Dániel Czuriga

Beneficial effects of SR33805 in failing myocardium

AIMS SR33805, a potent Ca(2+) channel blocker, increases cardiac myofilament Ca(2+) sensitivity in healthy rat cardiomyocytes. Therefore, the aim of the present study was to evaluate the effects of SR33805 on contractile properties in ischaemic failing hearts after myocardial infarction (MI) in vivo and in vitro at the cellular level. METHODS AND RESULTS The effect of SR33805 (10 µM) was tested on the excitation-contraction coupling of cardiomyocytes isolated from rat with end-stage heart failure. Cell shortening and Ca(2+) transients were measured in intact cardiomyocytes, while contractile properties were determined in Triton X-100 permeabilized myocytes. Acute treatment with SR33805 restored the MI-altered cell shortening without affecting the Ca(2+) transient amplitude, suggesting an increase of myofilament Ca(2+) sensitivity in MI myocytes. Indeed, a SR33805-induced sensitization of myofilament activation was found to be associated with a slight increase in myosin light chain-2 phosphorylation and a more significant decrease on troponin I (TnI) phosphorylation. Decreased TnI phosphorylation was related to inhibition of protein kinase A activity by SR33805. Finally, administration of a single intra-peritoneal bolus of SR33805 (20 mg/kg) improved end-systolic strain and fractional shortening of MI hearts. CONCLUSION The present study indicates that treatment with SR33805 improved contractility of ischaemic failing hearts after MI in the rat by selectively modulating the phosphorylation status of sarcomeric regulatory proteins, which then sensitized the myofilaments to Ca(2+). Our results gave a proof of concept that manipulation of the Ca(2+) sensitivity of sarcomeric regulatory proteins can be used to improve contractility of a failing heart.

Protein kinase C contributes to the maintenance of contractile force in human ventricular cardiomyocytes

Prolonged Ca2+ stimulations often result in a decrease in contractile force of isolated, demembranated human ventricular cardiomyocytes, whereas intact cells are likely to be protected from this deterioration. We hypothesized that cytosolic protein kinase C (PKC) contributes to this protection. Prolonged contracture (10 min) of demembranated human cardiomyocytes at half-maximal Ca2+ resulted in a 37 ± 5% reduction of active force (p < 0.01), whereas no decrease (2 ± 3% increase) was observed in the presence of the cytosol (reconstituted myocytes). The PKC inhibitors GF 109203X and Gö 6976 (10μmol/liter) partially antagonized the cytosol-mediated protection (15 ± 5 and 9 ± 2% decrease in active force, p < 0.05). Quantitation of PKC isoform expression revealed the dominance of the Ca2+-dependent PKCα over PKCδ and PKCϵ (189 ± 31, 7 ± 3, and 7 ± 2 ng/mg protein, respectively). Ca2+ stimulations of reconstituted human cardiomyocytes resulted in the translocation of endogenous PKCα, but not PKCβ1, δ, and ϵ from the cytosol to the contractile system (PKCα association: control, 5 ± 3 arbitrary units; +Ca2+, 39 ± 8 arbitrary units; p < 0.01, EC50,Ca = 645 nmol/liter). One of the PKCα-binding proteins were identified as the thin filament regulatory protein cardiac troponin I (TnI). Finally, the Ca2+-dependent interaction between PKCα and TnI was confirmed using purified recombinant proteins (binding without Ca2+ was only 28 ± 18% of that with Ca2+). Our data suggest that PKCα translocates to the contractile system and anchors to TnI in a Ca2+-dependent manner in the human heart, contributing to the maintenance of contractile force.

Myofilament protein carbonylation contributes to the contractile dysfunction in the infarcted LV region of mouse hearts

AIMS The region-specific mechanical function of left ventricular (LV) murine cardiomyocytes and the role of phosphorylation and oxidative modifications of myofilament proteins were investigated in the process of post-myocardial infarction (MI) remodelling 10 weeks after ligation of the left anterior descending (LAD) coronary artery. METHODS AND RESULTS Permeabilized murine cardiomyocytes from the remaining anterior and a remote non-infarcted inferior LV area were compared with those of non-infarcted age-matched controls. Myofilament phosphorylation, sulfhydryl (SH) oxidation, and carbonylation were also assayed. Ca(2+) sensitivity of force production was significantly lower in the anterior wall (pCa50: 5.81 ± 0.03, means ± SEM, at 2.3 µm sarcomere length) than that in the controls (pCa50: 5.91 ± 0.02) or in the MI inferior area (pCa50: 5.88 ± 0.02). The level of troponin I phosphorylation was lower and that of myofilament protein SH oxidation was higher in the anterior location relative to controls, but these changes did not explain the differences in Ca(2+) sensitivities. On the other hand, significantly higher carbonylation levels, [e.g. in myosin heavy chain (MHC) and actin] were observed in the MI anterior wall [carbonylation index (CI), CIMHC: 2.06 ± 0.46, CIactin: 1.46 ± 0.18] than in the controls (CI: 1). In vitro Fenton-based myofilament carbonylation in the control cardiomyocytes also decreased the Ca(2+) sensitivity of force production irrespective of the phosphorylation status of the myofilaments. Furthermore, the Ca(2+) sensitivity correlated strongly with myofilament carbonylation levels in all investigated samples. CONCLUSION Post-MI myocardial remodelling involves increased myofibrillar protein carbonylation and decreased Ca(2+) sensitivity of force production, leading potentially to contractile dysfunction in the remaining cardiomyocytes of the infarcted area.

