Impaired Myocardial Performance Research Articles

Echocardiography-Derived Hemodynamic Forces Are Associated with Clinical Outcomes in Patients with Non-Ischemic Dilated Cardiomyopathy.

Introduction: Non-ischemic dilated cardiomyopathy (NIDCM) is characterized by a reduced left ventricular (LV) ejection fraction (LVEF, <50%) and a high risk for heart failure (HF) and death. Echocardiography-derived hemodynamic forces (HDFs) may provide important information on LV mechanics, but their prognostic value is unknown. Aim: To explore the features of echocardiography-derived HDFs in NIDCM and their association with clinical endpoints. Methods: Asymptomatic, non-hospitalized NIDCM patients free from coronary artery disease and moderate or severe valvular heart disease were included in this single-center observational retrospective longitudinal study. Those with atrial fibrillation and a follow-up <12 months were excluded. Major adverse cardiovascular events (MACE) were defined as a composite of all-cause death, HF hospitalization, and ambulatory intravenous diuretics administration. LV HDFs were analyzed with a prototype software. Apex-base (HDFs-ab), lateral-septal (HDFs-ls), and HDFs-angle were computed. Results: Ninety-seven patients were included, sixty-seven (69%) were males, mean age was 62 ± 14 years, and mean LVEF was 39.2 ± 8.6%. During a median follow-up of 4.2 (3.1-5.1) years, 19 (20%) patients experienced MACE. These patients had a higher HDFs-angle (71.0 (67.0-75.0) vs. 68.0 (63.0-71.0)°, p = 0.005), lower HDFs-ls (1.36 (1.01-1.85) vs. 1.66 ([1.28-2.04])%, p = 0.015), but similar HDFs-ab (5.02 (4.39-6.34) vs. 5.66 (4.53-6.78)%, p = 0.375) compared to those without MACE. in a Cox regression analysis, HDFs-angle (HR 1.16 (95%-CI 1.04-1.30), p = 0.007) was associated with MACE, while other conventional echocardiography parameters, including LVEF and LV longitudinal strain, were not. Conclusions: HDFs-angle is associated with clinical endpoints in NIDCM. A higher HDFs-angle may be a marker of impaired myocardial performance in patients with reduced LVEF.

N-arachidonoylphenolamine alleviates ischaemia/reperfusion-induced cardiomyocyte necroptosis by restoring proteasomal activity

Necroptosis and apoptosis contribute to the pathogenesis of myocardial ischaemia/reperfusion (I/R) injury and subsequent heart failure. N-arachidonoylphenolamine (AM404) is a paracetamol lipid metabolite that has pleiotropic activity to modulate the endocannabinoid system. However, the protective role of AM404 in modulating I/R-mediated myocardial damage and the underlying mechanism remain largely unknown. A murine I/R model was generated by occlusion of the left anterior descending artery. AM404 (20 mg/kg) was injected intraperitoneally into mice at 2 and 24 h before the I/R operation. Our data revealed that AM404 administration to mice greatly ameliorated I/R-triggered impairment of myocardial performance and reduced infarct area, myocyte apoptosis, oxidative stress and inflammatory response accompanied by the reduction of receptor interacting protein kinase (RIPK)1/3- mixed lineage kinase domain-like (MLKL)-mediated necroptosis and upregulation of the immunosubunits (β2i and β5i). In contrast, administration of epoxomicin (a proteasome inhibitor) dramatically abolished AM404-dependent protection against myocardial I/R damage. Mechanistically, AM404 treatment increases β5i expression, which interacts with Pellino-1 (Peli1), an E3 ligase, to form a complex with RIPK1/3, thereby promoting their degradation, which leads to inhibition of cardiomyocyte necroptosis in the I/R heart. In conclusion, these findings demonstrate that AM404 could prevent cardiac I/R damage and may be a promising drug for the treatment of ischaemic heart disease.

Sleeve Gastrectomy-Induced AMPK Activation Attenuates Diabetic Cardiomyopathy by Maintaining Mitochondrial Homeostasis via NR4A1 Suppression in Rats.

