Accelerated Growth, Differentiation, and Ploidy with Reduced Proliferation of Right Ventricular Cardiomyocytes in Children with Congenital Heart Defect Tetralogy of Fallot

The myocardium of children with tetralogy of Fallot (TF) undergoes hemodynamic overload and hypoxemia immediately after birth. Comparative analysis of changes in the ploidy and morphology of the right ventricular cardiomyocytes in children with TF in the first years of life demonstrated their significant increase compared with the control group. In children with TF, there was a predominantly diffuse distribution of Connexin43-containing gap junctions over the cardiomyocytes sarcolemma, which redistributed into the intercalated discs as cardiomyocytes differentiation increased. The number of Ki67-positive cardiomyocytes varied greatly and amounted to 7.0–1025.5/106 cardiomyocytes and also were decreased with increased myocytes differentiation. Ultrastructural signs of immaturity and proliferative activity of cardiomyocytes in children with TF were demonstrated. The proportion of interstitial tissue did not differ significantly from the control group. The myocardium of children with TF under six months of age was most sensitive to hypoxemia, it was manifested by a delay in the intercalated discs and myofibril assembly and the appearance of ultrastructural signs of dystrophic changes in the cardiomyocytes. Thus, the acceleration of ontogenetic growth and differentiation of the cardiomyocytes, but not the reactivation of their proliferation, was an adaptation of the immature myocardium of children with TF to hemodynamic overload and hypoxemia.

Left Ventricular SGLT1 Protein Expression Correlates with the Extent of Myocardial Nitro-Oxidative Stress in Rats with Pressure and Volume Overload-Induced Heart Failure

Myocardial sodium-glucose cotransporter 1 (SGLT1) has been shown to be upregulated in humans with heart failure (HF) with or without diabetes. In vitro studies have linked SGLT1 to increased nitro-oxidative stress in cardiomyocytes. We aimed to assess the relation between left ventricular (LV) SGLT1 expression and the extent of nitro-oxidative stress in two non-diabetic rat models of chronic heart failure (HF) evoked by either pressure (TAC, n = 12) or volume overload (ACF, n = 12). Sham-operated animals (Sham-T and Sham-A, both n = 12) served as controls. Both TAC and ACF induced characteristic LV structural and functional remodeling. Western blotting revealed that LV SGLT1 protein expression was significantly upregulated in both HF models (both p < 0.01), whereas the phosphorylation of ERK1/2 was decreased only in ACF; AMPKα activity was significantly reduced in both models. The protein expression of the Nox4 NADPH oxidase isoform was increased in both TAC and ACF compared with respective controls (both p < 0.01), showing a strong positive correlation with SGLT1 expression (r = 0.855, p < 0.001; and r = 0.798, p = 0.001, respectively). Furthermore, SGLT1 protein expression positively correlated with the extent of myocardial nitro-oxidative stress in failing hearts assessed by 3-nitrotyrosin (r = 0.818, p = 0.006) and 4-hydroxy-2-nonenal (r = 0.733, p = 0.020) immunostaining. Therefore, LV SGLT1 protein expression was upregulated irrespective of the nature of chronic hemodynamic overload, and correlated significantly with the expression of Nox4 and with the level of myocardial nitro-oxidative stress, suggesting a pathophysiological role of SGLT1 in HF.

DIAGNOSIS OF EISENMENGER SYNDROME IN PREGNANCY: THERAPEUTIC CHALLENGES FACED DURING MANAGEMENT OF A COUPLE WITH PRECIOUS CONCEPTION

Eisenmenger Syndrome poses a hemodynamic overload and additional burden for the already compromised right ventricle. It causes right to left shunt thereby exaggerating central cyanosis, leading to various sequelae in the form of abortion, preterm labor and intrauterine fetal growth restriction. Vasodilators in the form of intravenous prostacyclin, phosphodiesterase inhibitors like sildenal and tadalal and inhaled nitric oxide during second stage of labor have been successfully used. Pregnancy is ideally contraindicated. Those continuing pregnancy must be adequately supervised by an experienced multidisciplinary team. Termination of pregnancy is done by Caesarean. Epidural analgesia is preferred.

