Concomitant presentation of spontaneous coronary artery dissection with Takotsubo syndrome: a case report.

Background: Spontaneous coronary artery dissection (SCAD) is still an underdiagnosed condition that requires a detailed assessment of angiographic signs. It also shares similar clinical presentations with Takotsubo syndrome (TTS). The concomitant presentation of SCAD with TTS is a possible occurrence, making it difficult for clinicians to treat and manage. Case summary: This study included a 49-year-old woman with retrosternal chest pain who was admitted to the emergency department. Coronary angiography indicated Type 2A SCAD involving the middle part of the left anterior descending artery, while the left ventriculography indicated a typical left ventricular apical ballooning compatible with TTS. A conservative approach to the management of SCAD was observed. After a 3-month follow-up, the control coronary angiography showed a complete angiographic resolution. The results of the transthoracic echocardiogram (TTE) and cardiac magnetic resonance revealed a complete normalization of the pathological features. The patient remained asymptomatic and showed no recurrence of chest pain. Discussion: Although TTS and SCAD are commonly observed in patients who share certain characteristics (women, without atheromatous terrain, stress-related factors), it is difficult to establish a pathophysiological link between them. This observation confirms the non-random association of two rare entities of myocardial infarction with no obstructive coronary arteries. Although TTS can be easily diagnosed via non-invasive imaging, the diagnosis of SCAD is more difficult. The findings of this study suggest a concomitant presentation between SCAD and TTS. Although the treatment approach to SCAD is usually conservative, severe forms of this disease require early diagnosis and appropriate treatment.

Downhill exercise training in monocrotaline-injected rats: Effects on echocardiographic and haemodynamic variables and survival.

BACKGROUND: Eccentric exercise training has been shown to improve muscle force strength without excessive cardiovascular stress. Such an exercise modality deserves to be tested in pulmonary arterial hypertension. AIM: We aimed to assess the effects of an eccentric training modality on cardiac function and survival in an experimental monocrotaline-induced model of pulmonary arterial hypertension with right ventricular dysfunction. METHODS: Forty rats were randomly assigned to one of four groups: 40mg/kg monocrotaline-injected sedentary rats; 40mg/kg monocrotaline-injected eccentric-trained rats; sedentary control rats; or eccentric-trained control rats. Eccentric exercise training consisted of downhill running on a treadmill with a -15° slope for 30minutes, 5 days a week for 4 weeks. Training tolerance was assessed by echocardiography, right ventricle catheterization and the rats' maximal eccentric speed. RESULTS: Survival in monocrotaline-injected eccentric-trained rats was not different from that in monocrotaline-injected sedentary rats. Monocrotaline-injected eccentric-trained rats tolerated this training modality well, and haemodynamic status did not deteriorate further compared with monocrotaline-injected sedentary rats. The eccentric maximal speed decline was less pronounced in trained compared with sedentary pulmonary arterial hypertension rats. CONCLUSIONS: Eccentric exercise training had no detrimental effects on right heart pressure, cardiac function and survival in rats with stable monocrotaline-induced pulmonary hypertension.

Right Heart Hemodynamics in Pulmonary Hypertension　- An Echocardiography and Catheterization Study.

BACKGROUND: Echocardiography (ECHO) plays a key role in both the diagnosis and prognosis of pulmonary hypertension (PH). Many equations have been published to assess right heart hemodynamics using ECHO. The objective of this study was to test the accuracy and precision of different echocardiographic equations in comparison with the right heart catheterization. METHODS AND RESULTS: Complete right heart hemodynamic assessments were prospectively obtained from 115 individuals (mean age 66±1 years; 57 males) who had known or suspected PH. Several equations were tested for the estimation of right atrial pressure, mean and systolic pulmonary artery pressure (MPAP), cardiac output, pulmonary capillary wedge pressure (PCWP), and pulmonary vascular resistance (PVR). The accuracy of ECHO was good, with a mean difference <2 mmHg for all of the pressure calculations and ±0.6 L/min for cardiac output. However, the PVR estimation was weak using any one of the formulae. For all the parameters, the precision of ECHO was moderate. The MPAP calculation detected PH with a sensibility of 97% and specificity of 83%. However, ECHO underdiagnosed post-capillary PH. CONCLUSIONS: ECHO is a good method for the diagnosis of PH, with an adequate calculation of right pressures, but cannot accurately calculate PCWP and PVR. (Circ J 2016; 80: 2019-2025).