Diabetic cardiomyopathy (DCM) is characterized by impaired diastolic and systolic myocardial performance and is a major cause of morbidity and mortality in patients with diabetes. Surgical bariatric procedures, such as sleeve gastrectomy (SG), result in remission of type 2 diabetes (T2DM) and have benefits with myocardial function. Maintaining cardiac mitochondrial homeostasis is a promising therapeutic strategy for DCM. However, whether SG surgery affects mitochondrial function and its underlying mechanism remains unclear. This study aimed to investigate the effect of SG surgery on mitochondrial homeostasis and intracellular oxidative stress in rats with DCM. We also examined cellular phenotypes and molecular mechanisms in high glucose and high fat-stimulated myocytes. The rat model of DCM was established by high-fat diet feeding and low-dose streptozotocin injection. We observed a remarkably metabolic benefit of SG, including a reduced body weight, food intake, blood glucose levels, and restored glucose tolerance and insulin sensitivity post-operatively. Also, SG ameliorated the pathological cardiac hypertrophy, myocardial fibrosis and the dysfunction of myocardial contraction and diastole, consequently delayed the progression of DCM. Also, SG restored the mitochondrial dysfunction and fragmentation through the AMPK signaling activation mediated nuclear receptor subfamily 4 group A member 1 (NR4A1)/DRP1 suppression in vivo. H9c2 cardiomyocytes showed that activation of AMPK could reverse the mitochondrial dysfunction somehow. Collectively, our study provided evidence that SG surgery could alleviate mitochondrial dysfunction in DCM. Moreover, AMPK-activated NR4A1/DRP1 repression might act as a significant reason for maintaining mitochondrial homeostasis in the myocardium, thus contributing to morphological and functional alleviation of DCM.

Current knowledge about cardiomyocytes maturation and endogenous myocardial regeneration. Background to apply this potential in humans with end-stage heart failure

Abstract Heart failure (HF) is a clinical status defined as a final stage of many cardiac diseases featured by severely impaired systolic myocardial performance in a result of dramatic decline in a number of properly functioning cardiomyocytes. Currently, the available therapeutic options for HF patients are not applicable in all of them. Up to now, many strategies to increase a number of normal cardiomyocytes have been proposed. One of them, the most physiological one at glance, seems to be a stimulation of post-mitotic cardiomyocytes to proliferate/or cardiac stem cells to differentiate. In this review article, detailed background of such method of myocardial regeneration, including the physiological processes of cardiomyocyte transformation and maturation, is presented. Moreover, the latest directions of basic research devoted to develop sufficient and safe cardiomyocyte-based therapies of the end-stage HF individuals are discussed. Concluding, this direction of further research seems to be justified particularly in a view of human population aging, an increased prevalence of HF and higher expectations of improved efficiency of patients’ care.

Abstract 12245: Surface Lin28a Expression Indicative of Cellular Stress Directed Towards Senescence

Introduction: Declining cellular functional capacity resulting from stress or aging is a primary contributor to impairment of myocardial performance. Molecular pathway regulation of biological processes in cardiac interstitial cells (CICs) is pivotal in stress and aging responses. Altered localization of the RNA binding protein Lin28A has been reported in response to environmental stress, but the role of Lin28A in response to stress in CICs has not been explored. Hypothesis: Lin28A redistribution is indicative of stress response in CIC associated with aging and senescence. Methods and Results: Localization of Lin28A was assessed by multiple experimental analyses and treatment conditions and correlated to oxidative stress, senescence, and ploidy in adult murine CICs. Surface Lin28A expression is present on 5% of fresh CICs and maintained through passage 2, increasing to 21% in hyperoxic conditions but lowered to 14% in physiologic normoxia. Surface Lin28A is coincident with elevated Beta-galactosidase (Beta-gal) expression in CICs expanded in hyperoxia, and also increases with polyploidization and binucleation of CICs regardless of oxygen culture. Transcriptional profiling of CICs using single cell RNASeq reveals upregulation of pathways associated with oxidative stress in CICs exhibiting surface Lin28A. Induction of surface Lin28A by oxidative stress is blunted by treatment of cells with the antioxidant Trolox in a dose-dependent manner, with 300uM Trolox exposure maintaining characteristics of freshly isolated CICs possessing low expression of surface Lin28A and Beta-gal with predominantly diploid content. Conclusion: Surface Lin28A is a marker of environmental oxidative stress in CICs and antioxidant treatment antagonizes this phenotype. The biological significance of Lin28 surface expression and consequences for myocardial responses may provide important insights regarding mitigation of cardiac stress and aging.

