Cardiac Pump Function Research Articles

Response to cardiac resynchronization therapy and treatment with ARNi and iSGLT2

Abstract Funding Acknowledgements Type of funding sources: None. Background Heart failure with reduced ejection fraction (HFrEF) is associated in about one third of patients with abnormal conduction of the cardiac electrical impulse, resulting in asynchronous activation of the ventricles and worsening of cardiac pump function. Cardiac resynchronization therapy via biventricular pacing (CRT) has demonstrated improvement in cardiac mechanical function. The pharmacological treatment of HFrEF with sacubitril/valsartan (ARNi) and glyphozines (iSGLT2) have been shown to significantly reduce mortality. Purpose The objective of our study was 1) to evaluate the effect of therapy with ARNi and iSGLT2 on the recovery of left ventricular ejection fraction (LVEF %) in a population affected by HFrEF and with CRT 2) to evaluate whether there are any differences in terms of improvement in LVEF among patients who introduced these drugs into therapy before CRT implantation and those who introduced them after. Methods This single-center retrospective study analyzed patients with HFrEF and CRTD. These patients in our center undergo regular follow-up with cardiology visit, ECG and echocardiography every 6 months. We analyzed clinical features, drug therapy, and echocardiographic data including LVEF. Patients were considered responders they had an increase in LVEF ≥ 5% or a decrease in end-systolic volume of 15% at 6 months. The data analysis was performed with the R software. Results 258 patients were included, 202 males (78%) with a mean age of 69.4 years, and 67.4% of them with ischemic HFrEF. Diabetes mellitus (68%), dyslipidemia (87%) and arterial hypertension (73%) were the most frequent comorbidities. Fifty-two percent of patients (133) were CRT responders and there was no difference in the proportion of responders between patients receiving ARNi and/or iSGLT2 therapy and those without (55% vs 47%; p=ns). The mean increase of LVEF was also similar between the two groups (+7.7% vs +10.3%; p=ns). In the group of patients taking ARNi or iSGLT2, no significant differences were found between patients taking these drugs already before CRT compared to those who started after. Conclusions In this population, HFrEF patients with CRT, therapy with ARNi or iSGLT2 does not affect the response to CRT.

Paraoxonase-1, a novel link between periodontitis and ischemic heart disease: A case-control study.

Periodontitis is a chronic inflammatory disease and might be a potential risk factor for ischemic heart disease (IHD). However, the link between periodontitis and atherosclerosis is not yet fully understood. Paraoxonase-1 (PON-1) is a new biomarker representing both anti-atherosclerotic and antioxidant activity, which also acts against dental biofilm formation and periodontitis. The possible contributing role of PON-1 in the relationship between periodontitis and atherosclerosis has not been studied to date. The aim of the present study was to investigate the serum level of PON-1 with regard to the periodontal status in IHD patients. In this case-control study, 67 patients with IHD underwent a periodontal examination and were accordingly allocated to one of the 2 study groups: the case group with chronic periodontitis (n = 36); or the control group with a healthy periodontium (n = 31). Serum PON-1 activity was measured by means of colorimetric analysis. There were no significant differences between the groups in terms of demographic data, cardiac risk factors, initial biochemical test results, cardiac pump function, and the number of grafted vessels. The activity of PON-1 in cardiac patients suffering from periodontitis was significantly lower than in cardiac patients with a healthy periodontal status (53.01 ±7.53 U/mL and 59.11 ±9.95 U/mL, respectively; p = 0.007). This finding suggests that the combination of IHD and periodontitis is associated with lower PON-1 activity. Further studies might be required to assess the possible role of periodontal treatment in increasing PON-1 activity and reducing IHD severity.

P2X3 receptor antagonism attenuates the progression of heart failure

Despite advances in the treatment of heart failure, prognosis is poor, mortality high and there remains no cure. Heart failure is associated with reduced cardiac pump function, autonomic dysregulation, systemic inflammation and sleep-disordered breathing; these morbidities are exacerbated by peripheral chemoreceptor dysfunction. We reveal that in heart failure the carotid body generates spontaneous, episodic burst discharges coincident with the onset of disordered breathing in male rats. Purinergic (P2X3) receptors were upregulated two-fold in peripheral chemosensory afferents in heart failure, and when antagonized abolished these episodic discharges, normalized both peripheral chemoreceptor sensitivity and the breathing pattern, reinstated autonomic balance, improved cardiac function, and reduced both inflammation and biomarkers of cardiac failure. Aberrant ATP transmission in the carotid body triggers episodic discharges that via P2X3 receptors play a crucial role in the progression of heart failure and as such offer a distinct therapeutic angle to reverse multiple components of its pathogenesis.

