Pachymic Acid Attenuated Doxorubicin-Induced Heart Failure by Suppressing miR-24 and Preserving Cardiac Junctophilin-2 in Rats.

Defects in cardiac contractility and heart failure (HF) are common following doxorubicin (DOX) administration. Different miRs play a role in HF, and their targeting was suggested as a promising therapy. We aimed to target miR-24, a suppressor upstream of junctophilin-2 (JP-2), which is required to affix the sarcoplasmic reticulum to T-tubules, and hence the release of Ca2+ in excitation-contraction coupling using pachymic acid (PA) and/or losartan (LN). HF was induced with DOX (3.5 mg/kg, i.p., six doses, twice weekly) in 24 rats. PA and LN (10 mg/kg, daily) were administered orally for four weeks starting the next day of the last DOX dose. Echocardiography, left ventricle (LV) biochemical and histological assessment and electron microscopy were conducted. DOX increased serum BNP, HW/TL, HW/BW, mitochondrial number/size and LV expression of miR-24 but decreased EF, cardiomyocyte fiber diameter, LV content of JP-2 and ryanodine receptors-2 (RyR2). Treatment with either PA or LN reversed these changes. Combined PA + LN attained better results than monotherapies. In conclusion, HF progression following DOX administration can be prevented or even delayed by targeting miR-24 and its downstream JP-2. Our results, therefore, suggest the possibility of using PA alone or as an adjuvant therapy with LN to attain better management of HF patients, especially those who developed tolerance toward LN.

HINT1 (Histidine Triad Nucleotide-Binding Protein 1) Attenuates Cardiac Hypertrophy Via Suppressing HOXA5 (Homeobox A5) Expression.

BACKGROUND: Cardiac hypertrophy is an important prepathology of, and will ultimately lead to, heart failure. However, the mechanisms underlying pathological cardiac hypertrophy remain largely unknown. This study aims to elucidate the effects and mechanisms of HINT1 (histidine triad nucleotide-binding protein 1) in cardiac hypertrophy and heart failure. METHODS: HINT1 was downregulated in human hypertrophic heart samples compared with nonhypertrophic samples by mass spectrometry analysis. Hint1 knockout mice were challenged with transverse aortic constriction surgery. Cardiac-specific overexpression of HINT1 mice by intravenous injection of adeno-associated virus 9 (AAV9)-encoding Hint1 under the cTnT (cardiac troponin T) promoter were subjected to transverse aortic construction. Unbiased transcriptional analyses were used to identify the downstream targets of HINT1. AAV9 bearing shRNA against Hoxa5 (homeobox A5) was administrated to investigate whether the effects of HINT1 on cardiac hypertrophy were HOXA5-dependent. RNA sequencing analysis was performed to recapitulate possible changes in transcriptome profile.Coimmunoprecipitation assays and cellular fractionation analyses were conducted to examine the mechanism by which HINT1 regulates the expression of HOXA5. RESULTS: The reduction of HINT1 expression was observed in the hearts of hypertrophic patients and pressure overloaded-induced hypertrophic mice, respectively. In Hint1-deficient mice, cardiac hypertrophy deteriorated after transverse aortic construction. Conversely, cardiac-specific overexpression of HINT1 alleviated cardiac hypertrophy and dysfunction. Unbiased profiler polymerase chain reaction array showed HOXA5 is 1 target for HINT1, and the cardioprotective role of HINT1 was abolished by HOXA5 knockdown in vivo. Hoxa5 was identified to affect hypertrophy through the TGF-ß (transforming growth factor ß) signal pathway. Mechanically, HINT1 inhibited PKCß1 (protein kinase C ß type 1) membrane translocation and phosphorylation via direct interaction, attenuating the MEK/ERK/YY1 (mitogen-activated protein kinase/extracellular signal-regulated kinase kinase/yin yang 1) signal pathway, downregulating HOXA5 expression, and eventually attenuating cardiac hypertrophy. CONCLUSIONS: HINT1 protects against cardiac hypertrophy through suppressing HOXA5 expression. These findings indicate that HINT1 may be a potential target for therapeutic interventions in cardiac hypertrophy and heart failure.

Treatment of the cardiac hypertrophic response and heart failure with ginseng, ginsenosides, and ginseng-related products.