Cellular mechanisms for diastolic dysfunction in the human heart.

Left ventricular (LV) diastolic dysfunction is an important contributor to many different cardiovascular diseases. LV diastolic dysfunction can manifest itself as slow LV relaxation, slow LV filling or high diastolic LV stiffness. Diastolic abnormalities have been described in the senescent heart, in heart failure with preserved ejection fraction (HFPEF), in diabetic cardiomyopathy, in aortic valve stenosis (AVS), in hypertrophic cardiomyopathy (HCM), as well as in Fabry disease (FD), however, exact cellular and molecular alterations behind the diastolic deterioration in these diseases are not yet completely characterized. Several studies thoroughly investigated altered cardiomyocyte function, changes of contractile myofilaments, extracellular collagen deposition and advanced glycation end products (AGEs) cross-linking in the background of diastolic dysfunction. These clinical and experimental data suggest that underlying mechanisms of LV diastolic dysfunction are divergent in different cardiac pathologies, therefore the present review aims to summarize mechanisms at the cellular level of diastolic abnormalities in various cardiovascular diseases.

Silent brain infarction – a review of recent observations

Silent brain infarction is a cerebral ischaemic event evident on brain imaging without any clinical symptom. Silent brain infarction is often detected in apparently healthy, elderly people and in different selected patient groups as well. Lately, several studies were carried out in order to identify the clinical conditions leading to silent brain infarction. A large number of clinical and paraclinical parameters were found to increase silent brain infarction prevalence, and the continuously growing list of risk factors revealed that the majority of them are similar to those related to stroke. Accordingly, some consider silent brain infarction the preclinical stage of clinically overt stroke. This point of view emphasizes the early recognition and management of silent brain infarction-related risk factors, and a great need for comparative studies, which could elicit the most sensitive indicators of the increased silent brain infarction risk, especially the ones that could be cost-effectively screened in the large populations as well.

Elevated LDL-C combined with hypertension worsens subclinical vascular impairment and cognitive function

Hypertension and dyslipidemia belong to the most prevalent modifiable risk factors for cerebrovascular and cardiovascular diseases. Hereby, we aimed to examine the combined effects of newly diagnosed hypertension and hyperlipidemia on the characteristics of the arterial wall and on cognitive function. We examined 72 hypertensive and 85 apparently healthy individuals. Based on serum lipid levels, four subgroups were created ranging from normotensive-normolipidemic to hypertensive-hyperlipidemic subjects. Carotid intima-media thickness (IMT), arterial stiffness, and cognitive function were assessed. IMT of controls was the lowest, whereas that of patients with both risk factors the highest. Stiffness parameters increased when both risk factors were present, whereas subjects with only one risk factor exhibited intermediate values. Hypertensive patients performed worse when memory, attention, reaction time, and trait anxiety were assessed. Significant worsening of IMT, arterial stiffness, and sum of neuropsychological scores was observed along with increasing mean arterial pressure. Generally, hyperlipidemia combining with hypertension resulted in further worsening of all examined parameters. Subclinical changes of the vascular wall and cognitive performance are already present in recently diagnosed hypertensive patients. Combination of hyperlipidemia and hypertension results in more severe impairments, therefore, early and intensive treatment may be crucial to prevent further deterioration.

Influence of Hypertension, Alone and in Combination with Other Vascular Risk Factors on Cognition

Hypertension is one of the most important modifiable risk factors of cardioand cerebrovascular diseases, responsible for the development of severe target organ damages. It has been shown that hypertension is associated with an increased prevalence of cognitive decline. It negatively affects the cognitive battery and accelerates dementia. Beside the known detrimental effects of senile hypertension on cognitive performance in the elderly population, previous studies pointed out that young, hypertensive individuals may also suffer from hypertension related changes in their cognitive capacity. Given the high prevalence of hypertension in a wide range of the age pyramid (young individuals, middle aged adults, elderly people), specific cognitive deficits may be present in a large portion of the population putting a heavy burden on society. Better understanding of the underlying mechanisms of hypertension induced cognitive impairment may contribute to the identification of its initiating pathophysiological factors, and serve an earlier diagnosis, intervention at an early stage and prevention of further deficits. Our aim with the current review was to summarize some of the previous findings regarding altered cognitive performance of individuals with hypertension and of those with the most common co-existing risk factors. Furthermore, efforts to explore effects of various antihypertensive medications on cognition and to survey proposed pathophysiological mechanisms of hypertension induced cognitive changes have been made.