Grape-Derived Polyphenols Prevent Doxorubicin-Induced Blunted EDH-Mediated Relaxations in the Rat Mesenteric Artery: Role of ROS and Angiotensin II.

This study determined whether doxorubicin, an anticancer agent, impairs endothelium-dependent relaxations mediated by nitric oxide (NO) and endothelium-derived hyperpolarization (EDH) in the mesenteric artery and, if so, the mechanism underlying the protective effect of red wine polyphenols (RWPs), a rich natural source of antioxidants. Male Wistar rats were assigned into 4 groups: control, RWPs, doxorubicin, and doxorubicin + RWPs. Vascular reactivity was assessed in organ chambers; the vascular formation of reactive oxygen species (ROS) using dihydroethidine and the expression levels of small and intermediate conductance calcium-activated potassium channels (SKCa, IKCa) and connexin 40 (Cx40), which are involved in EDH-type relaxations, endothelial NO synthase (eNOS), angiotensin II, and AT1 receptors by immunofluorescence. The doxorubicin treatment impaired EDH-mediated relaxations, whereas those mediated by NO were minimally affected. This effect was associated with reduced expression levels of SKCa, IKCa, and Cx40, increased expression levels of eNOS, angiotensin II, and AT1 receptors, and formation of ROS in mesenteric arteries. RWPs prevented both the doxorubicin-induced blunted EDH-type relaxations and the increased vascular oxidative stress, and they improved the expression levels of target proteins. These findings suggest that polyphenol-rich natural products might be of interest in the management of doxorubicin-induced vascular injury possibly by improving the vascular angiotensin system.

Cirrhotic cardiomyopathy and hepatopulmonary syndrome: prevalence and prognosis in a series of patients.

Hepatopulmonary syndrome (HPS) is of prognostic value in patients awaiting for orthotopic liver transplantation (OLT), but little is known about the effect of cirrhotic cardiomyopathy (CCM). The aim of the present study was to estimate the prevalence and possible relation between respiratory and cardiac abnormalities in a same series of patients awaiting OLT. Special attention was paid to the prognostic value of CCM in comparison to HPS. Eighty-three patients were included (19 females, 64 males; 52.1 ± 10.0 yrs). All had lung function testing with arterial blood gases and echocardiographic evaluation at rest with a contrast echocardiography in case of arterial oxygenation defect. To estimate the presence of CCM, patients underwent a complete left and right echocardiography and Doppler examination. Complete echocardiographic assessment could be obtained in 64 of the 83 patients of the study. HPS was observed in 16.9% (14/83) and CCM in 23.4% (15/64) of patients. There was a tendency of more serious adverse events before and after OLT in patients with HPS in comparison to others but CCM was not of prognostic value. HPS and CCM were frequent in these patients awaiting OLT but both abnormalities were not found in the same patients. CCM was neither related to death before OLT nor to death or serious adverse events after OLT.

Pretreatment with brain natriuretic peptide reduces skeletal muscle mitochondrial dysfunction and oxidative stress after ischemia-reperfusion.