The association of reduced left ventricular\xa0strains with increased extracellular volume and their collective impact on clinical outcomes

BackgroundMyocardial fibrosis and left ventricular (LV) longitudinal strain are independently associated with adverse clinical outcomes. However, the relationship between tissue properties and strain indices as well as their collective impact on outcomes are yet to be fully elucidated. We aim to investigate the relationship between LV global longitudinal strain (GLS), global circumferential strain (GCS) and global radial strain (GRS) with extracellular volume (ECV) and their collective impact.MethodsConsecutive patients referred for clinical cardiovascular magnetic resonance (CMR) due to cardiomyopathy were prospectively enrolled. All patients underwent CMR with T1 mapping. ECV was calculated incorporating native and post-contrast T1 as well as hematocrit. LV GLS, GCS, and GRS were assessed by feature tracking. Hazard ratios and Kaplan–Meier curves were produced to assess the association between strains and T1 mapping indices with a composite outcome of all-cause mortality and hospitalized heart failure.ResultsThe study consisted of 259 patients with mixed referring diagnoses of non-ischemic/ischemic cardiomyopathy and 21 normal controls. Decreased GLS, GCS and GRS were associated with increased ECV, increased native T1, and reduced post-contrast T1 in a dose dependent manner when T1 or ECV was in the abnormal range. After a mean follow-up of 31 ± 23 months, 41 events occurred including 37 heart failure admissions and 4 deaths. Kaplan–Meier plots demonstrated that reduced strains were associated with reduced event-free survival predominantly in patients with increased ECV (≥ 28.3%). The worst outcome was among those with both reduced strains and increased ECV. In the multivariable models, increased ECV, reduced post-contrast T1 and reduced strains in all 3 directions remained predictors of outcome risk, respectively.ConclusionOur findings highlight the intrinsic link between altered CMR tissue properties and impaired myocardial mechanical performance and additionally demonstrate improved risk stratification by characterizing tissue property among patients with reduced strain.

Moderate Intensity Continuous Training versus High Intensity Interval Training in Growth Restricted Mice to Improve Cardiac Function: A Pilot Study

IntroductionGrowth‐restriction during postnatal development has been linked to increased cardiovascular disease risk in adulthood, with greater impairment seen in females. Growth‐restricted mice present with thinner left ventricle posterior and anterior walls, compromised diastolic function and reduced stroke volume and cardiac output. Regular aerobic exercise training can promote cardiovascular health and well‐being, with recent evidence suggesting high intensity interval training may be more cardio protective as compared to moderate intensity continuous training. The purpose of this investigation was to determine if high intensity interval training (HIIT) promoted cardiac health in postnatally growth‐restricted female mice as compared to traditional moderate intensity continuous training (MICT).MethodsTo induce postnatal growth‐restriction, FVB mouse dams were fed either a 20% protein control diet or an 8% low‐protein isocaloric diet beginning 2 weeks before mating. Only pups born to control‐fed dams were used and cross‐fostered to either a low‐protein fed dam to induce growth‐restriction (PUN) or a different control fed dam (CON). On postnatal (PN) day 21 all pups were weaned and fed a control diet. At PN33 mice were allocated to MICT (PUN n=4, CON n=3), HIIT (PUN n= 4, CON n= 3) or a corresponding sedentary group (MICT: sedentary PUN n= 5, sedentary CON n=4; or HIIT: sedentary PUN n= 5, sedentary CON n=4). The MICT protocol was defined as treadmill running 3 days/week for 12 weeks at 17 m/min at −16 degree decline for 28 minutes and the HIIT protocol was treadmill running 5 days/week for 8 weeks with alternating intervals of 8 mins at 85% and 2 mins at 55% of maximum workload for 60 minutes. At PN 128 (MICT) and PN 98 (HIIT) echocardiography and Doppler blood flow was utilized to measure cardiac structure and function under 1% isoflurane anesthesia. Statistical analysis was performed using GraphPad Prism 8, utilizing two‐way ANOVAs with an alpha level of .05 set a priori and if significant Tukey’s post hoc for multiple comparisons was conducted.ResultsSedentary PUN groups exhibited cardiac dysfunction as evident by reduced left ventricle (LV) area during systole (p=.0290), LV diameter during diastole (p=.0156) and systole (p=.0003) and LV volume during systole (p=.0191). Systolic function was compromised in the PUN sedentary group by impaired myocardial performance index (MPI) (p=.0049), ejection fraction (EF) (p=.0023), aortic ejection time (AET) (p=.0345) and fractional shortening (FS) (p=.0111). Diastolic impairment manifested as reductions in isovolumic relaxation time (IVRT) (p=.0102) and mitral valve deceleration time (MVDT) (p=&lt;.0001) in the PUN sedentary group. Both MICT and HIIT were able to reverse impairments as no significant differences were noted between exercised PUN groups and their CON counterparts.ConclusionMICT and HIIT both reversed the cardiac impairments caused by growth‐restriction. Impairments caused by growth‐restriction can be mitigated with exercise training. Importantly, exercise professionals have flexibility in prescribing exercise as both MICT and HIIT were shown to be effective.

