy and the apoptosis index was calculated; the expression of apoptosis-related proteins Bax, Bcl-2 and PI3K/Akt/Caspase-9 signalling pathway proteins were detected by Western blot method. <bold>Results</bold> ① Cardiac ultrasound test results: compared with the normal group, the left ventricular anterior wall motion waveform of the model group was not obvious, close to linear motion, and LVEF and LVFS decreased significantly (<italic>P</italic>&lt;0.05), LVIDd and LVIDs increased significantly (<italic>P</italic>&lt;0.05), the left ventricle was significantly enlarged and the contractility was reduced. Compared with the model group, the amplitude of left ventricular anterior wall motion waveform increased at different degrees in the low, medium and high dose Yanshiqiangxin decoction group, LVEF and LVFS gradually increased with the increase of administration concentration (<italic>P</italic>&lt;0.05), while LVIDd decreased only in the medium dose Yanshiqiangxin decoction group (<italic>P</italic>&lt;0.05), LVIDs of the medium dose Yanshiqiangxin decoction group and the high dose Yanshiqiangxin decoction group were significantly reduced, the medium dose Yanshiqiangxin decoction group decreased the most significantly (<italic>P</italic>&lt;0.05). ② Serum BNP results: compared with the normal group, BNP of the model group was significantly increased (<italic>P</italic>&lt;0.05). Compared with the model group, BNP of the low, medium and high dose Yanshiqiangxin decoction group was significantly decreased, BNP gradually decreased with the increase of administration concentration (<italic>P</italic>&lt;0.05). ③ Myocardial histopathology results: Cardiomyocytes had no apoptosis and almost no positive signal was detected in the normal group; compared with the model group,the number of cardiomyocyte apoptosis of the low, medium, high dose Yanshiqiangxin decoction group and the perindopril group was significantly decreased, the number of cardiomyocyte apoptosis gradually decreased with the increase of administration concentration (<italic>P</italic>&lt;0.05). ④ PI3K/Akt/Caspase-9 signaling pathway protein expression levels and apoptotic factors: compared with the model group, PI3K and Akt protein expression, Bcl-2 content and Bcl-2/Bax ratio of the low, medium and high dose Yanshiqiangxin decoction group were significantly increased, PI3K and Akt protein expression, Bcl-2 content and Bcl-2/Bax ratio gradually increased with the increase of administration concentration (<italic>P</italic>&lt;0.05); Caspase-9 and Caspase-3 protein expression of the low, medium and high dose Yanshiqiangxin decoction group were significantly decreased, Bax content of the medium and high dose Yanshiqiangxin decoction group were significantly decreased, and gradually increased with the increase of administration concentration (<italic>P</italic>&lt;0.05). <bold>Conclusions</bold> Yanshiqiangxin decoction can improve cardiac function, reduce the content of BNP in serum and cardiomyocyte apoptosis, the mechanism may be related to the regulation of the PI3K/Akt/Caspase-9 signalling pathway.

Global and regional wall motion abnormalities and incident heart failure in the general population

BackgroundWall Motion Score Index (WMSI) is a simple method to quantify global and regional systolic function on echocardiography. We sought to investigate the prognostic importance of global and regional WMSI for the development of incident heart failure (HF) in the general population. MethodsWe included adults without HF or ischemic heart disease from the 4th Copenhagen City Heart Study (2001–2003). At baseline, participants underwent an echocardiography and physical examination and completed a self-administered health questionnaire. WMSI was assessed by conventional echocardiography using a 16-segment model obtaining WMSI assessments for the anterior, lateral, inferior, septal, and posterior left ventricular (LV) walls and calculating a global WMSI. The primary endpoint was incident HF. ResultsAmong 3415 participants (mean age 58 years, 42% male, 45% with hypertension), 83 (2.4%) had hypo-, a-, or dyskinesia of at least one LV wall segment at baseline. During a median follow-up of 15.4 years, 297 (8.7%) participants developed HF. After adjusting for important clinical variables, LV ejection fraction and E/A, hypo-, a- or dyskinesia of at least one segment in any of the LV regional walls was associated with a higher risk of incident HF (HR 3.63, 95% CI 2.15–6.12, p < 0.001). Similarly, global WMSI was independently associated with a higher risk of HF (HR 1.38 per 0.1 increase, 95%CI 1.22–1.56, p < 0.001). ConclusionWall motion abnormalities in any regional LV wall and global WMSI were associated with incident HF in this general population cohort independent of various baseline clinical data, LV ejection fraction and E/A.