Heart failure is a major medical and economic burden throughout the world. Although various treatment options are available to treat heart failure, death rates in both men and women remain high. Potential adjunctive therapies may lie with use of herbal medications, many of which possess potent pharmacological properties. Among the most widely studied is ginseng, a member of the genus Panax that is grown in many parts of the world and that has been used as a medical treatment for a variety of conditions for thousands of years, particularly in Asian societies. There are a number of ginseng species, each possessing distinct pharmacological effects due primarily to differences in their bioactive components including saponin ginsenosides and polysaccharides. While experimental evidence for salutary effects of ginseng on heart failure is robust, clinical evidence is less so, primarily due to a paucity of large-scale well-controlled clinical trials. However, there is evidence from small trials that ginseng-containing Chinese medications such as Shenmai can offer benefit when administered as adjunctive therapy to heart failure patients. Substantial additional studies are required, particularly in the clinical arena, to provide evidence for a favourable effect of ginseng in heart failure patients.

Phenylephrine-induced cardiac hypertrophy is attenuated by a histone acetylase inhibitor anacardic acid in mice.

Cardiac hypertrophy is a complex process involving highly coordinated but tight regulation of multiple elements, such as in epigenetics, which make an important contribution to myocardium remodeling and cardiac hypertrophy. Epigenetic regulations, particularly histone acetylation, have been implicated in cardiac hypertrophy, however, the exact mechanism is still largely unknown. In the present study, we explored the potential attenuating effects of Chinese herbal extract anacardic acid on phenylephrine-induced cardiac hypertrophy and the underlying mechanism. The mouse cardiac hypertrophy model was established and the hearts were collected from C57BL/6 mice for further analyses. The data showed that anacardic acid modulated the cardiac genes expression and attenuated the phenylephrine-induced cardiac hypertrophy via the suppression of histone acetylases activity and downstream cardiac genes. In addition, anacardic acid abrogated histone and MEF2A acetylation and DNA-binding activity by blocking p300-HAT and PCAF-HAT activities. In addition, anacardic acid normalized the cardiac hypertrophy-related genes expressions (ANP, BNP, cTnT, cTnI, ß-MHC, and Cx43) induced by phenylephrine at the level of transcription and translation. In addition, anacardic acid did not affect the blood routine index, hepatic function, renal function, and myocardial enzymes. Therefore, anacardic acid may prove to be a candidate drug to cure hypertrophic cardiomyopathy.

Central blockade of salusin ß attenuates hypertension and hypothalamic inflammation in spontaneously hypertensive rats.

Salusin ß is a multifunctional bioactive peptide and is considered as a promising candidate biomarker for predicting atherosclerotic cardiovascular diseases. The present study was designed to investigate the roles and mechanisms of salusin ß in the paraventricular nucleus (PVN) in attenuating hypertension and hypothalamic inflammation and whether central salusin ß blockade has protective effects in essential hypertension. Normotensive Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR) were used in this study. The rats were chronic PVN infusion either specific salusin ß blocker, antisalusin ß IgG (SIgG), or control IgG (CIgG) for 2 weeks. Hypertensive rats had significantly increased salusin ß expression compared with normotensive rats. Central blockade of salusin ß attenuated hypertension, reduced circulating norepinephrine (NE) levels, and improved cardiac hypertrophy and function in hypertensive rats. Salusin ß blockade significantly reduced proinflammatory cytokines (PICs), nuclear factor-kappa B (NF-κB) activity, reactive oxygen species (ROS) levels, and altered renin-angiotensin system (RAS) components in the PVN of hypertensive rats. These findings suggest that the beneficial effects of salusin ß blockade in essential hypertension are possibly due to down-regulate of inflammatory molecules and ROS in the PVN.

Complex fractionated atrial electrograms related to left atrial wall thickness.

INTRODUCTION: The mechanism of complex fractionated atrial electrogram (CFAE) in patients with atrial fibrillation (AF) remains controversial. This study investigated the relationship between CFAE and left atrial (LA) wall thickness. METHODS AND RESULTS: LA muscular wall thickness (excluding fat) was measured by cardiac computed tomography in 31 patients with AF (12 paroxysmal, 19 persistent) prior to catheter ablation procedures. Measurements were performed at 31 distinct LA locations: 3 at roof, 3 at floor, 9 at anterior wall, 9 at posterior wall, 3 at lateral wall, 3 at septum, and 1 at base of the anterior appendage. The range of LA wall thickness (LAWT) varied widely (average 2.4 ± 0.4 mm, range 1.5-3.1 mm) between patients. In addition, there were significant regional differences in LAWT. Each patient had an average of 7.3 ± 3.5 CFAE sites. The LA wall was thicker at CFAE sites (227 sites, 3.0 ± 1.0 mm) than at non-CFAE sites (734 sites, 2.2 ± 0.9 mm, P < 0.001). In 23 of 31 (74%) patients, the LA wall was thicker at CFAE area than at non-CFAE area. There was no difference in LAWT between sites where CFAE vanished and those where CFAE persisted after pulmonary vein isolation (PVI) among sites with CFAE before PVI. The LAWT > 2.5 mm predicted CFAE with a sensitivity of 70% and a specificity of 70%. CONCLUSION: The LAWT correlates well with CFAE areas, suggesting that one of the mechanisms of CFAE might be related to LAWT.