Brain natriuretic peptide (BNP) reduces the extent of myocardial infarction. We aimed to determine whether BNP may reduce skeletal muscle mitochondrial dysfunctions and oxidative stress through mitochondrial K(ATP) (mK(ATP)) channel opening after ischemia-reperfusion (IR). Wistar rats were assigned to four groups: sham, 3-h leg ischemia followed by 2-h reperfusion (IR), pretreatment with BNP, and pretreatment with 5-hydroxydecanoic acid, an mK(ATP) channel blocker, before BNP. Mitochondrial respiratory chain complex activities of gastrocnemius muscles were determined using glutamate-malate (V(max)), succinate (V(succ)), and N,N,N',N'-tetramethyl-p-phenylenediamine dihydrochloride ascorbate (V(TMPD/asc)). Apoptosis (Bax-to-Bcl2 mRNA ratio and caspase-3 activity) and oxidative stress (dihydroethidium staining) were also assessed. Compared with the sham group, IR significantly decreased V(max), reflecting complex I, II, and IV activities (-36%, 3.7 ± 0.3 vs. 5.8 ± 0.2 µmol O(2)·min(-1)·g dry wt(-1), P < 0.01), and V(TMPD/asc), reflecting complex IV activity (-37%, 8.6 ± 0.8 vs. 13.7 ± 0.9 µmol O(2)·min(-1)·g dry wt(-1), P < 0.01). IR increased Bax-to-Bcl2 ratio (+57%, 1.1 ± 0.1 vs. 0.7 ± 0.1, P < 0.05) and oxidative stress (+45%, 9,067 ± 935 vs. 6,249 ± 723 pixels, P > 0.05). BNP pretreatment reduced the above alterations, increasing V(max) (+38%, P < 0.05) and reducing Bax-to-Bcl2 ratio (-55%, P < 0.01) and oxidative stress (-58%, P < 0.01). BNP protection against deleterious IR effects on skeletal muscles was abolished by 5-hydroxydecanoic acid. Caspase-3 activities did not change significantly. Conversely, BNP injected during ischemia failed to protect against muscle injury. In addition to maintaining the activity of mitochondrial respiratory chain complexes and possibly decreasing apoptosis, pretreatment with BNP protects skeletal muscle against IR-induced lesions, most likely by decreasing excessive production of radical oxygen species and opening mK(ATP) channels.

Evaluation of viral load in infants hospitalized with bronchiolitis caused by respiratory syncytial virus.

The relationship between viral load, disease severity and antiviral immune activation in infants suffering from respiratory syncytial virus (RSV)-associated bronchiolitis has not been well identified. The main objective of this study was to determine the existence of a correlation between RSV load and disease severity and also between different clinical markers and mRNA levels of the interferon stimulated gene (ISG)56 in infants hospitalized for bronchiolitis. We also evaluated whether viral load tended to be persistent over the course of the RSV infection. The levels of RSV-RNA were quantified in nasopharyngeal washings, collected from 132 infants infected with RSV as a single (90.15%) or as a dual infection with other respiratory viruses (9.85%). Results indicated that viral load was positively related to the clinical severity of bronchiolitis, the length of hospital stay, the levels of glycemia and the relative gene expression of ISG56, whereas an inverse correlation was observed with the levels of hemoglobin. We also found that the RSV load significantly decreased between the first and second nasopharingeal washings sample in most subjects. These results suggest that infants with high RSV load on hospital admission are more likely to have both more severe bronchiolitis and a higher airway activation of antiviral immune response.

In vitro sensitivity of human metapneumovirus to type I interferons.

Human metapneumovirus (hMPV) has been recognized as an important respiratory pathogen. Due to its relatively recent discovery, only limited information is available on the relationship between hMPV and type I interferons (IFN). This study was designed to determine whether in vitro hMPV is sensitive to the antiviral activity of IFN-ß, leukocyte IFN-α, and several IFN-α subtypes in a human Hep-2 cell line. The results showed that 50% inhibitory concentration values against hMPV for the various type I IFN preparations were significantly higher than those against the IFN-sensitive vesicular stomatitis virus, and some IFN-α subtypes appeared to be more active against hMPV than others, with IFN-α subtypes 5, 6, 8, and 10 being the most potent, and IFN-α2, 17, and 21 the least potent. The results show that hMPV grown in Hep-2 is partially resistant to the antiviral activity of type I IFNs. Additional studies are required to understand whether and to what extent the relatively low sensitivity of hMPV to IFNs influences the clinical outcomes of infected individuals.

L-arginine supplementation improves exercise capacity after a heart transplant.