Integration between volumetric change and strain for describing the global mechanical function of the left ventricle

IntroductionEvaluations of left ventricular systolic function based on ejection fraction (EF) alone are unable to recognize impaired myocardial performance in some dysfunctional states, and strain parameters are often invoked for an improved description of cardiac contraction. A comprehensive framework integrating deformation measures with volumetric changes is therefore necessary. MethodsThis study presents a general mathematical background that confirms and generalizes a previously proposed framework relating volumetric changes and strain values. The model is then validated with 5450 data samples made of LV volume, global longitudinal strain (GLS) and global circumferential strain (GCS) from 109 heterogeneous subjects who underwent cardiac magnetic resonance imaging. The GCS was measured by either three short-axis slices or 3D LV geometry reconstructed from 3 long-axis slices. ResultsResults demonstrated the reliability of the relationship EF = 1 − (GLS + 1)(GCS + 1)2. Accuracy is higher (correlation coefficient r = 0.997) when GCS is obtained by 3D deformation, although it remains high (r = 0.98) when GCS is measured from short-axis slices. However, the latter may underestimate (about 10% in relative terms) the circumferential deformation due to through-plane motion. ConclusionsThe accuracy of this relationship permits a unitary description of LV systolic function in terms of both EF and global strain values by its position on the strain plane (GLS, GCS). This also allows to monitor pathologic or healing changes, as a consequence of exercise, drugs, surgery or other therapeutic options, as trajectories on that plane.

Abstract P2003: Loss of Trpa1 in Mice Leads to Age-Related Dilated Cardiomyopathy

Activation of the transient receptor potential ankyrin 1 (TRPA1) channel, a mechanical and oxidative stress sensor, has been shown to slow down aging process and promote longevity in invertebrate animal models like Caenorhabditis elegans . Although physiologic sensory functions of TRPA1 are conservative across species, the role of TRPA1 in regulation of organ development and function in mammals in the aging process is unknown. The present study tests the hypothesis that TRPA1 ablation leads to cardiac dilation and cardiomyopathy in aging mice. Echocardiography was performed in male 12-week-old (young) and 52-week-old (older) Trpa1 gene knockout ( Trpa1 -/- ) mice and wild-type (WT) littermates on a mixed C57BL/6 x 129 genetic background. Echocardiogram data showed that, compared to young WT littermates, young Trpa1 -/- mice had similar cardiac dimensions and left ventricular function, as demonstrated by left ventricular end-diastolic internal dimension (LVIDd, WT 4.29±0.62 vs. Trpa1 -/- 4.50±0.41 mm, P&gt;0.05), left ventricular ejection fraction (LVEF, a parameter of systolic function, WT 66.73±9.50 vs. Trpa1 -/- 63.39±12.76 %, P&gt;0.05), and E/A ratio (a parameter of diastolic function, WT 1.23±0.03 vs. Trpa1 -/- 1.39±0.14, P&gt;0.05). In contrast, older Trpa1 -/- mice developed dilated cardiomyopathy with dilated left ventricle (LVIDd: WT 4.60±0.16 vs. Trpa1 -/- 5.00±0.37 mm, P&lt;0.05) and impaired left ventricular systolic function (LVEF: WT 58.04±9.27 vs. Trpa1 -/- 41.79±7.19 %, P&lt;0.05) when compared to older WT mice. In addition, older Trpa1 -/- mice had impaired left ventricular myocardial performance index (LV MPI, a parameter of ventricular systolic and diastolic function, WT 0.62±0.15 vs. Trpa1 -/- 0.89±0.18, P&lt;0.05) albeit left ventricular diastolic function was not different between old Trpa1 -/- and WT mice (E/A ratio: WT 1.53±0.22 vs. Trpa1 -/- 1.99±0.92, P&gt;0.05). These results show that genetic knockout of TRPA1 leads to age-related left ventricular dilation and systolic dysfunction. These findings suggest that TRPA1 activation protects against age-related dilated cardiomyopathy.