Connexin hemichannels as candidate targets for cardioprotective and anti-arrhythmic treatments

Connexins are crucial cardiac proteins that form hemichannels and gap junctions. Gap junctions are responsible for the propagation of electrical and chemical signals between myocardial cells and cells of the specialized conduction system in order to synchronize the cardiac cycle and steer cardiac pump function. Gap junctions are normally open, while hemichannels are closed, but pathological circumstances may close gap junctions and open hemichannels, thereby perturbing cardiac function and homeostasis. Current evidence demonstrates an emerging role of hemichannels in myocardial ischemia and arrhythmia, and tools are now available to selectively inhibit hemichannels without inhibiting gap junctions as well as to stimulate hemichannel incorporation into gap junctions. We review available experimental evidence for hemichannel contributions to cellular pro-arrhythmic events in ventricular and atrial cardiomyocytes, and link these to insights at the level of molecular control of connexin-43-based hemichannel opening. We conclude that a double-edged approach of both preventing hemichannel opening and preserving gap junctional function will be key for further research and development of new connexin-based experimental approaches for treating heart disease.

Cardiac index: A superior parameter of cardiac function than left ventricular ejection fraction in risk stratification of hypertrophic cardiomyopathy

An appropriate indicator of cardiac function in the risk stratification of hypertrophic cardiomyopathy (HCM) patients is urgently needed. Cardiac index that reflects cardiac pumping function may be suitable. The purpose of this study was to investigate the clinical significance of reduced cardiac index in HCM patients. A total of 927 HCM patients were enrolled. The primary endpoint was cardiovascular death. The secondary endpoints were sudden cardiac death (SCD) and all-cause death. Combination models were constructed by adding reduced cardiac index and reduced left ventricular ejection fraction (LVEF) to the HCM risk-SCD model. Predictive accuracy was determined by C-statistics. Reduced cardiac index was defined as cardiac index ≤2.42 L/min/m2. During median follow-up of 4.3 years, 51 patients reached the endpoint. Reduced cardiac index independently increased the risk of cardiovascular death (adjusted hazard ratio [aHR] 2.976; P = .007), SCD (aHR 6.385; P = .001), and all-cause death (aHR 2.428; P = .010). By adding reduced cardiac index to the HCM risk-SCD model, the model C-statistic increased from 0.691 to 0.762, with an integrated discrimination improvement of 0.021 (P = .018) and a net reclassification improvement of 0.560 (P = .007). The addition of reduced LVEF failed to improve the original model. Better predictive accuracy for all endpoints was also indicated in reduced cardiac index than in reduced LVEF. Reduced cardiac index is an independent predictor of poor prognoses in HCM patients. Combining reduced cardiac index rather than reduced LVEF improved the HCM risk-SCD stratification strategy. The reduced cardiac index showed better predictive accuracy than reduced LVEF for all endpoints.

Case Studies in Physiology: Is blackout in breath-hold diving related to cardiac arrhythmias?

Syncope or "blackout" (BO) in breath-hold diving (freediving) is generally considered to be caused by hypoxia. However, it has been suggested that cardiac arrhythmias affecting the pumping effectivity could contribute to BO. BO is fairly common in competitive freediving, where athletes aim for maximal performance. We recorded heart rate (HR) during a static apnea (STA) competition, to reveal if arrhythmias occur. Four male freedivers with STA personal best (PB) of 349 ± 43 s, volunteered during national championships, where they performed STA floating face down in a shallow indoor pool. A non-coded Polar T31 chest strap recorded R-R intervals and a water- and pressure-proof pulse oximeter arterial oxygen saturation. Three divers produced STA near their PB without problems, whereas one diver ended with BO at 5 min 17s, which was 12 s beyond his PB. He was immediately brought up by safety divers and resumed breathing within 10 s. All divers attained similar lowest diving HR (47 ± 4 beats/min), but HR recordings displayed a different pattern for the diver ending with BO. After a short tachycardia, the three successful divers developed bradycardia, which became more pronounced during the second half of the apnea. The fourth diver developed pronounced bradycardia earlier, and at 2.5 min into the apnea, HR started alternating between approximately 50 and 140 beats/min, until the diver lost consciousness. At resumed breathing, HR returned to baseline. Nadir oxygen saturation was similar for all divers. We speculate that arrhythmia could have contributed to BO, by lowering stroke volume leading to a systolic blood pressure drop, affecting brain perfusion.NEW & NOTEWORTHY Heart rate during prolonged breath-holding until the point of loss of consciousness has not previously been published. The recordings show that blackout was preceded by a period of persistent alterations in R-R intervals, whereby an ectopic beat followed every normal heartbeat. Explanations for this deviating heart rate pattern could be either premature atrial contractions or premature ventricular contractions following every atrial beat, i.e., bigeminy, which could have compromised cardiac pumping function and caused/contributed to blackout.