Upregulation of microRNA-34a enhances myocardial ischemia-reperfusion injury via the mitochondrial apoptotic pathway

Mitochondrial oxidative injury can result in many cardiovascular diseases including cardiac ischemia-reperfusion (I/R) injury. This study was designed to investigate whether microRNA-34a (miR-34a) influences cardiac I/R or hypoxia/reoxygenation (H/R) injury by regulating the mitochondrial apoptotic pathway from oxidative injury.In vivo, myocardial infarction size was examined by Evan blue/TTC staining. Apoptosis was assessed by TUNEL assay. Heart function was measured by echocardiography. Lactate dehydrogenase (LDH) and creatine kinase (CK) were evaluated. In vitro, H9c2 cardiomyocytes were exposed to H/R stimulation. Cell viability was assessed by the CCK-8 assay and apoptosis was detected by Annexin V/PI staining. Mitochondrial superoxide, mitochondrial membrane potential (MMP) and ATP production was evaluated by detection kits, and related proteins were detected by western blotting analysis. We observed that the level of miR-34a was significantly upregulated in I/R rats compared to the sham group. Injection of adenovirus inhibiting miR-34a into the left ventricular anterior wall improved heart function and decreased I/R injury. H9c2 cardiomyocytes exposed to H/R stimulation displayed an obvious increase in miR-34a expression. In addition, miR-34a inhibitor alleviated, whereas miR-34a mimic aggravated H/R-induced mitochondrial injury. Bcl-2 was identified as a target gene of miR-34a by dual-luciferase reporter gene detection. Knockdown of Bcl-2 abolished the cardioprotection of the miR-34a inhibitor in H9c2 cells. In summary,our study demonstrates that inhibition of miR-34a exhibits therapeutic potential in treatment of myocardial I/R injury by restraining mitochondrial apoptosis.

Прогностические маркеры исхода острого периода инфаркта миокарда

Исход острого периода инфаркта миокарда прогнозировался на основании статистического метода с применением алгоритма Data Mining «дерево решений». В качестве входных данных использовались чувствительные и специфические векторкардиографические показатели. Установлены прогностически значимые маркеры исхода острого периода инфаркта миокарда. Если возраст больного был 57 лет и более, а скорость распространения возбуждения по миокарду высоких отделов передней стенки левого желудочка замедлялась до 6,33 мв/с, прогнозировался летальный исход с точностью 92,86 %. В случае регистрации у пациента увеличения площади предсердных петель более 0,188 мм2 (в ВА2) с угловым расхождением петель QRS-P более 15,5° (в ВА1), размыкания петли QRS менее 2,834 мм (в 3-й проекции) и скорости распространения возбуждения в конечной части петли Т менее 2,338 мв/с (в ВА1) при различных значениях углового расхождения вектора QRS-Т (в ВА5) прогнозировался благоприятный исход с точностью 97,67 %.

105 An intriguing case of pericardial effusion after acute coronary syndrome

Abstract Aims Left ventricular free wall rupture is one of the mechanical complications of myocardial infarction with an incidence of 2–4%. Sometimes the myocardial rupture hasn’t an immediate fatal evolution, nor is easy to be diagnosed because it is contained by the pericardium and thrombus formation, leading to pseudoaneurysm of the left ventricle. Pseudoaneurysms need a prompt surgical correction for their high risk of rupture both in the acute phase and later. Methods and results A 57 years old, smoker, woman with no previous cardiological history was admitted to our cardiological department for acute coronary syndrome with persistent ST segment elevation involving the postero-lateral wall (door to balloon time about 10 h, Killip class I and peak hs-TnI value was 27.67 ng/ml n.v. ˂0.02 ng/ml). The echocardiography showed mild left ventricular disfunction (LV EF 45%), postero lateral akinesia and moderate mitral regurgitation; ubiquitous pericardial effusion (1 cm) was present, particularly along the anterior left ventricular wall, with irregular echo-dense aspect. She underwent urgent coronarography that showed a critical stenosis of the distal third of the left circumflex and a thrombotic occlusion of the first marginal branch. The distal circumflex was treated with angioplasty and stent implantation but we couldn’t obtain the reperfusion of the marginal branch. Post procedural echocardiogram was unchanged and no free wall rupture was detected. 7 days after the admission, the patient showed persistent elevation of white blood count and CRP and developed fever, promptly empirically treated with a cephalosporin (blood cultures collected before were negative). After two new episode of fever with persisting biochemical flogistic parameters, a rheumatologic cause of the pericardial effusion was considered in the presence of positive antinuclear antibodies suggesting the diagnosis of Systemic Lupus Erythematosus. Steroidal therapy was prescribed which caused clinical improvement without complete resolution of the pericardial effusion. On day 20 of hospital stay a new echocardiographic evaluation showed a discontinuation of the postero lateral myocardial wall (Figure 1), about 1 cm in width, widely communicating with the left ventricular cavity and suggestive for a left postero-lateral ventricular pseudoaneurysm. The patient underwent surgical intervention and it was possible to expose a big clot occluding the pseudoaneurysmatic cavity communicating with the left ventricular chamber through an inlet about 1 cm in diameter, that was repaired with a bovine pericardial patch (Bard Sauvage technique). After surgery the patient was supported with an IABP and inotropes and was discharged to a rehabilitation structure on day 29 of hospital stay. Four months after the hospital discharge the patient died for a recently diagnosed pancreatic cancer. Conclusions Pseudoaneurisms are life-threatening complications of myocardial infarction that sometimes are hardly diagnosed. When correctly recognized surgical correction can lead to a good prognosis.