Myocardial Dysfunction after Severe Food Restriction Is Linked to Changes in the Calcium-Handling Properties in Rats.

Severe food restriction (FR) impairs cardiac performance, although the causative mechanisms remain elusive. Since proteins associated with calcium handling may contribute to cardiac dysfunction, this study aimed to evaluate whether severe FR results in alterations in the expression and activity of Ca2+-handling proteins that contribute to impaired myocardial performance. Male 60-day-old Wistar–Kyoto rats were fed a control or restricted diet (50% reduction in the food consumed by the control group) for 90 days. Body weight, body fat pads, adiposity index, as well as the weights of the soleus muscle and lung, were obtained. Cardiac remodeling was assessed by morphological measures. The myocardial contractile performance was analyzed in isolated papillary muscles during the administration of extracellular Ca2+ and in the absence or presence of a sarcoplasmic reticulum Ca2+-ATPase (SERCA2a) specific blocker. The expression of Ca2+-handling regulatory proteins was analyzed via Western Blot. Severe FR resulted in a 50% decrease in body weight and adiposity measures. Cardiac morphometry was substantially altered, as heart weights were nearly twofold lower in FR rats. Papillary muscles isolated from FR hearts displayed mechanical dysfunction, including decreased developed tension and reduced contractility and relaxation. The administration of a SERCA2a blocker led to further decrements in contractile function in FR hearts, suggesting impaired SERCA2a activity. Moreover, the FR rats presented a lower expression of L-type Ca2+ channels. Therefore, myocardial dysfunction induced by severe food restriction is associated with changes in the calcium-handling properties in rats.

Myocardial Energy Stress, Autophagy Induction, and Cardiomyocyte Functional Responses.

Significance: Energy stress in the myocardium occurs in a variety of acute and chronic pathophysiological contexts, including ischemia, nutrient deprivation, and diabetic disease settings of substrate disturbance. Although the heart is highly adaptive and flexible in relation to fuel utilization and routes of adenosine-5'-triphosphate (ATP) generation, maladaptations in energy stress situations confer functional deficit. An understanding of the mechanisms that link energy stress to impaired myocardial performance is crucial. Recent Advances: Emerging evidence suggests that, in parallel with regulated enzymatic pathways that control intracellular substrate supply, other processes of "bulk" autophagic macromolecular breakdown may be important in energy stress conditions. Recent findings indicate that cargo-specific autophagic activity may be important in different stress states. In particular, induction of glycophagy, a glycogen-specific autophagy, has been described in acute and chronic energy stress situations. The impact of elevated cardiomyocyte glucose flux relating to glycophagy dysregulation on contractile function is unknown. Critical Issues: Ischemia- and diabetes-related cardiac adverse events comprise the majority of cardiovascular disease morbidity and mortality. Current therapies involve management of systemic comorbidities. Cardiac-specific adjunct treatments targeted to manage myocardial energy stress responses are lacking. Future Directions: New knowledge is required to understand the mechanisms involved in selective recruitment of autophagic responses in the cardiomyocyte energy stress response. In particular, exploration of the links between cell substrate flux, calcium ion (Ca2+) flux, and phagosomal cargo flux is required. Strategies to target specific fuel "bulk" management defects in cardiac energy stress states may be of therapeutic value.

Assessment of cardiac allograft systolic function by global longitudinal strain: From donor to recipient.