BACKGROUND: Endothelial dysfunction is associated with the decreased exercise capacity observed in heart-transplant (HTx) recipients. L-arginine supplementation (LAS) stimulates the nitric oxide (NO) pathway and restores endothelial function. OBJECTIVE: We compared exercise capacity in healthy subjects and HTx patients and investigated whether chronic LAS might improve exercise capacity and NO/endothelin balance after an HTx. DESIGN: Clinical, echocardiographic, and exercise characteristics were measured in 11 control subjects and 22 HTx recipients. In a prospective, double-blind study, the 22 HTx recipients performed a 6-min exercise [6-min-walk test (6MWT)] and a maximal bicycle exercise test before and after a 6-wk period of placebo intake or LAS. Endothelial function was measured by analyzing blood NO metabolites, endothelin, and the resulting NO/endothelin balance. RESULTS: Exercise capacity decreased after transplantation. Unlike with the placebo intake, 6 wk of LAS improved quality of life in HTx recipients (mean +/- SEM Minnesota Score: from 15.3 +/- 1.3 to 10.6 +/- 1.1; P < 0.001) and their submaximal exercise capacity. The distance walked during the 6MWT increased (from 525 +/- 20 to 580 +/- 20 m; P = 0.002), and the ventilatory threshold during the incremental test was delayed by 1.2 min (P = 0.01). Central factors such as resting stroke volume, systolic pulmonary arterial pressure, cardiac systolodiastolic functions, and heart-rate reserve were not modified, but LAS significantly increased the NO:endothelin ratio (from 2.49 +/- 0.38 to 3.31 +/- 0.39; P = 0.03). CONCLUSION: Oral LAS may be a useful adjuvant therapeutic to improve quality of life and exercise tolerance in HTx recipients.

Endocrine heart after lung transplantation: increased brain natriuretic peptide is related to right ventricular function.

Brain natriuretic peptide (BNP) increases in proportion to the extent of right ventricular dysfunction in pulmonary hypertension and after heart transplantation. No data are available after lung transplantation. Clinical, biological, respiratory, echocardiographic characteristics and circulating BNP and its second messenger cyclic guanosine monophosphate (cGMP) were determined in thirty matched subjects (10 lung-, 10 heart-transplant recipients (Ltx, Htx) and 10 healthy controls). Eventual correlations between these parameters were investigated. Heart rate and pulmonary arterial blood pressure were slightly increased after transplantation. Creatinine clearance was decreased. Mean of forced expiratory volume in 1 s was 76.6 +/- 5.3% and vital capacity was 85.3 +/- 6.4% of the predicted values in Ltx. BNP was similarly increased in Ltx and Htx, as compared with control values (54.1 +/- 14.2 and 45.6 +/- 9.2 vs. 6.2 +/- 1.8 pg/ml, respectively). Significant relationships were observed between plasma BNP and cGMP values (r = 0.62; P < 0.05 and r = 0.75; P < 0.01, in Ltx and Htx) and between BNP and right ventricular fractional shortening and tricuspid E/Ea ratio in Ltx (r = -0.75 and r = 0.93; P < 0.01, respectively). BNP is increased after lung transplantation, like after heart transplantation. The relationships observed suggest that the cardiac hormone might counterbalance possible deleterious effects of lung-transplantation on right functioning of patient's heart.

Lack of endothelial dysfunction in patients under tacrolimus after orthotopic liver transplantation.

BACKGROUND: Endothelial dysfunction is a significant cause of vascular and end-organ damage after solid organ transplantation. The aim of this study was to compare endothelial function in healthy controls and in patients who received tacrolimus for immunosuppression after orthotopic liver transplantation (OLT). METHODS: Eight OLT patients and eight age- and BMI-matched healthy subjects were included in the study. Apart from hemodynamic parameters, enzymatic liver function, fasting plasma glucose levels, creatinine, cholesterol, nitric oxide and endothelin-1 levels were measured. Flow-mediated dilatation (FMD) in the brachial artery was determined by bi-mode ultrasound. RESULTS: Systolic and diastolic blood pressure and heart rate were higher in OLT recipients compared with the control group, but remained within normal limits. Blood results did not differ significantly between the groups. Circulating nitric oxide (152.2 +/- 29.7 vs. 180.6 +/- 40.1 micromol/L) and endothelin-1 (20.5 +/- 1.0 vs. 18.9 +/- 1.3 pmol/L) values were similar, and the FMD was normal in both groups (10.29 +/- 0.89 vs. 9.86 +/- 2.43% in controls and OLT recipients, respectively). There was a significant positive correlation between plasma tacrolimus levels after OLT and FMD (r = 0.72, p < 0.05). CONCLUSION: As assessed by both laboratory and functional approaches, endothelial function was unaltered in patients taking tacrolimus after OLT. The positive correlation between tacrolimus plasma levels and FMD suggest that tacrolimus might have beneficial effects on endothelial function after OLT.

