Utility of Left Atrial Expansion Index and Stroke Volume in Management of Chronic Systolic Heart Failure.

BACKGROUND: Titration of evidence-based medications, important for treating heart failure (HF), is often underdosed by symptom-guided treatment. The aim of this study was to investigate, using echocardiographic parameters, stroke volume and left ventricular (LV) filling pressure to guide up-titration of medications, increasing prognostic benefits. METHODS: A total of 765 patients with chronic HF and severely reduced LV ejection fractions (<35%), referred from 2008 to 2016, were prospectively studied. Echocardiographic guidance was performed in 149 patients. LV filling pressure was assessed by left atrial expansion index, and stroke volume was estimated from diameter and time-velocity integral in the LV outflow tract. Up-titration of evidence-based medications and adjustment for side effects or worsening clinical conditions according to those parameters were performed. Propensity score matching was used to match pairs of patients with (n = 110) or without (n = 110) echocardiographic guidance. End points were 4-year frequencies of HF hospitalization and all-cause mortality. RESULTS: During a mean follow-up time of 4.1 years, rates of adverse events were 58 (52.7%) with no echocardiographic guidance and 36 (32.7%) with echocardiographic guidance (P < .0001). Echocardiography provided effective guidance to reduce prescribing frequency and dose of diuretics and to promote evidence-based medication prescription. It reduced HF rehospitalization and all-cause mortality. By multivariate analysis, prognostic improvement was associated with up-titration of medications with echocardiographic guidance. CONCLUSIONS: There was a statistically significant difference in long-term prognosis between propensity score-matched pairs of patients with chronic severe HF with and without echocardiographic guidance. These findings need further validation in large prospective clinical trials.

Anti-Inflammatory and Antinociceptive Effects of Ethyl Acetate Fraction of an Edible Red Macroalgae Sarcodia ceylanica.

Research so far has only shown that edible red macroalgae, Sarcodia ceylanica has the ability to eliminate free radicals and anti-diabetic, anti-bacterial properties. This study was conducted both in vitro and in vivo on the ethyl acetate extract (PD1) of farmed red macroalgae in order to explore its anti-inflammatory properties. In order to study the in vitro anti-inflammatory effects of PD1, we used lipopolysaccharide (LPS) to induce inflammatory responses in murine macrophages. For evaluating the potential in vivo anti-inflammatory and antinociceptive effects of PD1, we used carrageenan-induced rat paw edema to produce inflammatory pain. The in vitro results indicated that PD1 inhibited the LPS-induced pro-inflammatory protein, inducible nitric oxide synthase (iNOS) in macrophages. Oral PD1 can reduce carrageenan-induced paw edema and inflammatory nociception. PD1 can significantly inhibit carrageenan-induced leukocyte infiltration, as well as the protein expression of inflammatory mediators (iNOS, interleukin-1ß, and myeloperoxidase) in inflammatory tissue. The above results indicated that PD1 has great potential to be turned into a functional food or used in the development of new anti-inflammatory and antinociceptive agents. The results from this study are expected to help scientists in the continued development of Sarcodia ceylanica for other biomedical applications.

Excavatolide B Modulates the Electrophysiological Characteristics and Calcium Homeostasis of Atrial Myocytes.

Severe bacterial infections caused by sepsis always result in profound physiological changes, including fever, hypotension, arrhythmia, necrosis of tissue, systemic multi-organ dysfunction, and finally death. The lipopolysaccharide (LPS) provokes an inflammatory response under sepsis, which may increase propensity to arrhythmogenesis. Excavatolide B (EXCB) possesses potent anti-inflammatory effects. However, it is not clear whether EXCB could modulate the electrophysiological characteristics and calcium homeostasis of atrial myocytes. This study investigated the effects of EXCB on the atrial myocytes exposed to lipopolysaccharide. A whole-cell patch clamp and indo-1 fluorimetric ratio technique was employed to record the action potential (AP), ionic currents, and intracellular calcium ([Ca2+]i) in single, isolated rabbit left atrial (LA) cardiomyocytes, with and without LPS (1 µg/mL) and LPS + EXCB administration (10 µM) for 6 ± 1 h, in order to investigate the role of EXCB on atrial electrophysiology. In the presence of LPS, EXCB-treated LA myocytes (n = 13) had a longer AP duration at 20% (29 ± 2 vs. 20 ± 2 ms, p < 0.05), 50% (52 ± 4 vs. 40 ± 3 ms, p < 0.05), and 90% (85 ± 5 vs. 68 ± 3 ms, p < 0.05), compared to the LPS-treated cells (n = 12). LPS-treated LA myocytes showed a higher late sodium current, Na⁺/Ca2+ exchanger current, transient outward current, and delayed rectifier potassium current, but a lower l-type Ca2+ current, than the control LA myocytes. Treatment with EXCB reversed the LPS-induced alterations of the ionic currents. LPS-treated, EXCB-treated, and control LA myocytes exhibited similar Na⁺ currents. In addition, the LPS-treated LA myocytes exhibited a lower [Ca2+]i content and higher sarcoplasmic reticulum calcium content, than the controls. EXCB reversed the LPS-induced calcium alterations. In conclusion, EXCB modulates LPS-induced LA electrophysiological characteristics and calcium homeostasis, which may contribute to attenuating LPS-induced arrhythmogenesis.