Cardiac allografts are routinely evaluated by left ventricular ejection fraction (LVEF) before and after transplantation. However, myocardial deformation analyses with LV global longitudinal strain (GLS) are more sensitive for detecting impaired LV myocardial systolic performance compared with LVEF. We analyzed echocardiograms in 34 heart donor-recipient pairs transplanted at Duke University from 2000 to 2013. Assessments of allograft LV systolic function by LVEF and/or LV GLS were performed on echocardiograms obtained pre-explanation in donors and serially in corresponding recipients. Donors had a median LVEF of 55% (25th, 75th percentile, 54% to 60%). Median donor LV GLS was -14.6% (-13.7 to -17.3%); LV GLS was abnormal (ie, >-16%) in 68% of donors. Post-transplantation, LV GLS was further impaired at 6 weeks (median -11.8%; -11.0 to -13.4%) and 3 months (median -11.4%; -10.3 to -13.9%) before recovering to pretransplant levels in follow-up. Median LVEF remained ≥50% throughout follow-up. We found no association between donor LV GLS and post-transplant outcomes, including all-cause hospitalization and mortality. GLS demonstrates allograft LV systolic dysfunction in donors and recipients not detected by LVEF. The clinical implications of subclinical allograft dysfunction detected by LV GLS require further study.

Estimating the influence of aortic-stent grafts after endovascular aneurysm repair: Are we missing something?

The implantation of a stiff aortic endograft for endovascular abdominal aneurysm repair (EVAR) has been reported to increase aortic stiffness and pulse wave velocity (PWV), raising potential concern over deterioration of myocardial performance. Yet, additional stiffness indices such as the augmentation index (AIx), reflection magnitude (RM) and changes in augmentation pressure (AP) have not been studied adequately to facilitate and improve our knowledge regarding the ways that EVAR affects central hemodynamics. In this article it is suggested that the implantation of an aortic stent-graft exerts its immediate effects not only by interposing extra stiffness on the infrarenal segment but by also modifying the pulse wave reflection site and changing the aortic flow field without necessarily causing significant alterations in PWV. Hence, further studies on myocardial performance in large patient populations are expected to delineate the precise influence of different designs of EVAR endografts on the cardiovascular hemodynamic which, in turn, can affect the morbidity and survival of these patients.

Abstract P232: Dipeptidyl Peptidase-4 (DPP-4) Inhibitor, Linagliptin, Prevents Aortic Stiffening and Vascular and Cardiac Diastolic Dysfunction Caused by Western Diet Feeding in Female Mice

Aortic stiffness, endothelial dysfunction and diastolic dysfunction (DD) are cardiovascular (CV) abnormalities seen in obesity associated with consumption of high fat/fructose western diet (WD). Moreover, CV dysfunction is increasingly prevalent in obese women. Herein, we examined whether the DPP-4 inhibitor, linagliptin (LINA), improves these outcomes in WD fed female C57BL/6 mice. Four week old mice were fed control diet (CD) or WD with or without LINA for 16 weeks, after which pulse wave velocity (aortic stiffness) (PWV), echocardiography (diastolic function), atomic force microscopy (endothelial stiffness) and wire myography (aortic vascular reactivity) were performed. Compared to CD mice, WD mice exhibited 21% and 353% higher PWV and endothelial stiffness, respectively. WD induced DD, indicated by impaired septal wall motion (&lt;E’/A’ ratio), left atrial filling pressure (&gt;E/Vp ratio), prolonged isovolumic relaxation time (IVRT) and impaired myocardial performance index (&gt;MPI). These vascular and cardiac abnormalities were prevented by LINA. LINA also prevented WD-induced impairments in acetylcholine-, sodium nitroprusside-, and insulin-mediated aortic vascular relaxation. These results show that LINA exerts CV protection in a translational model of obesity.

Anoxia and Acidosis Tolerance of the Heart in an Air-Breathing Fish (Pangasianodon hypophthalmus)

Air breathing has evolved repeatedly in fishes and may protect the heart during stress. We investigated myocardial performance in the air-breathing catfish Pangasianodon hypophthalmus, a species that can withstand prolonged exposure to severe hypoxia and acidosis. Isometric ventricular preparations were exposed to anoxia, lactic acidosis, hypercapnic acidosis, and combinations of these treatments. Ventricular preparations were remarkably tolerant to anoxia, exhibiting an inotropic reduction of only 40%, which fully recovered during reoxygenation. Myocardial anoxia tolerance was unaffected by physiologically relevant elevations of bicarbonate concentration, in contrast to previous results in other fishes. Both lactic acidosis (5 mM; pH 7.10) and hypercapnic acidosis (10% CO2; pH 6.70) elicited a biphasic response, with an initial and transient decrease in force followed by overcompensation above control values. Spongy myocardial preparations were significantly more tolerant to hypercapnic acidosis than compact myocardial preparations. While ventricular preparations were tolerant to the isolated effects of anoxia and acidosis, their combination severely impaired myocardial performance and contraction kinetics. This suggests that air breathing may be a particularly important myocardial oxygen source during combined anoxia and acidosis, which may occur during exercise or environmental stress.