Gene expression of nucleic acid-sensing pattern recognition receptors in children hospitalized for respiratory syncytial virus-associated acute bronchiolitis.

Given the critical role of pattern recognition receptors (PRRs) in acid nucleic recognition in the initiation of innate immunity and the orchestration of adaptive immunity, the aim of this study was to determine whether any heterogeneity of PRR expression in the airway tracts of infants with respiratory syncytial virus (RSV) infection might explain the broad clinical spectrum of RSV-associated bronchiolitis in infants. For this purpose, the levels of melanoma differentiation-associated protein-5 (MDA-5), retinoic acid inducible gene-1 (RIG-1), and Toll-like receptor 3 (TLR-3), TLR-7, TLR-8, and TLR-9 mRNAs were evaluated, using TaqMan quantitative reverse transcription-PCR, in cells from nasopharyngeal washes collected from 157 infants suffering from acute bronchiolitis whether or not they were associated with respiratory viruses. High interindividual variability was observed in both virus-positive and -negative infants; however, the relative gene expression levels of MDA-5, RIG-1, TLR-7, and TLR-8 were significantly higher in the virus-infected group, whereas the expression levels of TLR-3 and TLR-9 were not significantly different. The differences in the gene expression of MDA-5, RIG-1, TLR-7, and TLR-8 were more evident in infants with RSV infection than in those with bocavirus or rhinovirus infection. In RSV-infected infants, PRR-mRNA levels also were analyzed in relation to interferon protein levels, viral load, clinical severity, days of hospitalization, age, and body weight. A significant positive correlation was observed only between RSV viral load and RIG-1 mRNA levels. These findings provide the first direct evidence that, in infants with respiratory virus-associated bronchiolitis, especially RSV, there are substantial changes in PRR gene expression; this likely is an important determinant of the clinical outcome of bronchiolitis.

Contralateral leg as a control during skeletal muscle ischemia-reperfusion.

BACKGROUND: Recent data demonstrated that hind limb ischemia induces skeletal muscle mitochondrial dysfunctions. Improvement of such metabolic myopathy improves patient's symptomatology, supporting the development of experimental models focused on mitochondrial function analysis. However, although the nonischemic contralateral leg is often used as a control during unilateral leg ischemia, whether it might be useful when assessing ischemia-induced mitochondrial dysfunction remains to be investigated. MATERIALS AND METHODS: Both ischemic (IR) and nonischemic contralateral legs (CTL) of rats (n=13) submitted to 5 h ischemia induced by a rubber band tourniquet applied on the root of the hind limb were studied and compared to that of sham-operated animals (SHAM, n=13). Maximal oxidative capacities (V(max)) and complexes I, II and IV activities of the gastrocnemius mitochondrial respiratory chain were determined, using glutamate-malate, succinate (Vs) and TMPD-ascorbate (V(TMPD)) substrates. RESULTS: V(max) was decreased in IR (4.6+/-0.4 microM/min/g dry weight) compared to both SHAM and CTL muscles (8.5+/-0.5 and 7.1+/-0.4 microM/min/g dry weight, -46% and -36%, P<0.001, respectively). V(S) and V(TMPD) were reduced in IR muscle (-56% and -48% for V(S); and -25% and -24% for V(TMPD), P<0.001) as compared to SHAM and CTL). V(S) and V(TMPD) were similar in SHAM and CTL muscles. CONCLUSIONS: Five hours ischemia-reperfusion significantly impaired complexes I, II and IV of the ischemic skeletal muscle mitochondrial respiratory chain. Interestingly, only V(max) was slightly altered in the contralateral leg, supporting that the nonischemic leg might be used as a control when assessing mitochondrial function in the experimental setting of unilateral hind limb ischemia.

Can the six-minute walk test predict peak oxygen uptake in men with heart transplant?