17-DMAG, an HSP90 Inhibitor, Ameliorates Multiple Organ Dysfunction Syndrome via Induction of HSP70 in Endotoxemic Rats.

Sepsis is a systemic inflammatory disorder, accompanied with elevated oxidative stress, leading to multiple organ dysfunction syndrome (MODS), and disseminated intravascular coagulation. 17-Dimethylaminoethylamino- 17-demethoxygeldanamycin (17-DMAG), a heat shock protein (HSP) 90 inhibitor, has been reported to possess anti-inflammatory effects. In this study, the beneficial effects of 17-DMAG on lipopolysaccharide (LPS) induced MODS and DIC was evaluated in anesthetized rats. 17-DMAG (5 mg/kg, i.p.) was significantly increased survival rate, and prevented hypotension in LPS (30 mg/kg i.v. infused for 4 h) induced endotoxemia. The elevated levels of alanine aminotransferase (ALT), creatine phosphokinase (CPK), lactate dehydrogenase, creatinine, nitric oxide (NO) metabolites, IL-6, and TNF-α in LPS-exposed rat plasma were significantly reduced by 17-DMAG. Moreover, 17-DMAG suppressed LPS-induced superoxide anion production and caspase 3 activation in heart tissues. LPS induced the prolongation of prothrombin time, and a pronounced decrease in platelet count, which were improved by 17-DMAG. 17-DMAG markedly induced HSP70 and heme oxygenase (HO)-1, and suppressed inducible nitric oxide synthase (iNOS) and phosphorylated NF-κB p65 protein expression in organs 6 h after LPS initiation. Pretreatment with high dose of quercetin (300 mg/kg, i.p.), as an HSP70 inhibitor, reversed the beneficial effects of 17-DMAG on survival rate, plasma levels of ALT, CPK, creatinine, IL-6, and NO metabolites, iNOS induction, and caspase-3 activation in LPS-treated rats. In conclusion, 17-DMAG possesses the anti-inflammatory and antioxidant effects that were proved through LPS-induced acute inflammation, which is associated with induction of HSP70 and HO-1, leading to prevent MODS in sepsis.

The cardioprotective effect of hypertonic saline is associated with inhibitory effect on macrophage migration inhibitory factor in sepsis.

Sepsis can cause myocardial dysfunction, which contributes to the high mortality of sepsis. Hypertonic saline (HS) has been reported to increase myocardial contractility in sepsis. In the present study, mechanisms of action of HS resuscitation (4 mL of 7.5% NaCl per kilogram) on cardiac function have been evaluated in septic rats. HS was administered 1 h after LPS (10 mg/kg, i.v.) challenge. The mean arterial blood pressure significantly decreased 4 h after LPS challenge, and septic shock was observed at the end of experiment (6 h). Posttreatment with HS prevented hypotension caused by LPS and significantly improved cardiac function, evidenced by increases in left ventricular developed pressure, mean +dP/dt and -dP/dt. The amplitude of electrical-stimulated intracellular Ca(2+) transient in isolated single cardiomyocytes was significantly reduced after 6 h LPS insult, which was recovered by HS. In addition, LPS resulted in significant increases in neutrophil myeloperoxidase activity, macrophage migration inhibitory factor (MIF), and NF-κB phospho-p65 protein levels in myocardium at 6 h, which were significantly attenuated by HS. In conclusion, HS improved myocardial contractility and prevented circulatory failure induced by endotoxemia, which may attribute to improvement of intracellular calcium handling process and inhibitory effects on neutrophil infiltration and MIF production in hearts.

Body Mass Index and Outcome of Acute Myocardial Infarction - Is There an Obesity Paradox?