Emerging Concepts in the Molecular Basis of Pulmonary Arterial Hypertension: Part II: Neurohormonal Signaling Contributes to the Pulmonary Vascular and Right Ventricular Pathophenotype of Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH) is defined foremost by a distinct pulmonary vascular pathophenotype that occurs as a result of dysregulated vascular cell proliferation, intimal and medial hypertrophy, inflammation, and fibrosis. This plexogenic arteriopathy with subtotal luminal obliteration increases pulmonary vascular resistance and imposes a hemodynamic stress on the right ventricle (RV). The chronically increased afterload leads to RV hypertrophy and failure that contributes to premature death. Owing to the functional interrelatedness of the pulmonary vasculature and the RV, these 2 compartments are increasingly considered as a collective unit and assessed by examining RV-pulmonary arterial coupling in studies that focus on the pathophysiology of PAH.1 Ideal RV-pulmonary arterial coupling is present when contractility of the RV is sufficient to match the afterload imposed by the pulmonary artery, which is determined by its distensibility or compliance, and is recognized by minimal pressure fluctuation during systole.2 Optimal RV-pulmonary arterial coupling may be defined further based on the ratio of ventricular to arterial elastance, which typically achieves a ratio of 1.5:2.0 and reflects a balance between RV work and oxygen consumption.3 RV-pulmonary arterial uncoupling, therefore, occurs when there is a mismatch between RV contractility and pulmonary arterial compliance. Based on this premise, it is now acknowledged that factors that decrease normal pulmonary vascular compliance to increase resistance adversely affect RV-pulmonary arterial coupling kinetics. This results in a decline in ventricular efficiency and an increased probability of developing right-sided heart failure.4 Similarly, a decrease in RV contractility owing to RV cardiomyocyte dysfunction or impaired RV myocardial performance decreases RV tolerance to increased afterload and lowers the threshold at which pulmonary vascular disease may become clinically evident.5 Although PAH is a disease of pulmonary vascular origin with subsequent effects on the RV, the pathobiology and PAH disease severity may be subject …

Lower serum 25-hydroxyvitamin D level is associated with impaired myocardial performance and left ventricle hypertrophy in newly diagnosed hypertensive patients.

Objective:Vitamin D deficiency is an independent risk factor for cardiovascular mortality. The relationship between vitamin D level and left ventricle (LV) myocardial performance index (MPI=Tei index), which incorporates both LV systolic function and diastolic function, was not investigated in previous studies. We hypothesized that vitamin D level may be associated with LV function and geometry. We aimed to investigate the association between serum 25-hydroxyvitamin D (25 [OH] D) levels and MPI and LV hypertrophy in hypertensive patients with newly diagnosed and preserved ejection fraction.Methods:We studied 151 sequential newly diagnosed hypertensive subjects who lived in the Çukurova region without known cardiovascular risk factors or overt heart disease (mean age: 62.8±10.4 years). Serum 25 (OH) D was measured using a direct competitive chemiluminescent immunoassay. The patients were divided into two groups according to serum 25 (OH) D level: vitamin D-non-deficient group (vitamin D> 20.00 ng/mL, n=53) and vitamin D-deficient group (vitamin D< 20.00 ng/mL, n=98). MPI was defined as the sum of isovolumic contraction and relaxation times divided by the ejection time. LV mass index (LVMI) was calculated by using the Devereux formula and body surface area.Results:MPI and LVMI values were lower and low-density lipoprotein (LDL) levels were higher in patients who were vitamin D-non-deficient than patients who were vitamin D-deficient (p<0.05 for all). Multivariate linear regression analysis showed that serum 25 (OH) D was indepen-dently associated with MPI (β=-0.426, p<0.001), LVMI (β=-0.345, p=<0.001), and LDL (β=0.140, p<0.026).Conclusion:Lower serum 25 (OH) D levels are significantly associated with impaired myocardial performance and LVMI.