Gefapixant, a Novel P2X3 Antagonist, Protects against Post Myocardial Infarction Cardiac Dysfunction and Remodeling Via Suppressing NLRP3 Inflammasome.

The ATP responsive P2 purinergic receptors can be subdivided into metabotropic P2X family and ionotropic P2Y family. Among these, P2X3 is a type of P2X receptor which is specifically expressed on nerves, especially on pre-ganglionic sensory fibers. This study investigates whether gefapixant possesses the potential of inhibiting cardiac sympathetic hypersensitivity to protect against cardiac remodeling in the context of myocardial infarction. The Sprague-Dawley rats were divided randomly into three groups: sham group-myocardial infarction group, and myocardial infarction with gefapixant treatment group. Myocardial infarction was induced by left anterior descending branch ligation. The gefapixant solution was intraperitoneally injected each time per day for 7 days and the appropriate dosage of gefapixant was determined according to the results of hematoxylin-eosin (HE) staining and myocardial injury biomarkers. Conditions of cardiac function were assessed by echocardiograph and cardiac fibrosis was evaluated by Western blotting and immunofluorescence staining of collagen I and collagen III. The sympathetic innervation was detected by norepinephrine concentration (pg/mL), in-vivo electrophysiology, and typical sympathetic biomarkers. Inflammatory cell infiltration was shown from immunofluorescence staining and pro-inflammatory signaling pathway activation was checked by immunohistology, quantitative realtime PCR (qPCR) and Western blotting. It was found that gefapixant injection of 10 mg/kg per day had the highest dosage-efficacy ratio. Furthermore, gefapixant treatment improved cardiac pump function as shown by increased LVEF and LVFS, and decreased LVIDd and LVIDs. The expression levels of collagen I and collagen III, and TNF-α were all decreased by P2X3 inhibition. Mechanistically, the decreased activation of nucleotide-binding and oligomerization domain-like receptors family pyrin-domain-containing 3 (NLRP3) inflammasome and subsequent cleavage of caspase-1 which modulated interleukin-1β (IL-1β) and IL-18 level in heart after gefapixant treatment were associated with the suppressed cardiac inflammation. It is suggested that P2X3 inhibition by gefapixant ameliorates post-infarct autonomic nervous imbalance, cardiac dysfunction, and remodeling possibly via inactivating NLRP3 inflammasome.

Development of ventricular trabeculae affects electrical conduction in the early endothermic heart.

The ventricular trabeculae play a role, among others, in the impulse spreading in ectothermic hearts. Despite the morphological similarity with the early developing hearts of endotherms, this trabecular function in mammalian and avian embryos was poorly addressed. We simulated impulse propagation inside the looping ventricle and revealed delayed apical activation in the heart with inhibited trabecular growth. This finding was corroborated by direct imaging of the endocardial surface showing early activation within the trabeculae implying preferential spreading of depolarization along with them. Targeting two crucial pathways of trabecular formation (Neuregulin/ErbB and Nkx2.5), we showed that trabecular development is also essential for proper conduction patterning. Persistence of the slow isotropic conduction likely contributed to the pumping failure in the trabeculae-deficient hearts. Our results showed the essential role of trabeculae in intraventricular impulse spreading and conduction patterning in the early endothermic heart. Lack of trabeculae leads to the failure of conduction parameters differentiation resulting in primitive ventricular activation with consequent impact on the cardiac pumping function.