OBJECTIVE: To determine whether the six-minute walk test (6MWT) might predict peak oxygen consumption (VO2peak) after heart transplantation. DESIGN: Case-control prospective study. SETTING: Public hospital. PARTICIPANTS: Patients with heart transplant (n=22) and age-matched sedentary male subjects (n=13). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Exercise performance using a maximal exercise test, distance walked using the 6MWT, heart rate, and VO2peak. RESULTS: Compared with controls, exercise performance was decreased in patients with heart transplant with less distance ambulated (516+/-13m vs 592+/-13m; P<.001) and a decrease in mean VO2peak (23.3+/-1.3 vs 29.6+/-1mL x min(-1) x kg(-1); P<.001). Patients with heart transplant showed an increased resting heart rate, a response delayed both at the onset of exercise and during recovery. However, the patient's heart rate at the end of the 6MWT was similar to that obtained at the ventilatory threshold. The formula did not predict measured VO2, with a weak correlation observed between the six-minute walk distance and both VO2peak (r=.53; P<.01) and ventilatory threshold (r=.53; P<.01) after heart transplantation. Interestingly, when body weight was considered, correlations coefficient increased to .74 and .77, respectively (P<.001). CONCLUSIONS: In heart transplant recipients, the 6MWT is a safe, practical, and submaximal functional test. The distance-weight product can be used as an alternative method for assessing the functional capacity after heart transplantation but cannot totally replace maximal VO2 determination.

Upregulation of interferon-induced genes in infants with virus-associated acute bronchiolitis.

To determine whether there is an airway IFN response in infants with acute bronchiolitis and to establish whether the rate of such a response is related to the severity of illness, the expression of some IFN-induced genes was measured in nasopharyngeal washes from 39 infants with acute bronchiolitis. The results indicate that in infants with a virus-associated acute bronchiolitis there is a strong activation of IFN system and that the severity of illness is inversely related to the level of expression of IFN-induced genes. This suggests that the IFN response plays an important role in determining virus-associated respiratory disease in early life.

Detection and typing by molecular techniques of respiratory viruses in children hospitalized for acute respiratory infection in Rome, Italy.

Detection of a broad number of respiratory viruses is not undertaken currently for the diagnosis of acute respiratory infection due to the large and always increasing list of pathogens involved. A 1-year study was undertaken on children hospitalized consecutively for acute respiratory infection in a Pediatric Department in Rome to characterize the viruses involved. Two hundred twenty-seven children were enrolled in the study with a diagnosis of asthma, bronchiolitis, bronchopneumonia, or laringo-tracheo bronchitis. A molecular approach was adopted using specific reverse transcription (RT)-PCR assays detecting 13 respiratory viruses including metapneumovirus (hMPV) and the novel coronaviruses NL63 and HKU1; most amplified fragments were sequenced to confirm positive results and differentiate the strain. Viral pathogens were detected in 97 samples (42.7%), with 4.8% of dual infections identified; respiratory syncytial virus (RSV) was detected in 17.2% of children, followed by rhinovirus (9.7%), parainfluenza virus type 3 (PIV3) (7.5%), and influenza type A (4.4%). Interestingly, more than half the patients (9/17) that have rhinovirus as the sole respiratory pathogen had pneumonia. HMPV infected children below 3 years in two peaks in March and June causing bronchiolitis and pneumonia. One case of NL63 infection is described, documenting NL63 circulation in central Italy. In conclusion, the use of a comprehensive number of PCR-based tests is recommended to define the burden of viral pathogens in patients with respiratory tract infection.

A novel assay to detect low-titred antibodies to interferon beta in multiple sclerosis patients.

Neutralizing antibodies (NAbs) may compromise interferon (IFN) clinical efficacy in patients with multiple sclerosis (MS) receiving IFN-beta treatment. When bioassays are used for anti-IFN-beta antibody detection, they are unable to discriminate between NAbs or other interfering substances with anti-IFN activity. Here we report the development of an anti-IFN-beta Western blot method that facilitates the detection of IFN low-titred antibodies and characterizes such low neutralizing activity as specifically due to the presence of particular IFN antibodies. The assay was characterized using serum samples from patients with MS treated with IFN-beta. It was developed by adding anti-IFN-positive antibody sera to Dynabeads M-280 tosylactivated followed by Western blot analysis. All sera samples from MS patients with IFN-betala NAbs (< or = 50 t1/10) proved to be antibody-positive using this new method and, more importantly, four of 27 binding antibody-negative sera samples were scored as IFN antibody-positive. The method was found to be rapid, specific and sensitive and consistent with respect to well-established antiviral neutralization or commercial enzyme-linked immunosorbent assays.