BACKGROUND: Although there have been some studies focusing on the relationship between body mass index (BMI), coronary artery disease (CAD) and acute coronary syndrome, the clinical effects of BMI on outcomes after percutaneous coronary intervention (PCI) in patients with acute myocardial infarction (AMI) are not well known in a Taiwanese population. METHODS: From January 2005 to December 2011, 1298 AMI patients who received PCI were enrolled from a single center in Taiwan. The patients were divided into 4 groups according to their BMI: underweight (BMI < 18.5 kg/m(2)); normal weight (18.5 ≤ BMI < 24 kg/m(2)); overweight (24 ≤ BMI < 27 kg/m(2)) and obese (BMI ≥ 27). All patients had been followed up for at least 12 months, and 30-day and 5-year all-cause and cardiovascular-cause mortality were compared among the study groups. RESULTS: The patients in the underweight group had a lower 30-day survival rate than the other 3 groups, and the underweight and normal weight patients had a lower 5-year survival rate than the overweight and obese patients. The multivariate regression analysis showed that Killip class ≥ 2, non-use of statin, older age, hemoglobin < 12 g/dl and chronic kidney disease, but not BMI, are independent predictors of all-cause mortality. CONCLUSIONS: In this present study, the major factors affecting long-term survival are lack of using statin and older age, but not obese paradox. KEY WORDS: Acute myocardial infarction; Mortality; Obesity; Percutaneous coronary intervention; Survival.

Adenosine modulates cardiovascular functions through activation of extracellular signal-regulated kinases 1 and 2 and endothelial nitric oxide synthase in the nucleus tractus solitarii of rats.

BACKGROUND: The nucleus tractus solitarius (NTS) is the primary integrative center for baroreflex. Adenosine has been shown to play an important modulatory role in blood pressure control in the NTS. Our previous results demonstrated that adenosine decreases blood pressure, heart rate, and renal sympathetic nerve activity and modulates baroreflex responses in the NTS. We also demonstrated that a nitric oxide synthase (NOS) inhibitor may block the cardiovascular effects of adenosine in the NTS, which suggests interaction between the adenosine receptor and NOS. However, the signaling mechanisms of adenosine that induce nitric oxide release in the NTS remain uncertain. The aim of the present study was to investigate the possible signal pathways involved in the cardiovascular regulation of adenosine in the NTS. METHODS AND RESULTS: Adenosine was microinjected into the NTS of urethane-anesthetized male Sprague-Dawley rats. Blood pressure and heart rate decreased significantly after microinjection. The cardiovascular effects of adenosine were attenuated by prior administration of the mitogen-activated protein kinase/extracellular signal-regulated kinase inhibitor PD98059 (6 nmol/60 nL) or an endothelial NOS-selective inhibitor, L-NIO (6 nmol/60 nL); however, the neuronal NOS-specific inhibitor vinyl-L-NIO (600 pmol/60 nL) did not attenuate the cardiovascular effects of adenosine. Western blot and immunohistochemistry studies demonstrated that adenosine induced extracellular signal-regulated kinases 1 and 2 and endothelial NOS phosphorylation in the NTS. Pretreatment with PD98059 diminished the endothelial NOS phosphorylation evoked by adenosine. CONCLUSIONS: These results represent a novel finding that extracellular signal-regulated kinases 1 and 2 is involved in cardiovascular regulation in the NTS. They also indicate that the cardiovascular modulatory effects of adenosine in the NTS are accomplished by activation of mitogen-activated protein kinase/extracellular signal-regulated kinases 1 and 2 and then endothelial NOS.

Role of shortened QTc dispersion in in-hospital cardiac events in patients undergoing percutaneous coronary intervention for acute coronary syndrome.

BACKGROUND: QT dispersion (QTD) refers to the difference between maximal and minimal QT values on the electrocardiogram (ECG). QTD values are calculated and corrected with Bazett's formula (corrected QTD = QTcD = QTD/square root of RR). QTcD increases in patients with acute coronary syndrome (ACS). Recovery of increased QTcD (shortened QTcD) develops after successful revascularization, but prolonged QTcD occurs in certain patients. The aim of this study is to ascertain the clinical significance between shortened and prolonged QTcD groups after percutaneous coronary intervention (PCI). METHODS: We retrospectively enrolled 128 patients with ACS who had received PCI. The values of QTcD were measured manually on 12-lead standard ECGs obtained within 3 days before and after PCI (pre-PCI QTcD and post-PCI QTcD). All the patients were divided into 2 groups. The shortened QTcD group was defined as those patients with a decrease in QTcD after PCI and the prolonged QTcD group as those with an increase in QTcD after PCI. The underlying diseases, various clinical classifications and some prognostic factors were taken into comparison and statistical analysis between these 2 groups. RESULTS: The shortened QTcD group showed a significantly higher rate of in-hospital cardiac death (13% vs. 0%, p = 0.006) and a greater pre-PCI QTcD (100.8 +/- 39.5 vs. 61.3 +/- 24.1 ms, p < 0.001) than the prolonged QTcD group. There was a significantly greater pre-PCI QTcD in patients with cardiac death than those without cardiac death (111.6 +/- 38.3 vs. 83.3 +/- 38.3ms, p = 0.027). Furthermore, the patients with in-hospital cardiac death presented with a significantly more frequent occurrence of in-hospital ventricular arrhythmia, compared with those without cardiac death (30.0% vs. 4.0%, p = 0.014). CONCLUSION: Among the patients with ACS undergoing PCI, directly divided into shortened and prolonged QTcD groups regardless of initial pre-PCI QTcD, the shortened QTcD group showed a higher occurrence of in-hospital cardiac death and a greater pre-PCI QTcD. Shortened QTcD might be 1 risk factor for in-hospital cardiac death.