Abstract 15848: Prognostic Value of Left Ventricular Diastolic Function in Patients With Hypertrophic Cardiomyopathy

Background: Diastolic dysfunction (DD) is frequently present in patients with hypertrophic cardiomyopathy (HCM) due to abnormal left ventricular (LV) relaxation, wall hypertrophy, increased LV filling pressures and myocardial disarray and fibrosis, even though ejection fraction (EF) remains preserved until late stages. Our aim was to investigate in a large cohort whether contemporary markers of DD and increased filling pressures are associated with outcomes in these patients. Methods: We screened consecutive patients with HCM who had transthoracic echocardiography and no significant valvular heart disease. The associations of septal/lateral e’ velocity, E/e’, left atrial volume index (LAVi), and tricuspid regurgitant velocity (TR) with all-cause mortality were tested. A diastolic score (DS) was also calculated (1 point for each abnormality in e’, E/e’, TR, LAVi). Results: 1,496 patients with HCM were studied (mean age 52±15 yrs; 61% men; LV EF 69±7%; Table). Diastolic abnormalities were highly prevalent in these patients ( Table ). In the subset without septal reduction therapy (SRT; n=900), at a median followup of 9 years (IQR 7-11 yrs; n=78 deaths), increased E/e’ and DS were strongly associated with mortality (log-rank P <.0001 for both; Figure ). However, E/e’ did not remain significant in multivariable models after adjustment for known cardiac risk factors or other significant confounders ( Table ). In contrast, DS >2 remained independently associated with ~2-fold higher mortality risk (adjusted HR 1.91 [1.14-3.20, P =.01]; n=693; Table). In patients who underwent SRT (n=596), these associations showed the same trend but attenuated. Conclusion: In HCM patients who did not require SRT, the severity of DD was associated with mortality, independent of cardiac pump function or known cardiac risk factors. The composite score was more powerful than E/e’. Further studies are needed to fully understand the impact of DD in these patients with and without SRT.

RESPOSTA CARDIOVASCULAR EM CORREDORES DE MÉDIA E LONGA DISTÂNCIA SOB TREINAMENTO

ABSTRACT Introduction: Research on the effects of exercise on the cardiovascular system has a long history that has recently been expanded with echocardiography. Research using Doppler echocardiography has been increasing because of the safe and non-invasive method of examination to study cardiac morphology and function. However, few studies on functional cardiac changes in mid and long-distance runners under training are still few. Objective: Study the monitoring of cardiovascular response in middle and long-distance runners during training. Methods: The CFOCS-I cardiovascular function detector was used to observe 24 indices of cardiac pump function, vascular function, and microcirculation in 12 female middle-distance runners. Results: According to the test results, diastolic force, systolic force, systolic function, left ventricular ejection fraction increased during the proposed loading exercise. The mean systolic and mean pulse pressures increased significantly with exercise load (P<0.01). Conclusion: Mid and long-distance runners demonstrated significant cardiac changes in ventricular shape, size, and systolic function, accompanied by significant changes in diastolic function when subjected to intense exercise. Evidence Level II; Therapeutic Studies - Investigating the result.

Pathophysiological alterations of left ventricular myocardial systolic function during normal pregnancy assessed by speckle tracking echocardiography: a prospective cohort echocardiography study.

By using conventional echocardiographic indices, cardiac pumping function remains unaltered during pregnancy. However, two-dimensional speckle tracking echocardiography (2D-STE) can detect subclinical changes of myocardial function even in patients with normal and stable left ventricular ejection fraction (LVEF).The aim of this study was to evaluate LV systolic performance during normal low risk pregnancy by using both conventional 2D and 3D echo indices and 2D-STE. One hundred and twelve pregnant women without any history of heart disease were prospectively recruited. They underwent serial echocardiographic evaluation in each pregnancy trimester and 6 months after delivery (time indicated as 1,2,3 and 4). 2D LVEF, 3D LVEF, LV global longitudinal strain (LVGLS), LV global circumferential strain (LVGCS) and LV-twist were measured and compared to the control group (c). 2D-LVEF and 3D-LVEF were not significantly different among the three trimesters, postpartum and controls. LVGLS progressively decreased during pregnancy (1st :21.71 ± 2.13%, 2nd : 21.20 ± 2.30%, 3rd : 19.82 ± 2.10%, 4th : 21.81 ± 2.05%, c: 21.71 ± 2.2%, overall p < 0,001) which receded during puerperium. No significant difference was noted in LVGCS (1st : 18.08 ± 5.54%, 2nd : 18.57 ± 3.41%, 3rd :18.20 ± 3.33%, 4th : 17.95 ± 3.39%, c: 18.8 ± 2.2%, p > 0.3). LV-Twist was significantly higher in the 1st trimester compared to controls (p = 0.04) and remained constantly high during the rest of the pregnancy and puerperium (1st :13.80 ± 5.09°, 2nd :13.46 ± 5.35°, 3rd :13.58 ± 4.32°, 4th :13.37 ± 4.26°, c: 11.5 ± 4.3°). In low risk individuals with normal pregnancy, a redistribution of force occurs especially in the 3rd trimester. Longitudinal strain decreases, while torsional movement of the heart increases and counterbalances the temporal change of longitudinal systolic function. These changes would probably reflect the pathophysiological alterations related to pregnancy.