272 Combined rotational atherectomy and intravascular lithotripsy for heavy calcified coronary artery

Abstract Aims Percutaneous coronary intervention (PCI) of heavily calcified coronary lesions still represents a challenge for interventional cardiologists, with higher risk of immediate complications, late failure due to stent underexpansion or malapposition and consequent poor clinical outcome. Rotational atherectomy (RA) is a well-known calcium debulking modality. However, when coronary plaques present a significant amount of circumferential deep calcium, RA alone may not be able to achieve adequate lesion preparation. The combined use of intravascular lithotripsy (IVL) and RA, a technique called ‘Rotatripsy’, can be an effective approach in order to enable optimal stent implantation. We present a case of a calcific right coronary artery (RCA) PCI successfully treated by ‘Rotatripsy’ technique. Methods and results A 78-years-old man presented to our emergency department complaining of acute chest pain and dyspnoea. The electrocardiogram revealed ST-segment elevation in aVR and a diffuse ST-segment depression. Transthoracic echocardiography showed left ventricular anterior, septal, and apical walls akinesia. An urgent coronary angiography showed a critical distal left main (LM) stenosis involving the left anterior descending (LAD) artery ostium and a heavy calcified dominant RCA with two tandem sub-occlusive stenosis in the mid segment (Figure 1A). An immediate PCI with two drug eluting stents (DES) in the LM and LAD was performed. The patient was scheduled two days later for RCA PCI. RCA was engaged via left radial approach with a 6-Fr AL1 guiding catheter and the lesions were crossed with a Sion Blue wire. Using a Finecross MG microcatheter, an extra-support Rotawire was placed distally in the RCA. However, after multiple rotablation with 1.5 mm burr (Figure 1B), the mid segment lesion (Figure 1C) was still undilatable with a 3.5 mm non-compliant balloon (NCB) at 22 atm showing a partial dog bone effect (Figure 1D). We decided to attempt adjunctive IVL for calcium debulking. Using a Finecross MG and the trapping technique, a Gran Slam wire was placed distally; a 4.0 mm IVL balloon was delivered at the undilatable lesion and 80 pulses were applied (Figure 1E). Once the IVL treatment was completed (Figure 1F), a 4.0 mm NCB was inflated to 20 atm to further dilate the segment with an optimal expansion (Figure 1G). Finally, a DES Synergy 4.0 × 48 mm was implanted (Figure 1H) and it was post-dilated with a 4.5 mm NCB inflated to 22 atm (Figure 1I) with a perfect angiographic result (Figure 1J). Conclusions Coronary calcifications can lead to stent underexpansion, which is related to a higher rate of future complications, such as restenosis or thrombosis. If conventional lesion dilatations are not effective, alternative techniques should be considered (cutting balloon, scoring balloon, RA, orbital atherectomy, IVL). In case of circumferential deep calcium plaques, RA may not be able to achieve an adequate lesion preparation. RA allows the treatment of intimal calcium and permits to cross balloons or stents through severe lesions. However, when adequate expansion of the balloons is not achieved after RA, Shockwave IVL, that is not usually able to cross critical stenosis due to its bulky profile, represents an optimal complementary device, in order to fracture deep calcium and facilitate stent delivery and optimal expansion. In this case, we have successfully used the hybrid approach called ‘Rotatripsy’, which combines RA and IVL, in order to avoid more aggressive RA, which would have required the use of 7-Fr guiding catheter setting and may have increased the risk of complications.

C25. Cardiogenic shock in a 25-year-old male with tombstone ST-segment elevation pattern in emergency department, early hemodynamic assessment to guide the management: a case report of mixed cardiogenic shock phenotype

Abstract Background Cardiogenic shock (CS) is a lethal condition. There are several phenotypes, and classification based hemodynamic and/or clinical parameters for CS. We present CS with tombstone ST-segment elevation in emergency department (ED) with assessment of hemodynamic using bedside ultrasound to classify and guide the management. Case Description A 25-year-old-male complained sense of fatigue, fever, and myalgia for 2 days. The initial blood pressure and SpO2 were unrecordable, heart rate 112x/m, respiration rate 28x/m, temperature 36.8 °C. The patient was pale, anxious, with difficult jugular venous pressure assessment due to overweight appearance, diminished S1, and cold extremity. Electrocardiogram revealed tombstone ST-elevation in V2-V6, I, and aVL. After oxygenation management, initial dobutamine and norepinephrine, we performed bedside cardiac ultrasound revealed anterior left ventricular wall hypokinesis, mild pericardial effusion, ejection fraction 52%, mitral E/A ratio 2.7, E deceleration time 90.82ms, positive lung B-lines, inferior vena cava diameter 2.14cm with collapsibility &amp;lt;50%. Tricuspid annular plane systolic excursion 19mm. Estimated cardiac index 1.88L/m/cm2, and systemic vascular resistance (SVR) 775dynes.sec/cm5. This pattern suggests mixed CS phenotype. Vasopressor was up titrated with improved blood pressure, SpO2, and urinary output. CXR revealed cardiomegaly, troponin T &amp;gt; 10.000pg/ml. The patient was successfully stabilized in ED and transferred to ICCU. Discussion We classify our case as mixed CS. With hemodynamic assessment, we can determine the character of the shock with more objective parameters, guide the treatment, and avoiding over (increase oxygen demand, afterload, arrhythmia) and underused of vasopressor to bridging the treatment of causative factor.