Diurnal physiology: core principles with application to the pathogenesis, diagnosis, prevention, and treatment of myocardial hypertrophy and failure.

The circadian system has been shown to be fundamentally important in human health and disease. Recently, there have been major advances in our understanding of daily rhythmicity, and its relevance to human physiology, and to the pathogenesis and treatment of cardiac hypertrophy and heart failure. Cardiovascular tissues, such as heart and blood vessels, show remarkable daily variation in gene expression, metabolism, growth, and remodeling. Moreover, synchrony of daily molecular and physiological rhythms is integral to healthy organ growth and renewal. Disruption of these rhythms adversely affects normal growth, also the remodeling mechanisms in disease, leading to gross abnormalities in heart and vessels. These observations provide new insights into the pathogenesis, diagnosis, treatment, and prevention of heart disease. In this review, we focus on the recent advances in circadian biology and cardiovascular function, with particular emphasis on how this applies to human myocardial hypertrophy and heart failure, and the implications and importance for translational medicine.

[Total carnitine level in infants with cystic fibrosis and deficit supplementation by means of pharmacologic preparations and diet. Introductory remarks]. / Poziom karnityny calkowitej u niemowlat z mukowiscydoza oraz uzupelnianie jej niedoborów za pomoca preparatów farmakologicznych i diety. Doniesienie wstepne.

Carnitine deficiency in the serum was found in 5 infants with cystic fibrosis, impaired liver function and neurological symptoms. Clinical improvement and progressive normalization of the carnitine level in the serum, as well of the biochemical parameters of liver function were obtained after enteral pharmacotherapy and a carnitine-rich diet.

Changes in left ventricular dimensions and systolic function in 100 mildly hypertensive men during one year's treatment with atenolol vs. hydrochlorothiazide and amiloride (Moduretic): a double-blind, randomized study.

In a randomized double-blind study to compare the effect of atenolol vs. hydrochlorothiazide and amiloride (Moduretic) on left ventricular dimensions and systolic function, 100 hypertensive men were followed up during 1 year of treatment, 50 subjects being randomized to each drug. Echocardiography was performed at baseline, and after 3 and 12 months of treatment. A significant reduction in left ventricular mass with atenolol was paralleled by a decrease in left ventricular wall thickness and an increase in stroke volume. A similar reduction of left ventricular mass with Moduretic without a change in relative wall thickness and a decrease in stroke volume was observed. Cardiac output decreased in both groups.

[Electrocardiographic and echocardiographic changes during antihypertensive therapy]. / Modificazioni elettrocardiografiche ed ecocardiografiche durante terapia antipertensiva.

To investigate the changes of electrocardiographic and echocardiographic indexes of left ventricular hypertrophy (LVH) during antihypertensive therapy, 100 hypertensive patients, mean age 46 years, were studied in pretreatment condition and during 12 months of antihypertensive therapy. In pretreatment condition, 83 patients showed LVH by echocardiography (echo; left ventricular mass index greater than 130 g/m2) and 30 patients had LVH by electrocardiography (ECG) (Sokolow index greater than 35 mm). In comparison to echo index of LVH, Sokolow index showed a sensibility of 34% and a specificity of 88%. Both LV mass echo index and ECG index significantly decreased after 3 months but in different way. LV mass index mainly decreased after 12 months, whereas Sokolow index particularly decreased after 6 months, with no further changes in the subsequent months. After 12 months of therapy, the LV mass echo index normalized in 19% of the patients (16/83) and Sokolow index normalized in 57% (17/30). ECG sensibility and specificity, in comparison to LV mass echo, was 20% and 100%, respectively. Thus, ECG appears less sensitive than echo in the detection of LVH. During antihypertensive therapy ECG index of LVH normalized more precociously and to a greater extent than the echo index. However, the normalization of LVH by ECG does not necessarily mean that a complete anatomic regression of LVH has occurred.