Fluid–structure interaction simulation of pathological mitral valve dynamics in a coupled mitral valve-left ventricle model

Background Understanding the interaction between the mitral valve (MV) and the left ventricle (LV) is very important in assessing cardiac pump function, especially when the MV is dysfunctional. Such dysfunction is a major medical problem owing to the essential role of the MV in cardiac pump function. Computational modelling can provide new approaches to gain insight into the functions of the MV and LV.Methods In this study, a previously developed LV–MV model was used to study cardiac dynamics of MV leaflets under normal and pathological conditions, including hypertrophic cardiomyopathy (HOCM) and calcification of the valve. The coupled LV–MV model was implemented using a hybrid immersed boundary/finite element method to enable assessment of MV haemodynamic performance. Constitutive parameters of the HOCM and calcified valves were inversely determined from published experimental data. The LV compensation mechanism was further studied in the case of the calcified MV.Results Our results showed that MV dynamics and LV pump function could be greatly affected by MV pathology. For example, the HOCM case showed bulged MV leaflets at the systole owing to low stiffness, and the calcified MV was associated with impaired diastolic filling and much-reduced stroke volume. We further demonstrated that either increasing the LV filling pressure or increasing myocardial contractility could enable a calcified valve to achieve near-normal pump function.Conclusion The modelling approach developed in this study may deepen our understanding of the interactions between the MV and the LV and help in risk stratification of heart valve disease and in silico treatment planning by exploring intrinsic compensation mechanisms.

Left ventricular global function index and peculiarities of daily blood pressure profile in patients with arterial hypertension

BACKGROUND: The left ventricular global function index (LVGFI), determined using transthoracic echocardiography, is a simple clinical marker of left ventricular dysfunction and has superior prognostic value to the standard ejection fraction-based assessment of cardiac pump function. The methodology for calculating this index was proposed in 2019. Currently, the clinical factors that influence the state of left ventricular global functions are not examined.&#x0D; AIM: This study aimed to assess the association of LVGFI with the peculiarities of daily blood pressure (BP) profile in patients with arterial hypertension (AH).&#x0D; MATERIALS AND METHODS: A total of 104 patients [51 men (49%) and 53 (51%) women] with AH were examined. The mean age of the patients was 58.711.73 years, and disease duration was 6.0310.93 years. AH corresponded to grades 1, 2, and 3 in 47 (45.2%), 26 (25.0%), and 31 (29.8%) patients, respectively. Patients with myocardial infarction or stroke, cardiomyopathies, heart defects, diabetes mellitus, thyroid dysfunction, or chronic kidney disease were not included in the study. All patients underwent daily BP monitoring, echocardiography, carotid artery examination, and biochemical blood tests.&#x0D; RESULTS: A significant inverse weak correlation of LVGFI with age (r=0.215, p=0.028), body mass index (r=0.378, p=0.001), BP variability (r=0.307, p=0.002), and daily mean values of systolic (r=0.223, p=0.026) and diastolic (r=0.237, p=0.018) BP were observed. In the regression analysis, an increase in body mass index, abnormal diurnal BP with excessive BP reduction at night, and high BP variability demonstrated a significant and independent association with decreased LVGFI.&#x0D; CONCLUSIONS: The study revealed an independent association of decreased LVGFI with increased body mass index, excessive BP reduction at night, and high systolic BP variability. These factors should be considered in the possible development of a strategy to prevent target organ damage in AH.