C25. Cardiogenic shock in a 25-year-old male with tombstone ST-segment elevation pattern in emergency department, early hemodynamic assessment to guide the management: a case report of mixed cardiogenic shock phenotype

Abstract Background Cardiogenic shock (CS) is a lethal condition. There are several phenotypes, and classification based hemodynamic and/or clinical parameters for CS. We present CS with tombstone ST-segment elevation in emergency department (ED) with assessment of hemodynamic using bedside ultrasound to classify and guide the management. Case Description A 25-year-old-male complained sense of fatigue, fever, and myalgia for 2 days. The initial blood pressure and SpO2 were unrecordable, heart rate 112x/m, respiration rate 28x/m, temperature 36.8 °C. The patient was pale, anxious, with difficult jugular venous pressure assessment due to overweight appearance, diminished S1, and cold extremity. Electrocardiogram revealed tombstone ST-elevation in V2-V6, I, and aVL. After oxygenation management, initial dobutamine and norepinephrine, we performed bedside cardiac ultrasound revealed anterior left ventricular wall hypokinesis, mild pericardial effusion, ejection fraction 52%, mitral E/A ratio 2.7, E deceleration time 90.82ms, positive lung B-lines, inferior vena cava diameter 2.14cm with collapsibility &amp;lt;50%. Tricuspid annular plane systolic excursion 19mm. Estimated cardiac index 1.88L/m/cm2, and systemic vascular resistance (SVR) 775dynes.sec/cm5. This pattern suggests mixed CS phenotype. Vasopressor was up titrated with improved blood pressure, SpO2, and urinary output. CXR revealed cardiomegaly, troponin T &amp;gt; 10.000pg/ml. The patient was successfully stabilized in ED and transferred to ICCU. Discussion We classify our case as mixed CS. With hemodynamic assessment, we can determine the character of the shock with more objective parameters, guide the treatment, and avoiding over (increase oxygen demand, afterload, arrhythmia) and underused of vasopressor to bridging the treatment of causative factor.

Periplocymarin Alleviates Doxorubicin-Induced Heart Failure and Excessive Accumulation of Ceramides.

Doxorubicin-driven cardiotoxicity could result in dilated cardiomyopathy and heart failure (HF). Previously, we showed that periplocymarin exerted a cardiotonic role by promoting calcium influx and attenuating myocardial fibrosis induced by isoproterenol (ISO) by improving the metabolism of cardiomyocytes. However, the impact of periplocymarin on doxorubicin (DOX)-triggered cardiomyopathy has not been investigated. In the current study, C57BL/6 mice were randomly divided into three groups, namely, the control, DOX, and DOX+periplocymarin groups. The cardiac function and apoptosis were measured. Our results revealed that periplocymarin administration greatly improved the DOX-induced cardiac dysfunction manifested by the ejection fraction (EF%), fractional shortening (FS%), left ventricular posterior wall thickness (LVPW), left ventricular anterior wall thickness (LVAW), left ventricular (LV) mass, and attenuated DOX-induced cardiomyocyte apoptosis assessed by hematoxylin and eosin (H&E) staining, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining, and western blotting. Further study using H9c2 cells revealed that the pretreatment of periplocymarin suppressed DOX-induced apoptosis evidenced by annexin V staining. Moreover, liquid chromatography with tandem mass spectrometry (LC-MS/MS) analysis demonstrated that DOX lead to an accumulation in serum ceramide, and the pre-treatment of periplocymarin could reverse this phenomenon. Network pharmacology also demonstrated that ceramide metabolism was involved in the process. Consistently, real-time PCR showed that periplocymarin significantly abolished the induction of the genes involved in the de novo synthesis of ceramide, i.e., CerS2, CerS4, CerS5, and CerS6, and the induction was attributed to the treatment of DOX. Collectively, these results suggested that periplocymarin reduced cardiomyocyte apoptosis to protect hearts from DOX-induced cardiotoxicity and the de novo synthesis of ceramides was involved in this process.