Tetramethylpyrazine induces heme oxygenase-1 expression and attenuates myocardial ischemia/reperfusion injury in rats.

The accumulation of oxygen free radicals and activation of neutrophils are strongly implicated as pathophysiological mechanisms mediating myocardial ischemia/reperfusion injury. Heme oxygenase-1 (HO-1) has been reported to play a protective role in oxidative tissue injuries. In this study, the cardioprotective activity of tetramethylpyrazine (TMP), an active ingredient of Chinese medicinal herb Ligusticum wallichii Franchat, was evaluated in an open-chest anesthetized rat model of myocardial ischemia/reperfusion injury. Pretreatment with TMP (5 and 10 mg/kg, i.v.) before left coronary artery occlusion significantly suppressed the occurrence of ventricular fibrillation. After 45 min of ischemia and 1 h of reperfusion, TMP (5 and 10 mg/kg) caused a significant reduction in infarct size and induced HO-1 expression in ischemic myocardium. The HO inhibitor ZnPP (50 microg/rat) markedly reversed the anti-infarct action of TMP. Superoxide anion production in ischemic myocardium after 10 min reperfusion was inhibited by TMP. Furthermore, TMP (200 and 500 microM) significantly suppressed fMLP (800 nM)-activated human neutrophil migration and respiratory burst. In conclusion, TMP suppresses ischemia-induced ventricular arrhythmias and reduces the infarct size resulting from ischemia/reperfusion injury in vivo. This cardioprotective activity of TMP may be associated with its antioxidant activity via induction of HO-1 and with its capacity for neutrophil inhibition.

Effects of cyclopiazonic acid on triggered activities in ventricular muscle and cardiomyocytes isolated from hamster hearts.

The present experiments were performed to study the actions of cyclopiazonic acid on triggered activities generated in vitro in ventricular papillary muscle and cardiomyocytes isolated from the hearts of healthy male Syrian hamsters (Biobreeders F1B). Action potentials (APs) of ventricular muscle with a diameter around 1.5 mm were recorded using a microelectrode technique and force was recorded using a transducer. Ventricular preparations were driven at 2 Hz in high [Ca]o (9 mM)-low [K]o (1 mM) solution to induce delayed after depolarizations (DADs). Triggered activities were induced on resumption of electrical stimulation after a rest period of 20 sec. Effects of cyclopiazonic acid (3-10 microM) on steady-state rhythms and post-rest triggered activities were determined. Results revealed that cyclopiazonic acid initially enhanced the amplitude of DADs and induced post-rest triggered rhythms. However, after several minutes of cyclopiazonic acid exposure, AP duration (APD) was prolonged and DADs were significantly depressed. The effects on APD and DADs were reversible after washout of cyclopiazonic acid, but the diastolic potential during rest period oscillated and was able to generate high-frequency spontaneous APs at a reduced potential level. In ventricular myocytes isolated enzymatically, ionic currents were measured using of whole-cell patch-clamp techniques. In a high [Ca]o-low [K]o solution, a series of oscillatory transient inward currents (I(ti)) were obtained on repolarization to the holding potential (-45 mV) after a depolarizing pulse to the test potential of +20 mV for 1.2 sec. Cyclopiazonic acid (10 microM) reduced significantly the magnitude of I(ti). The present results in hamster ventricular cells suggested that cyclopiazonic acid by inhibiting the sarcoplasmic reticulum (SR)-Ca2+ pump would gradually deplete the amount of Ca2+ within the SR. The consequent reduction in the amount of Ca2+ released into the cytoplasm by cyclopiazonic acid might inhibit triggered arrhythmia through a reduction of DADs and I(ti).