Heart failure with preserved ejection fraction (diastolic heart failure)

Diastolic heart failure, which is also called as heart failure with preserved ejection fraction, is a clinical syndrome in which patients have signs and symptoms of heart failure, normal or near normal left ventricular ejection fraction (≥ 50%) and evidence of diastolic dysfunction. Recent epidemiological studies have demonstrated that more than half of all heart failure patients have diastolic heart failure. The syndrome is more common in women than in men and the prevalence increases with age. Patients with diastolic heart failure form a fairly heterogeneous group with complex pathophysiologic mechanisms. The disease is often in association with other comorbidities, such as hypertension, diabetes mellitus or obesity. The diagnosis of diastolic heart failure is best achieved by two-dimensional and Doppler echocardiography, which can detect abnormal myocardial relaxation, decreased compliance and increased filling pressure in the setting of normal left ventricular dimensions and preserved ejection fraction. Unlike heart failure with reduced ejection fraction, there is no such an evidence-based treatment for heart failure with preserved ejection fraction, which would improve clinical outcomes. Thus, pharmacological therapy of diastolic heart failure is based mainly on empiric data, and aims to the normalization of blood pressure, reduction of left ventricular dimensions and increased heart rate, maintenance of normal atrial contraction and treatment of symptoms caused by congestion. Beneficial effects of angiotensin-converting enzyme inhibitors and angiotensin-receptor blockers may be utilized in patients with diastolic dysfunction, especially in those with hypertension. Beta-blockers appear to be useful in lowering heart rate and thereby prolonging left ventricular diastolic filling time, while diuretic therapy is the mainstay of treatment for preventing pulmonary congestion. Nonetheless, treatment of the underlying disease is also an important therapeutic approach. This review summarizes the state of current knowledge with regard to diastolic heart failure.

How Cardiomyocytes Make the Heart Old

Naturally occurring decline in cardiovascular reserve with age associates with a combination of the reduction in cardiomyocyte number and altered cardiomyocyte function. Recent investigations suggested that about half of the cardiomyocytes is the same as at birth, while the other half of the cardiomyocytes is the result of cardiomyocyte renewal in the senescent heart. In addition, the total number of cardiomyocytes is estimated to be less by one third in the old heart than the number of cardiomyocytes at birth. Thus, the reduction in cardiomyocyte number of the aging heart cannot be fully compensated by cardiomyocyte renewal. Aging of long-lived differentiated myocardial cells, as well as of cardiac progenitor stem cells may contribute to an increased rate of apoptosis, and decreased capacity of cell duplication and/or differentiation. In addition, differentiated cardiomyocytes are prone for accumulating biological by-products of cellular metabolism and of incompletely processed oxidative insults. In this context, interactions between lysosomes and mitochondria may provide a mechanistic background for the age-dependent alterations in cardiac macromolecules. This reasoning postulates a direct relationship between the number of pro-oxidative, ill-functioning mitochondria and the amount of ballast- overloaded lysosomes in long-lived cardiomyocytes. Accumulation of biological garbage and telomere shortening might be considered as hallmarks of cardiomyocyte aging with implications for depressed cardiac function and cardiomyocyte renewal. Changes in protein expression together with posttranslational modifications of myocardial proteins affect excitation-contraction coupling and explain the declining mechanical function of the cardiomyocytes. Altogether, these changes represent a significant part of the reduced cardiovascular reserve in aged individuals.

Transtelephonic electrocardiography in the management of patients with acute coronary syndrome

BACKGROUND The efficacy of the transtelephonic ECG system (TTECG) in the management of ST segment elevation myocardial infarction (STEMI) was examined with regard to the ambulance service- and percutaneous coronary intervention (PCI)-related delay times, the prehospital medical therapy and the in-hospital mortality rate. METHODS The study was conducted as a collaborative effort between the University of Debrecen and the Hungarian National Ambulance Service. Altogether 397 patients were recruited in the TTECG group, while 378 patients transported to the PCI centre without TTECG served as controls. RESULTS More accurate prehospital medical therapy was achieved in the TTECG group. The PCI-related delay times were significantly shorter, while the in-hospital mortality rate was significantly lower in the TTECG group than among the controls. CONCLUSIONS The findings illustrate that TTECG is a valuable tool which may potentially improve the regional management of STEMI patients.