Abstract 9430: A Novel Soluble Epoxide Hydrolase Peptide Vaccine Attenuates Cardiac Remodeling After Myocardial Infarction Through Angiogenesis

Introduction: Vaccination therapy has long-lasting effects and solves medication non-adherence. However, vaccination therapy on myocardial infarction (MI) has not been developed. Epoxyeicosatrienoic acids (EETs) play an important role in cardio-protective mechanisms through angiogenesis. Here, we developed a soluble epoxide hydrolase (sEH) peptide vaccine to increase the level of EETs and assessed its therapeutic effect for MI-induced heart failure. Hypothesis: We predicted that neovascularization by a sEH vaccine would reduce infract size and prevent post-MI cardiac remodeling. Methods and Results: We made a sEH peptide vaccine based on the amino-acid sequences and administrated the vaccine to rats. ELISA showed that the vaccine induced anti-sEH antibody. Mass spectrometry also confirmed that the vaccine significantly increased blood EETs levels compared to the saline group (P=0.007). We evaluated the effects of the sEH vaccine in the rat model of MI. One week after the left anterior descending artery (LAD) ligation, the vaccinated group significantly suppressed the increase of left ventricular systolic diameter (LVDs) and prevented the decline in left ventricular anterior wall (LVAW), fractional shortening (FS), and ejection function (EF) in echocardiography (P&lt;0.001, P&lt;0.001, P=0.002, and P&lt;0.001 respectively). With the pathological evaluation of the hearts, it was clear that the number of micro-vessels increased in the vaccinated group by immunostaining for CD31 and α-SMA (P=0.015 and P=0.027 respectively). Azan staining showed that infarct-induced fibrosis was lower in the vaccinated group (P=0.029). Western blot showed higher vascular endothelial growth factor (VEGF) expressions of heart muscles in the vaccinated group (P=0.040). Conclusion: The sEH vaccine therapy for MI induces angiogenesis, which promotes reverse cardiac remodeling. This vaccine is expected to be a treatment option to prevent heart failure after MI.

Abstract 12060: Comparison of Sites of Wall Thickening and Abnormal Late Enhancement on Cardiac CT and Magnetic Resonance Imaging with Electrocardiography Findings in Patients with Confirmed Cardiac Amyloidosis

Introduction: Left ventricular (LV) wall thickening and diastolic dysfunction on a TTE without a high voltage R wave on V5 leads on an ECG to a diagnosis of cardiac amyloidosis (CA). However, amyloid sometimes invades right ventricle (RV), and left (LA) and right (RA) atria, causing ECG changes such as sick sinus syndrome (SSS), arrhythmia, and QRS wave axis deviation. Hypothesis: We hypothesize that there is the relationship between sites of wall thickening and abnormal late enhancement (LE) on cardiac CT and MRI, suggesting amyloid invasion, with ECG findings in patients with CA confirmed by biopsy. Methods: A total of 26 patients (11 females) with suspected CA, who had LV wall thickening by TTE without a high voltage R wave in V5 leads, underwent cardiac CT. 5 patients (3 females, mean age 73 years) were diagnosed with CA. 4 patients underwent MRI. Results: Case 1 had wall thickening in the basal interventricular septum (IVS), LV inferior-posterior wall, LA on CT, LE in endocardium in whole LV, RV, and RA on CT, and LE in endocardium in whole LV, RV, LA, and IVS on MRI. ECG showed SSS (junctional rhythm), left QRS axis deviation, no low voltage R wave in limb leads, and a mild LA load. Case 2 had wall thickening in whole LV, RV, LA, and IVS on CT, and unclear (CT) or no (MRI) LE. ECG revealed SSS (junctional rhythm), a normal QRS axis, no low voltage R wave in limb leads, and no LA load. Case 3 had wall thickening in LA and basal IVS on CT, abnormal LE in the LA and basal IVS on CT, and LE in the LA only on MRI. ECG revealed atrial tachycardia, a normal QRS axis with low voltage R wave in limb leads, and no LA load. Case 4 had wall thickening in the LA, an RV moderator band on CT, an unclear LE on CT, and LE in whole LV, endocardium in the RV, and whole IVS on MRI. ECG showed a normal sinus rhythm, left QRS axis deviation, with low voltage R wave in limb leads, and no LA load. Case 5 had wall thickening in the IVS, LV lateral wall, LV anterior wall, RA, RV outflow tract, and RA appendage, and no abnormal LE on CT (MRI not performed). ECG revealed a normal sinus rhythm, right QRS axis deviation, with low voltage R wave in limb leads, and a mild LA load. Conclusions: This pilot study revealed the presence of wall thickening and abnormal LE in RV, LA, and RA in addition to LV would be important which may influence ECG changes in patients with CA.

Abstract 12086: Relationship of Cardiac Rhythm and Other Electrocardiogram Findings with Sites of Wall Thickening and Abnormal Late Enhancement in Patients with Confirmed Cardiac Amyloidosis