[Regression of left ventricular hypertrophy in hypertensive patients under long-term therapy with antihypertensive agents]. / Rückbildung der Linksherzhypertrophie bei Hochdruckkranken durch antihypertensive Langzeittherapie.

The effect of long-term therapy of hypertension with antihypertensive drugs was investigated in 117 previously untreated patients (15 women, 102 men; mean age 46.4 +/- 9 years) with echocardiographically proven left-ventricular hypertrophy. 22 patients (group 1) received 100 mg/d Gallopamil, 25 (group 2) received 200 mg/d Metoprolol, 35 daily received both 50 mg Atenolol and 20 mg Nifedipine (group 3), 14 received daily 200 mg Acebutolol plus 20 mg Nifedipine (group 4), and 21 (group 5) 50 mg Atenolol plus 10 mg Enalapril daily. The treatment period lasted a mean of 38 (36.2-42.3) months. Left-ventricular muscle mass index (LVMI) as well as septal and posterior-wall thickness decreased significantly after 12.8 and 38.5 months (P less than 0.001). After a mean of 38.5 months LVMI had decreased by 36.7% in group 1, 35.1% in group 2, 42.3% in group 3, 45% in group 4 and 39.6% in group 5. LVMI was within normal range (less than or equal to 95 g/m2) in 81 of the 117 patients (69.2%) at the end of the treatment period. There was, however, no significant increase of the end-diastolic dimension of the left ventricle, but a significant increase of "fractional shortening" as a measure of myocardial contractility.

Postischemic recovery of mechanical performance and energy metabolism in the presence of left ventricular hypertrophy. A 31P-MRS study.

The present study was undertaken to define the effects of left ventricular hypertrophy on postischemic recovery of myocardial performance and high energy phosphate metabolism. Hemodynamics and 31P-magnetic resonance spectra were monitored simultaneously in the isolated Langendorff-perfused rat heart during 30 minutes of ischemia and 30 minutes of reperfusion. Left ventricular hypertrophy was produced by either suprarenal aortic constriction or chronic thyroxine administration. In chronic pressure overload hypertrophy, minimal coronary resistance was significantly higher (p less than 0.001) and the loss of purine nucleosides in the coronary effluent during early reperfusion significantly larger (p less than 0.001) compared with both normal hearts and thyroxine-induced hypertrophied hearts. Postischemic recovery of the baseline values for left ventricular developed pressure and phosphorylation potential was 43 +/- 4% and 82 +/- 4%, respectively, in chronic pressure overload hypertrophied hearts; 86 +/- 4% and 91 +/- 3%, respectively, in normal hearts (chronic pressure overload hypertrophy versus normal hearts, p less than 0.001 and p less than 0.05); and 100 +/- 4% and 98 +/- 2%, respectively, in thyroxine-induced hypertrophied hearts (normal hearts versus thyroxine-induced hypertrophied hearts, p less than 0.05 and p less than 0.05). Recovery after reperfusion was not related to intracellular pH, ATP, phosphocreatine, or inorganic phosphate levels during ischemia. Also, recovery was not related to developed pressure or oxygen consumption before ischemia. However, recovery was inversely related to coronary resistance and directly related to coronary flow before ischemia. Thus, functional and/or anatomic alterations of the coronary vascular bed and a greater loss of purine nucleosides during reperfusion are likely responsible for the attenuated compensatory response to ischemia and reperfusion in left ventricular hypertrophy induced by chronic pressure overload. On the other hand, the excess muscle mass per se does not seem to alter recovery, since thyroxine-induced myocardial hypertrophied hearts responded at least as well as normal hearts.

A critical review of NMR imaging and spectroscopy for the evaluation of cardiac hypertrophy in humans and experimental animals.

Nuclear magnetic resonance (NMR) is a product of modern technology and of great value for the noninvasive evaluation of cardiac hypertrophy. Among image diagnosis methodologies, 1H-magnetic resonance imaging is clinically available for exact visualization of the hypertrophic portion in the ventricular wall or septum. 31P-magnetic resonance spectroscopy is also promising for the evaluation of muscle energetics or intracellular environments. Various pitfalls that might be encountered in clinical or basic studies with NMR and desirable directions to be developed are described to make the modality more feasible for the evaluation of cardiac hypertrophy in humans and/or experimental animals.

[Nifedipine in the treatment of hypertension. An echocardiographic assessment of the hemodynamic effects]. / Nifedipin pri lechenii gipertonicheskoi bolezni. Ekhokardiograficheskaia otsenka gemodinamicheskikh éffektov.