The cardiac sarcoidosis consortium: elucidating a mysterious disease through collaborative research

Cardiac sarcoidosis (CS) is an inflammatory disease of unknown aetiology that can lead to life-threatening arrhythmias, heart failure, and death. The hallmark pathophysiology involves the development of noncaseating granulomas in cardiac tissue disrupting normal electrical signalling and ultimately impairing cardiac pump function. Advanced cardiac imaging has improved the clinician’s ability to detect the disease, and there has been a significant rise in the number of patients diagnosed with this disorder in the last 20 years. Critical knowledge gaps remain in the domains of aetiology, genetic basis, and immunological mechanisms. There is also uncertainty as to the most appropriate diagnostic criteria, risk stratification, and treatments. The CS literature is mostly comprised of case reports and small retrospective studies; high-quality data from randomized controlled trials are lacking. After collaborating on a multicentre analysis of safety and efficacy of implantable cardioverter defibrillator (ICD) in CS,1 the founding members [Dr Thomas Crawford and Dr Frank Bogun (University of Michigan), Dr William Sauer (then at the University of Colorado), and Dr Kenneth Ellenbogen and Dr Jordana Kron (Virginia Commonwealth University)] established an international, prospective registry, the Cardiac Sarcoidosis Consortium (CSC). The consortium identified five primary aims (Figure 1). The CSC has advocated for inclusion of CS sessions at major national and international meetings and proposed and championed the development of the first CS-specific guidelines, which resulted in the 2014 Heart Rhythm Society Expert Consensus Statement on the Diagnosis and Management of Arrhythmias Associated with Cardiac Sarcoidosis.2 Since the inception of the CSC, we have witnessed an increase in academic interest in CS at national meetings and in research publications.

Sulfasalazine exacerbates angiotensin II-induced cardiac remodelling by activating Akt signal pathway.

A thorough understanding of the pathological process underlying hypertension-induced cardiac remodelling may help in prevention and treatment of heart failure. Angiotensin II (AngII) results in cardiac fibrosis and hypertrophy partly through activation of inflammation, which increases the fibroblasts and promotes extracellular matrix production. Sulfasalazine (SASP) has evident anti-inflammatory effects and pharmacological functions on autoimmune disease. The roles of SASP in the cardiac remodelling remain unknown. In this study, we established AngII-induced cardiac remodelling mice model and then treated with SASP. Blood pressure, cardiac pump function and pathological changes of cardiac remodelling were analysed in these mice. To explore the mechanism, phosphorylated Akt was detected in vivo and vitro. In this study, we found that SASP aggravated cardiac dysfunction, hypertrophy and fibrosis after AngII infusion. In addition, SASP activated Akt in AngII-remodelled mouse hearts and cardiac cells. Our findings indicate that independent of anti-inflammatory property, SASP exacerbates AngII-induced cardiac remodelling by activation of Akt signalling pathway.

Montelukast, cysteinyl leukotriene receptor 1 antagonist, inhibits cardiac fibrosis by activating APJ

Montelukast, cysteinyl leukotriene receptor 1 (CysLT1R) antagonist, is used clinically for patients with asthma, chronic obstructive pulmonary diseases (COPD), and allergic rhinitis. It has been reported that CysLT1R antagonists could reduce the risks of cardiovascular diseases in animal studies. Cardiac fibrosis is one of the major causes of heart failure. But little is known about the role of Montelukast in cardiac fibrosis and its underlying mechanism. In transverse aortic constriction (TAC) mice, Montelukast improved cardiac pumping function and inhibited cardiac fibrosis by down-regulation of the proteins related to the fibrosis, such as connective tissue growth factor (CTGF), Transforming Growth Factor β (TGF-β), and Alpha-smooth muscle actin (α-SMA). Montelukast reduced cell proliferation and collagen production in neonatal cardiac fibroblasts (CFs) with the pretreatment of 20% serum, while down-regulating the expression of TGF-β, CTGF and α-SMA. Molecules docking methods estimated a high affinity of Montelukast to Apelin receptor (APJ) and an effective chemical structure for Montelukast binding APJ. In Chinese hamster ovary (CHO) cells with stable overexpressing APJ, Montelukast inhibited forskolin (1 μM)-mediated cyclic adenosine monophosphate (cAMP) production and extracellular signal-regulated kinase1/2 (ERK1/2) phosphorylation, while these effects were reversed by pertussis toxin (PTX) pretreatment. APJ silence disrupted the effects of Montelukast in CFs pretreatment by serum 20%. So we concluded that Montelukast inhibited cardiac fibrosis due presumably to the coupling to the APJ-mediated Gi signaling pathway, which may be a promising therapeutic target for cardiac fibrosis.