Introduction: Left ventricular (LV) wall thickening and diastolic dysfunction on TTE without high voltage R wave on ECG to a diagnosis of cardiac amyloidosis (CA). However, amyloid sometimes invade right ventricle (RV), and left (LA) and right (RA) atria to cause ECG changes such as sick sinus syndrome (SSS), arrhythmia, and QRS axis deviation. Hypothesis: We hypothesized that sites of wall thickening and abnormal late enhancement (LE) on cardiac CT and MRI, suggesting amyloid invasion, correlated with cardiac rhythm and other ECG findings in patients with CA confirmed by biopsy. Methods: 26 patients (11 females) with suspected CA, showing LV wall thickening by TTE without a high voltage R wave, underwent cardiac CT. 5 patients (3 females, mean 73 years) were diagnosed with CA: complicated multiple myeloma, 2; senile ATTR (transthyretin) amyloidosis, 1; immunoglobulin light chain amyloidosis 1; and transthyretin mutation, 1. 4 patients underwent cardiac MRI. Results: 2 patients (cases 1 and 2) had SSS (junctional rhythm), 1 had atrial tachycardia, and the remaining 2 (cases 4 and 5) had a normal sinus rhythm. In case 1, ECG showed a left QRS axis deviation, no low voltage R wave and a mild LA load. Wall thickening in basal interventricular septum (IVS), LV inferior-posterior wall, LA on CT, LE in endocardium in whole LV, RV, and RA on CT, and LE in endocardium in whole LV, RV, LA, and IVS on MRI were observed. In case 2, ECG showed a normal QRS axis, no low voltage R wave, no LA load, wall thickening in whole LV, RV, LA, and IVS on CT, and unclear (CT) or no (MRI) LE. In case 3, ECG showed a normal QRS axis, with low voltage R wave, no LA load, wall thickening in LA and basal IVS on CT, LE in LA and basal IVS on CT, and LE in LA only on MRI. In case 4, ECG showed left QRS axis deviation, a low voltage R wave, and no LA load, wall thickening in LA and RV on CT, unclear LE on CT, and LE in whole LV, endocardium in RV, and whole IVS on MRI. In case 5, ECG showed a right QRS axis deviation, low voltage R wave, and a mild LA load, wall thickening in IVS, LV lateral wall, LV anterior wall, RA, RV outflow tract, and RA appendage, and no LE on CT (MRI not performed). Conclusions: The presence of wall thickening and abnormal LE in RV, LA, and RA in addition to LV on CT or MRI would be important which may influence ECG changes in patients with CA.

Abstract 11800: Inhibition of Pyruvate Dehydrogenase Kinase Does Not Improve Cardiac Abnormalities in a Mouse Model of Human Barth Syndrome

Introduction/Hypothesis: Heart failure presents as the leading cause of infant mortality in individuals with the rare genetic disease, Barth Syndrome (BTHS). The causative mutation underlying the BTHS phenotype has been mapped to the tafazzin ( TAZ) g ene, which encodes for a phospholipid transacylase critical for the remodelling of the mitochondrial phospholipid, cardiolipin. Perturbations in myocardial energy metabolism may contribute to the development and progression of cardiomyopathy in BTHS. Given that cardiac glucose oxidation is impaired in a mouse model of human BTHS, we hypothesized that pharmacological enhancement of glucose oxidation through dichloroacetate (DCA) treatment could mitigate BTHS-related cardiac dysfunction. Methods: DCA was added to the drinking water (84 mM) of 6-week-old mice with experimental BTHS (doxycycline-inducible Taz knockdown (TazKD) mice) for 6-weeks. In vivo cardiac function was assessed via ultrasound echocardiography prior to and following the DCA treatment period. Hearts were extracted from TazKD mice and their wild-type (WT) littermates for protein expression profiling and enzyme activity assessment at the end of the treatment protocol. Results: Prior to treatment at 4-5 weeks of age, TazKD mice exhibited hypertrophic cardiomyopathy as demonstrated by an increase in the ratio between left ventricular (LV) anterior and posterior wall thickness during diastole in relation to lean body mass (0.042±0.003 vs 0.062±0.008 mm/g; 0.049±0.002 vs 0.069±0.005 mm/g). TazKD mice also exhibited impaired LV systolic and diastolic volumes. Treatment with DCA decreased inhibitory phosphorylation of pyruvate dehydrogenase, the rate-limiting enzyme of glucose oxidation, and trended to increase its activity ( p =0.19) in ventricular extracts from TazKD mice compared to their WT littermates, thus suggestive of increased myocardial glucose oxidation. However, despite a potential improvement of cardiac energy metabolism, treatment with DCA did not improve cardiac structural and functional parameters in TazKD mice. Conclusions: Our findings suggest that optimization of cardiac glucose oxidation may not be a feasible strategy for alleviating BTHS-associated cardiomyopathy.

Wenxin Granules Regulate Endoplasmic Reticulum Stress Unfolded Protein Response and Improve Ventricular Remodeling on Rats with Myocardial Infarction.