As many as 32 patients with moderate arterial hypertension were examined. According to unidimensional echocardiography, the improvement of early diastolic filling of the hypertrophied left ventricle of the heart was recorded during 4 weeks of the treatment with nifedipine, a dihydropyridine blocker of calcium channels. The favourable effect on diastolic filling function was combined with an efficient control over arterial pressure which was determined by a decrease in the systemic vascular resistance. Nifedipine did not produce any depression of contractile and pump functions of the heart.

Diagnosis and therapeutic evaluation of a pediatric case of cardiomyopathy using phosphorus-31 nuclear magnetic resonance spectroscopy.

An 8 month old girl presented with undiagnosed non-anatomic congenital cardiomyopathy with massive cardiomegaly on chest X-ray film. Her older sibling had died suddenly at 6 months of age from what appeared to be a similar abnormality. Utilizing phosphorus-31 nuclear magnetic resonance (P-31 NMR) surface coil spectroscopy, a metabolic disorder was demonstrated in both her myocardium and skeletal muscle, revealing a phosphocreatine (PCr) to inorganic phosphate (Pi) ratio of half of that for a normal control infant. Manipulation of serum substrate availability indicated that medium chain triglycerides alone did not improve myocardial metabolism, but that intravenous glucose or oral carbohydrate loading raised the myocardial PCr/Pi ratio from 1.0 +/- 0.05 to 1.8 +/- 0.1 (p less than 0.01) without significantly affecting the PCr/Pi value of her resting skeletal muscle. This study demonstrates the feasibility of using P-31 nuclear magnetic resonance to evaluate the biochemistry of the human myocardium in vivo and to diagnose a metabolic abnormality. Phosphorus-31 nuclear magnetic resonance can thus be used to optimize therapy for human disease.

Mitral valve prolapse secondary to right ventricular enlargement in patients with pulmonary hypertension after toxic rapeseed oil ingestion.

A high incidence of mitral valve prolapse (MVP) has been reported in various entities which produce important right ventricular (RV) enlargement with normal or decreased left ventricular (LV) volume. To evaluate the importance of RV enlargement in the genesis of MVP in these cases, we analyzed the echocardiographic studies from 176 patients with 'Síndrome Tóxico'. These patients underwent M-mode, cross-sectional and pulsed Doppler examination because of the suspicion of having dietary pulmonary hypertension, a complication which occurred in almost 20% of patients with this epidemic poisoning and which showed a course of gradual resolution in most of them. RV size was classified according to the RV/LV maximal short-axis dimension ratio as normal, border-line, moderately enlarged and severely enlarged. MPV was diagnosed according to standard M-mode and cross-sectional echocardiographic criteria. A second echocardiographic examination was obtained in 38 patients 12.5 +/- 5.3 months after the first one. The incidence of MVP was 9.3% in patients with normal RV size (N = 107), 9.5% in patients with border-line RV size (N = 23), 30% in patients with moderate RV enlargement (N = 30) and 56% in patients with severe RV enlargement (N = 16) (P less than 0.001). Fourteen (77%) of the 18 patients with MVP and moderate or severe RV enlargement (N = 16) (P less than 0.001). Fourteen (77%) of the 18 patients with MVP and moderate or severe RV enlargement had holosystolic MVP. At pulsed Doppler examination, no patient showed signs of mitral regurgitation.(ABSTRACT TRUNCATED AT 250 WORDS)

[Use of graded bicycle ergometry as a method for the objective evaluation of the efficacy of reflexotherapy in the early stages of hypertension]. / Ispol'zovanie dozirovannoi veloérgometricheskoi nagruzki kak matoda ob"ektivnoi ostenki éffektivnosti refleksoterapii rannikh stadii gipertonicheskoi bolezni.

Graded bicycle ergometry was used to evaluate the efficacy of pathogenetic auriculo-paravertebral reflexotherapy (RT) in 24 patients with stages IB and IIA of essential hypertension (EH). After RT was completed the subjective symptomatology, central hemodynamics, and heart work improved. The increment of the minute volume of the circulation in response to graded exercise decreased, especially in patients with stage IB of EH. These patients also showed a reduction in the heart rate. The total peripheral vascular resistance dropped both at rest and after exercise. After RT the patients with stages IB and IIA of EH manifested a decrease in the loading heart index and intensity of the functioning of the structures, with that decrease being more demonstrable in patients with stage IIA EH, which attested to the lowering of heart muscle oxygen consumption. The decreased intensity of the functioning of the structures in patients with stage IB EH points to the diminution of myocardial hyperfunction marking the hyperkinetic circulatory pattern in these patients.