Pathophysiological alterations of left ventricular myocardial systolic function during normal pregnancy assessed by speckle tracking echocardiography: a prospective cohort echocardiography study

Abstract Funding Acknowledgements Type of funding sources: None. Introduction Pregnancy induces a variety of haemodynamic and morphological changes, leading to the amplification of cardiac pumping function. These changes do not cause any significant left ventricular (LV) dysfunction by using conventional echocardiographic indices, but it is not fully elucidated whether subclinical or/and reversible myocardial dysfunction is provoked during pregnancy. Two-dimensional speckle tracking echocardiography (2D-STE) can detect subclinical myocardial dysfunction even when conventional echocardiography reveal LV normal ejection fraction (LVEF).Purpose: The aim of this study was to evaluate whether LV systolic performance is impaired during normal low risk pregnancy by using both conventional 2D and 3D echo indices and 2D-STE. Materials and methods: One hundred and twelve consecutive pregnant women without any history of heart disease were prospectively recruited. They underwent serial echocardiographic evaluation in each pregnancy trimester (1st: 8th-12th week, 2nd: 22th-26th week, 3rd: 32-36th week) and 6 months after delivery (time indicated as 4). LV dimensions, relative wall thickness (RWT), 2D-LVEF, 3D-LVEF, systolic S wave from Tissue Doppler Imaging, LV global longitudinal strain (LVGLS), LV global circumferential strain (LVGCS) and LV-twist were measured and compared to 31 nulliparous women of similar age, who served as a control group (c).Results: Progressive eccentric LV hypertrophy was observed during pregnancy, which was subsided postpartum (p1-2 = 0.08, p2-3= 0.002, p3-4 = 0.001, p1-3 &amp;lt; 0.001, p1-4= 0.789), while no significant change in LV dimensions was found. 2D-LVEF, 3D-LVEF and S wave values were not significantly different among the three trimesters, postpartum and controls. LVGLS progressively decreased during pregnancy (1st:-21.71 ± 2.13%, 2nd: -21.20 ± 2.30%, 3rd: -19.82 ± 2.10%,4th: -21.81 ± 2.05%, c: -21.71 ± 2.2[E1]%,overall p &amp;lt; 0,001 ) and returned to normal during puerperium. No significant difference was noted in LVGCS (1st: -18.08 ± 5.54%, 2nd: -18.57 ± 3.41%, 3rd: -18.20 ± 3.33%,4th: -17.95 ± 3.39%,c: -18.8 ± 2.2% , p &amp;gt; 0.3). LV-Twist was significantly higher in the 1st trimester compared to controls (p= 0.04) and remained constantly high during the rest of the pregnancy and puerperium (1st:13.80 ± 5.09°, 2nd :13.46 ± 5.35°, 3rd:13.58 ± 4.32°, 4th:13.37 ± 4.26°, c: 11.5 ± 4.3°, ).Conclusion: Left ventricular subclinical dysfunction seems to occur in the longitudinal axis even in low risk individuals with normal pregnancy. Increased torsional movement of the heart seems to counterbalance the temporal impairment of longitudinal systolic function.

Pathophysiological mechanism of worsened clinical outcome by lowered left ventricular cardiac power output in heart failure