Background. Arrhythmia after myocardial infarction is the leading cause of death in clinical heart disease. Increasing studies have shown that the response to endoplasmic reticulum (ER) stress (ERS) caused by myocardial infarction is related to prognosis and the development of arrhythmias. The unfolded protein response (UPR) could serve as an important regulatory signaling pathway following myocardial infarction. The traditional Chinese medicine Wenxin Granules improve arrhythmias following myocardial infarction, which may be related to ERS intervention and the activation of the UPR and apoptosis. We aimed to investigate the involvement of Wenxin Granules in the activation of the UPR and apoptosis following myocardial infarction. Left coronary artery ligation was established as a rat model of myocardial infarction. The rats were randomly divided into the model group, low-dose Wenxin Granule group, high-dose Wenxin Granule group, and metoprolol group. Rats with only wire insertion and no ligature were used as the sham group. Small animal ultrasound systems were used to detect changes in heart structure and function, and the electrical stimulation threshold for ventricular fibrillation was detected. The expression of glucose-regulated protein (GRP)78, activating transcription factor (ATF)6, X-box binding protein (XBP)1, protein kinase–like ER kinase (PERK), phosphorylated (p)-PERK, Bax, Bcl2, C/EBP homologous protein (CHOP), caspase 12, caspase 8, and caspase 3 were detected by western blot, and terminal deoxynucleotidyl transferase dUTP Nick end labeling (TUNEL) was used to determine the cardiomyocyte apoptosis index. Compared with the sham group, rats in the model group displayed immediate ST-segment elevation and pathological Q waves after 24 hours. After 2 weeks, the left ventricular (LV) anterior wall thickness (LVAW) became thinner, and the inner diameter (LVID) increased. The end-diastolic LVAW (LVAWd), end-systolic LVAW (LVAWs), ejection fraction (EF), and fractional shortening (FS) were significantly reduced (P < 0.01), whereas the LVIDd, LVIDs, diastolic LV volume (LV Vold), and systolic LV volume (LV Vols) significantly increased (P < 0.01). The ventricular fibrillation threshold decreased significantly (P < 0.01). ERS proteins GRP78, p-PERK, PERK, ATF6, and XBP1 and apoptotic proteins CHOP, Bax, caspase 12, caspase 8, and caspase 3 significantly increased (P < 0.01, P < 0.05), whereas Bcl-2 expression and the Bcl-2/Bax ratio decreased (P < 0.01). Compared with the sham group, LVAWd, LVAWs, FS, and Bcl-2 protein expression were significantly increased in the low-dose Wenxin Granule group (P < 0.01, P < 0.05), and p-PERK and ATF6 decreased (P < 0.01, P < 0.05). Compared with the sham group, LVAWd, LVAWs, EF, FS, and the ventricular fibrillation threshold significantly increased in the high-dose Wenxin Granule and metoprolol groups (P < 0.01, P < 0.05), whereas LVIDs, LV Vols, and ERS proteins were significantly decreased (P < 0.01, P < 0.05). CHOP, Bax, caspase 12, caspase 8, and caspase 3 protein expression decreased in the Wenxin Granule group (P < 0.01, P < 0.05), whereas Bcl-2 and the Bcl-2/Bax ratio increased (P < 0.01, P < 0.05). LVIDd and Bax decreased in the metoprolol group (P < 0.01, P < 0.05), and the Bcl-2/Bax ratio increased (P < 0.05). The cardiomyocyte apoptosis index values for the low- and high-dose Wenxin Granule and metoprolol groups were significantly reduced (P < 0.05). This study suggested that the UPR is an essential mechanism underlying pathological injury after myocardial infarction. Wenxin Granule treatment can improve ventricular remodeling and cardiac function and inhibit arrhythmia by preventing excessive ERS from activating the UPR and apoptosis.

Alterations in ACE and ACE2 Activities and Cardiomyocyte Signaling Underlie Improved Myocardial Function in a Rat Model of Repeated Remote Ischemic Conditioning.

Post-ischemic left ventricular (LV) remodeling and its hypothetical prevention by repeated remote ischemic conditioning (rRIC) in male Sprague–Dawley rats were studied. Myocardial infarction (MI) was evoked by permanent ligation of the left anterior descending coronary artery (LAD), and myocardial characteristics were tested in the infarcted anterior and non-infarcted inferior LV regions four and/or six weeks later. rRIC was induced by three cycles of five-minute-long unilateral hind limb ischemia and five minutes of reperfusion on a daily basis for a period of two weeks starting four weeks after LAD occlusion. Sham operated animals served as controls. Echocardiographic examinations and invasive hemodynamic measurements revealed distinct changes in LV systolic function between four and six weeks after MI induction in the absence of rRIC (i.e., LV ejection fraction (LVEF) decreased from 52.8 ± 2.1% to 50 ± 1.6%, mean ± SEM, p < 0.05) and in the presence of rRIC (i.e., LVEF increased from 48.2 ± 4.8% to 55.2 ± 4.1%, p < 0.05). Angiotensin-converting enzyme (ACE) activity was about five times higher in the anterior LV wall at six weeks than that in sham animals. Angiotensin-converting enzyme 2 (ACE2) activity roughly doubled in post-ischemic LVs. These increases in ACE and ACE2 activities were effectively mitigated by rRIC. Ca2+-sensitivities of force production (pCa50) of LV permeabilized cardiomyocytes were increased at six weeks after MI induction together with hypophosphorylation of 1) cardiac troponin I (cTnI) in both LV regions, and 2) cardiac myosin-binding protein C (cMyBP-C) in the anterior wall. rRIC normalized pCa50, cTnI and cMyBP-C phosphorylations. Taken together, post-ischemic LV remodeling involves region-specific alterations in ACE and ACE2 activities together with changes in cardiomyocyte myofilament protein phosphorylation and function. rRIC has the potential to prevent these alterations and to improve LV performance following MI.