Myocardial work index better reflects contractility than longitudinal strain in rat models of pressure- and volume overload-induced heart failure

Funding Acknowledgements Type of funding sources: None. Speckle-tracking echocardiography (STE)-derived global longitudinal strain (GLS) is considered to be a sensitive marker of left ventricular (LV) function in a wide variety of cardiovascular diseases. Still, evidence suggests that GLS is significantly influenced by loading conditions. Myocardial work index (MWI) evaluates myocardial deformation in the context of afterload through the interpretation of strain in relation to instantaneous LV pressure. MWI may potentially overcome the limitations of mere strain calculation, and may better reflect cardiac contractility in hemodynamic overload states. Accordingly, our aim was to examine the relationship of GLS and MWI with load-independent markers of LV contractility in rat models of pressure- and volume overload-induced heart failure. Male Wistar rats underwent transverse aortic constriction (TAC; n = 12) to generate LV pressure overload, or aortocaval fistula (ACF; n = 12) was established to induce severe LV volume overload. In case of the control groups, sham procedures were performed (n = 12/12). Echocardiography loops were obtained to determine STE-derived GLS and global MWI. Pressure-volume analysis with transient occlusion of the inferior vena cava was carried out to calculate preload recruitable stroke work (PRSW), as a load-independent „gold-standard" parameter of LV contractility. GLS was mildly reduced in the ACF group (-13.2 ± 2.4 vs. -15.4 ± 2.0%, p &lt; 0.05), while it was significantly lower in TAC group compared to controls (-7.0 ± 2.8 vs. -14.5 ± 2.5%; p &lt; 0.001). In contrast with these findings, PRSW and also MWI were significantly reduced in ACF (58 ± 14 vs. 111 ± 40 mmHg; 1328 ± 411 vs. 1934 ± 308 mmHg%, both p &lt; 0.01), however, they were comparable between TAC and the corresponding sham group (110 ± 26 vs. 116 ± 68 mmHg; 1687 ± 275 Hgmm% vs. 1537 ± 662 Hgmm%; both p = NS). In the pooled population, GLS did not show relationship with PRSW (r=-0.23; p = 0.12), while MWI showed significant correlation with it (r = 0.70; p &lt; 0.001). GLS is significantly influenced by loading conditions, therefore, in case of severe pressure- or volume overload it may not be a reliable marker of LV contractility. In our rat model of pressure overload induced heart failure, contractility was maintained despite decreased GLS, while in the model of volume overload induced heart failure, GLS was maintained despite decreased contractility. MWI reflects contractility in hemodynamic overload states, therefore, it may be a more suitable marker of systolic function. Abstract Figure. Pressure-strain loops of the groups

Longitudinal strain reflects the interaction of myocardial contractility to afterload in rat models of hemodynamic overload-induced heart failure

Background Two-dimensional (2D) speckle tracking echocardiography (STE)-derived myocardial strain parameters are sensitive markers of left ventricular (LV) systolic function. Novel findings suggest that the contractile state of the myocardium, afterload and preload are major determinants of STE measurements. However, the hypothesis that longitudinal strain expresses the interaction between contractility and loading conditions rather than contractility alone in hemodynamic overload-induced heart failure (HF) has not been tested. Purpose This study aimed to explore the connection between longitudinal strain and contractility, afterload and preload in rat models of pressure overload (PO)- and volume overload (VO)-induced heart failure (HF). Methods Pressure overload (PO)-induced HF was evoked by transverse aortic constriction ([TAC], n=14). Volume overload (VO)-induced HF was established by an aortocaval fistula ([ACF], n=12). Age-matched sham operated animals served as controls. Pressure-volume analysis was carried out to compute cardiac contractility (slope of end-systolic pressure-volume relationship [ESPVR]), afterload (arterial elastance [Ea]) and ventriculo-arterial coupling ([VAC] = Ea/ESPVR). Preload was evaluated by meridional end-diastolic wall stress (σend-diastolic). STE was performed to assess global longitudinal strain (GLS). Results GLS was impaired in both PO-induced HF (−5.9±0.6 vs. −12.9±0.5%, TAC vs Sham, P&lt;0.001) and VO-evoked HF (−11.7±0.7 vs. −13.5±0.4%, ACF vs Sham, P=0.048). Hemodynamic measurements indicated that the TAC group presented with maintained ESPVR, increased Ea and enhanced σend-diastolic. In contrast, the ACF group was characterized by reduced ESPVR, decreased Ea and enhanced σend-diastolic. Ordinary least squares non-linear regression revealed that GLS was predominantly determined by afterload (Ea) in the TAC model and by contractility (ESPVR) in the ACF model. In accordance, GLS showed a strong correlation with Ea in case of PO-induced HF (R= 0.848, P&lt;0.001) and with ESPVR in case of VO-evoked HF (R=−0.526; P=0.008), respectively. Furthermore, GLS also demonstrated strong correlation with VAC in both the TAC and the ACF models. Of particular interest, a robust correlation between VAC and GLS could also be detected in the entire study population (R= 0.654, P&lt;0.001). Conclusion Both afterload and contractility define GLS. Hence, under conditions when both factors become altered, GLS reflects VAC. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): NVKP_16-1-2016-0017