Abstract Funding Acknowledgements Type of funding sources: None. Background Cardiac power output (CPO) is a measure of cardiac pumping function, and CPO during exercise is known to be a powerful prognostic marker of heart failure. Despite its prognostic significance, pathophysiological mechanism of the association between reduced CPO and worse clinical outcome is unknown. We hypothesized that reduced CPO is associated with worse outcome through the reduced exercise capacity and enhanced ventilatory response. Methods Cardiopulmonary exercise testing and exercise stress echocardiography were performed in consecutive 64 patients with chronic heart failure who admitted to our department for the management of heart failure [60 ± 14 years old, left ventricular (LV) ejection fraction 39 ± 16%, ischemic etiology 16%, brain natriuretic peptide 124 pg/ml (51-313)]. Peak oxygen uptake (peak VO2) and the lowest minute ventilation / carbon dioxide production ratio (VE/VCO2) were measured as a parameter of exercise tolerance and that of ventilatory response, respectively. LV ejection fraction was measured by disk summation method at peak exercise. By using Doppler images, E/e" at peak exercise was measured as a marker of LV filling pressure, and CPO normalized by LV mass was obtained as 0.222 × cardiac output × mean blood pressure / LV mass [W/100 g]. Cardiac events defined as hospitalization for heart failure, cardiac death, or implantation of a LV assist device after the examinations were recorded. Results CPO at rest was weakly correlated with peak VO2 (r = 0.25, p = 0.046) but not with VE/VCO2. In contrast, CPO at peak exercise was positively correlated with peak VO2 (r = 0.50, p &amp;lt; 0.001) and inversely correlated with VE/VCO2 (r=-0.40, p = 0.002). Moreover, CPO at peak exercise determined both peak VO2 (b = 0.50) and VE/VCO2 (β=-0.54) independently of LV ejection fraction and E/e" at peak exercise. During a median follow-up period of 1211 days, 12 cardiac events were observed. Each of reduced peak VO2 (hazard ratio 0.78, 95% confidence interval 0.66-0.90) and increased VE/VCO2 (hazard ratio 1.10, 95% confidence interval 1.02-1.18) was associated with worse clinical outcome. Conclusions In patients with chronic heart failure, CPO during exercise was associated with prognosis of heart failure through the reduced exercise capacity and enhanced ventilatory response.

Effects of dispersed fibres in myocardial mechanics, Part II: active response.

This work accompanies the first part of our study "effects of dispersed fibres in myocardial mechanics: Part I passive response" with a focus on myocardial active contraction. Existing studies have suggested that myofibre architecture plays an important role in myocardial active contraction. Following the first part of our study, we firstly study how the general fibre architecture affects ventricular pump function by varying the mean myofibre rotation angles, and then the impact of fibre dispersion along the myofibre direction on myocardial contraction in a left ventricle model. Dispersed active stress is described by a generalised structure tensor method for its computational efficiency. Our results show that both the myofibre rotation angle and its dispersion can significantly affect cardiac pump function by redistributing active tension circumferentially and longitudinally. For example, larger myofibre rotation angle and higher active tension along the sheet-normal direction can lead to much reduced end-systolic volume and higher longitudinal shortening, and thus a larger ejection fraction. In summary, these two studies together have demonstrated that it is necessary and essential to include realistic fibre structures (both fibre rotation angle and fibre dispersion) in personalised cardiac modelling for accurate myocardial dynamics prediction.

Several Theoretical and Applied Problems of Human Extreme Physiology: Mathematical Modeling

Human cardiovascular system (CVS) and hemodynamics are critically sensitive to essential alterations of mechanical inertial forces in directions of head-legs (+Gz) or legs-head (-Gz). Typically, such alterations appear during pilotage maneuvers of modern high maneuverable airspace vehicles (HMAV).The vulnerability of pilots or passengers of HMAV to these altering forces depends on their three main characteristics: amplitude, dynamics, and duration. Special protections, proposed to minimize this vulnerability, should be improved in parallel with the increasing of these hazardous characteristics of HMAVs. Empiric testing of novel protection methods and tools is both expensive and hazardous. Therefore computer simulations are encouraged. Autonomic software (AS) for simulating and theoretical investigating of the main dynamic responses of human CVS to altering Gz is developed. AS is based on a system of quantitative mathematical models (QMM) consisting of about 1300 differential and algebraic equations. QMM describes the dynamics of both CVS (the cardiac pump function, baroreceptor control of parameters of cardiovascular net presented by means of lumped parameter vascular compartments) and non-biological variables (inertial forces, and used protections). The main function of AS is to provide physiologist-researcher by visualizations of calculated additional data concerning characteristics of both external and internal environments under high sustained accelerations and short-time microgravity. Additionally, AS can be useful as an educational tool able to show both researchers and young pilots the main hemodynamic effects caused by accelerations and acute weightlessness with and without use of different protection tools and technics. In this case, AS does help users to optimize training process aimed to ensure optimal-like human tolerance to the altered physical environment. Main physiological events appearing under different scenarios of accelerations and microgravity have been tested.