Impaired myocardial performance in a normotensive rat model of intrauterine growth restriction

Intrauterine growth restriction (IUGR) is an important risk factor for cardiovascular disease. Previous studies revealed altered myocardial matrix composition after IUGR. We hypothesized that IUGR is accompanied by compromised myocardial performance independently from arterial hypertension. IUGR was induced in Wistar rats by maternal protein restriction, and hearts of male offspring were studied using echocardiography, immunohistochemistry, real-time PCR, and western blot analysis. At day 70 of life, in the absence of arterial hypertension (mean arterial blood pressure: 101.3 ± 7.1 mmHg in IUGR vs. 105.3 ± 4.6 mmHg in controls, not significant (NS)), echocardiography showed a reduced contractility (ejection fraction: 65.4 ± 1.8% in IUGR vs. 82.2 ± 1.5% in controls, P < 0.001) of a more distensible myocardium in IUGR rats. Altered expression patterns of myosin chains and titin isoforms and increased expression levels of atrial natriuretic peptide, Na/K-ATPase, and β-adrenergic receptor 1 were detected. A higher number of cardiac fibroblasts and vascular cross-sections were observed in IUGR rats, accompanied by elevated expression of hypoxia inducible factor 1 target genes, such as vascular endothelial growth factor and its receptors. We observed a blood pressure-independent impairment of myocardial function after IUGR, which possibly favors cardiovascular disease later in life. Some IUGR-induced myocardial changes (e.g., sarcomeric components) may partly explain the compromised cardiac performance, whereas others (e.g., elevated vascular supply) reflect compensatory mechanisms.

NT-proBNP predicts impaired myocardial function in newly diagnosed hypertensive patients with preserved ejection fraction

N-terminal pro-brain natriuretic peptide (NT-proBNP) is an excellent biomarker to diagnose left ventricular (LV) dysfunction. LV myocardial performance index (MPI-Tei index) is commonly used as a measure of combined systolic and diastolic function. We aimed to investigate the relationship between NT-proBNP and tissue Doppler derived MPI in newly diagnosed hypertensive patients with preserved LV ejection fraction (LVEF). We studied 236 patients with newly diagnosed HT (mean age; 52.9 ± 5.2 years). Echocardiographic examination was performed in all patients. LV mass index (LVMI) was calculated. Conventional Doppler indices (E and A waves) were recorded. The MPI value was obtained from the tissue Doppler derived ejection time, isovolumic contraction and relaxation times. The patients were divided into two groups according to the median NT-proBNP value (NT-proBNPlow group <114 pg/ml and NT-proBNPhigh group ≥114 pg/ml). Patients with NT-proBNPhigh were older and had higher levels of glucose and creatinine, lower E/A ratio and higher LVMI and MPI values than patients with NT-proBNPlow. However, LVEF were similar among the groups. Multiple linear regression analysis showed that NT-proBNP was independently associated with age, LVMI, MPI and E/A ratio. Increased NT-proBNP level was independently associated with impaired myocardial performance index in newly diagnosed hypertensive patients with preserved LVEF.

The Relationship between Coronary Sinus and Impaired Right Ventricular Myocardial Performance Index in Mitral Stenosis

We aimed to investigate whether coronary sinus (CS) dilatation develops in patients with mitral stenosis (MS) and to demonstrate its relationship with the global myocardial performance of the right ventricle (RV). We enrolled 34 patients with MS who underwent echocardiography after exhibiting typical symptoms (31 female; mean age 41±12years) and 20 age- and sex-matched controls without MS who underwent echocardiography (16 female; mean age 38±13years). The RV myocardial performance index (MPI) was detected using tissue Doppler echocardiography (TDE), and maximum CS diameter was measured from the posterior atrioventricular groove in the apical four-chamber view during the ventricular systole. The RV MPI was significantly higher in the MS group compared to the control group (0.60±0.11 vs. 0.41±0.08, P<0.001). Moreover, the maximum CS dimension was higher in the MS group compared to the control group (8.5±1.1mm vs. 6.5±1.4mm, P<0.001). The maximum CS dilatation was positively correlated with the RV MPI (r=0.691; P<0.001). The RV MPI, which represents both systolic and diastolic functions, is increased in patients with MS and correlates with CS dilatation.