In vivo [U-13C]glucose labeling to assess heart metabolism in murine models of pressure and volume overload

This study implemented a method for assessing the fate of glucose carbons in the heart in vivo and used this to demonstrate that pressure and volume overload are associated with distinct changes. In contrast to volume overload, pressure overload-induced changes affect the tricarboxylic acid cycle, glycolytic pathways, and glutamine synthesis. A better understanding of cardiac glucose metabolism under pathological conditions in vivo may provide new therapeutic strategies specific for different types of hemodynamic overload.

Fusiform aneurysm of the basilar artery associated with internal carotid artery agenesis

Internal carotid artery (ICA) agenesis is rare and corresponds to the concomitant absence of ICA and the carotid canal. Two possible mechanisms involve the association between ICA agenesis and intracranial aneurysms: hemodynamic overload and hyperflow by demand of a given territory. We describe a case of Type I agenesis of the left ICA associated with fusiform aneurysm and fenestration of the basilar artery (BA).

Arterial Hypertension and Heart Failure in General Practice

The Framingham study demonstrated that myocardial infarction (25% of cases) and arterial hypertension (AH) (75% of cases) caused the development of chronic heart failure (CHF). The most significant predictor of CHF development was an increase in systolic blood pressure (SBP) and pulse pressure and each increase in SBP by 20 mm Hg and pulse blood pressure by 16 mm Hg led to an increase in the incidence of CHF by 52% and 55%, respectively. The presented clinical case of a patient with CHF, developed due to long-term hypertension, considered the mechanisms of CHF development, as well as the issue of pharmacotherapy of AH in combination with chronic heart failure with systolic dysfunction. The key mechanisms that directly lead to the development of CHF in AH are hemodynamic overload, reduction of myocardial contractility, left ventricular hypertrophy (LVH). The likelihood of CHF development in patients with AH is by 4 times higher, whilst in patients with LVH it is by 15 times higher. Along with LVH, one of the early manifestations of LV remodeling in AH is the development of diastolic dysfunction, which precedes the development of systolic abnormalities in AH and LVH. Antihypertensive therapy resulted in reduction of the incidence of CHF by approximately 52% compared to patients who did not receive adequate therapy. The decrease in the incidence of CHF was linearly dependent on the decrease in SBP: each decrease of SBP by 10 mm Hg led to a 26% reduction in the relative risk in CHF development. It has been established that AH is not only one of the leading etiological factors in CHF development, but also have similar key links in pathogenesis. The strategy for the selection of pathogenetic pharmacotherapy should be determined taking into account the above circumstance. Currently, the European Society of Cardiology recommends prescribing beta-blockers to all patients with stable CHF Class II–IV as a standard treatment in combination with ACE inhibitors and diuretics in the absence of contraindications. In addition to RAAS blockers, medications for patients with AH in combination with systolic CHF can be supplemented with thiazide or loop diuretics, as well as mineralocorticoid receptor ant agonists (MRA).

Troponin elevation: is it ischemia?

Cardiac troponin is the preferred biomarker for myocardial infarction, thanks to its sensitivity and absolute specificity for the heart. The availability of high-sensitivity assays (hs-cTnT and hs-cTnI), capable of measuring with excellent analytical precision very low levels of circulating troponin, raised the issue of whether transient ischemia is a sufficient stimulus for troponin release. For this purpose, in a series of patients submitted to a stress test (exercise ECG/echo test; dipyridamole echo test; dobutamine echo test), we measured plasma levels of hs-cTnT at baseline and 6 hours after the end of the test. Plasma concentrations of hs-cTnT significantly increased in the vast majority of patients after the test. Significant elevations were documented in response to each stressor, regardless of the test result, after both positive and negative tests. Moreover, troponin significantly increased in response to the stress, both in patients with and in patients without obstructive coronary artery disease. Despite a good sensitivity (80% and 89%), troponin showed a very low specificity (32% and 47%) for stress-induced ischemia and coronary artery disease, respectively. Myocardial release of troponin is a multifactorial process, mediated not only by cardiomyocyte necrosis, but also through several different mechanisms such as myocardial ischemia, increase in cardiac work, and hemodynamic overload. Transient elevation of high sensitivity cardiac troponin is not a useful tool for detecting spontaneous or stress-induced ischemia. L