Epicardial adipose tissue and nonvalvular atrial fibrillation

Abstract Background Several studies revealed the relationship between epicardial fat tissue (EF) and development of atrial fibrillation (AF). Though pathophysiological mechanisms are not clear enough, the anatomy and location EF as a part of visceral adiposity tissue could lead to proinflammatory and fibrotic changes in atrial myocardium. Purpose To evaluate the paracrine effects of EF and detect the association of tissue Doppler imaging (TDI) parameters, EF thickness by cardiac magnetic resonance tomography (CMR) and biochemical markers of fibrosis and inflammation in patients with nonvalvular AF without concomitant coronary artery disease. Methods Thirty-nine patients with idiopathic paroxysmal AF, normal or slightly enlarged left atria (LA) (mean LA diameter 4,5±0,6cm) were included. The mean age was 50,8±13,9 y.o., 19 (49%) were men. The absence of coronary lesions was confirmed by angiography in all cases. Besides standard ECG and ECHO, all patients underwent TDI and CMR with late gadolinium enhancement. EP thickness at anterior left ventricular (LV) wall was estimated by CMR. The myocardial fibrotic and proinflammatory biomarkers levels - matrix metalloproteinases (MMP-2, MMP-9), tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) were estimated. Kendall rank correlation coefficient was used. If the |τ| &amp;gt;Tcr, the correlation ranked as statistically significant. Results The epicardial fat thickness was associated with TIMP-1 plasma level (τ=0,71; Tcr=0,18) and MMP-9 (τ=0,65; Tcr=0,16). Among clinical factors weight was slightly associated with fat thickness (τ=0,33; Tcr=0,26). Besides, we found correlation of MMP-9, TIMP-1 with E/e' by TDI (τ=0,65; Tcr=0,16 and τ=0,56; Tcr=0,21, relatively); and with maximal systolic strain of lateral LV wall (τ=−0,37; Tcr=0,18 and τ=−0,44; Tcr=0,16, relatively) and interventricular septum (τ=−0,36; Tcr=0,18 and τ=−0,44; Tcr=0,16, relatively). Conclusion The epicardial fat thickness by CMR is significantly associated with myocardial fibrosis markers (MMP-9, TIMP-1) in patients with AF without structural heart disease. The increasing levels of MMP-9 and TIMP-1 are associated with LV local contractility disturbances by TDI in patients with AF. This association demonstrates the paracrine effect of EF, which could lead to atrial remodeling and formation AF substrate even in patients without valvular and ischemic heart disease and with normal or slightly enlarged LA Funding Acknowledgement Type of funding sources: None.

MicroRNA-195-5p Downregulation Inhibits Endothelial Mesenchymal Transition and Myocardial Fibrosis in Diabetic Cardiomyopathy by Targeting Smad7 and Inhibiting Transforming Growth Factor Beta 1-Smads-Snail Pathway.

Diabetic cardiomyopathy (DCM) is a complication of diabetes mellitus, which is associated with fibrosis and microRNAs (miRs). This study estimated the mechanism of miR-195-5p in endothelial mesenchymal transition (EndMT) and myocardial fibrosis in DCM. After the establishment of DCM rat models, miR-195-5p was silenced by miR-195-5p antagomir. The cardiac function-related indexes diastolic left ventricular anterior wall (LVAW, d), systolic LVAW (d), diastolic left ventricular posterior wall (LVPW, d), systolic LVPW (d), left ventricular ejection fraction (LVEF), and fractional shortening (FS) were measured and miR-195-5p expression in myocardial tissue was detected. Myocardial fibrosis, collagen deposition, and levels of fibrosis markers were detected. Human umbilical vein endothelial cells (HUVECs) were exposed to high glucose (HG) and miR-195-5p was silenced. The levels of fibrosis proteins, endothelial markers, fibrosis markers, EndMT markers, and transforming growth factor beta 1 (TGF-β1)/Smads pathway-related proteins were measured in HUVECs. The interaction between miR-195-5p and Smad7 was verified. In vivo, miR-195-5p was highly expressed in the myocardium of DCM rats. Diastolic and systolic LVAW, diastolic and systolic LVPW were increased and LVEF and FS were decreased. Inhibition of miR-195-5p reduced cardiac dysfunction, myocardial fibrosis, collagen deposition, and EndMT, promoted CD31 and VE-cadehrin expressions, and inhibited α-SMA and vimentin expressions. In vitro, HG-induced high expression of miR-195-5p and the expression changes of endothelial markers CD31, VE-cadehrin and fibrosis markers α-SMA and vimentin were consistent with those in vivo after silencing miR-195-5p. In mechanism, miR-195-5p downregulation blocked EndMT by inhibiting TGF-β1-smads pathway. Smad7 was the direct target of miR-195-5p and silencing miR-195-5p inhibited EndMT by promoting Smad7 expression. Collectively, silencing miR-195-5p inhibits TGF-β1-smads-snail pathway by targeting Smad7, thus inhibiting EndMT and alleviating myocardial fibrosis in DCM.