Analysis of the effect of CPAP on hemodynamics using clinical data and a theoretical model: CPAP therapy decreases cardiac output mechanically but increases it via afterload reduction.

BACKGROUND: Noninvasive positive pressure ventilation (NIPPV) has been established as an effective treatment for heart failure. Positive airway pressure such as continuous positive airway pressure (CPAP) increases cardiac output (CO) in some patients but decreases it in others. However, the mechanism behind such unpredictable responses remains undetermined. METHODS AND RESULTS: We measured hemodynamic parameters of 38 cases using Swan-Ganz catheter before and after CPAP in chronic heart failure status. In those whose CO increased by CPAP, pulmonary vascular resistance (PVR) was significantly decreased and SpO2 significantly increased, but the other parameters were not changed. On the other hand, PVR was not changed, but systemic vascular resistance (SVR) was increased in those whose CO decreased by CPAP. To explain this phenomenon, we simulated the cardiovascular system using a cardiac model of time-varying elastance. In this model, it was indicated that CPAP decreases CO irrespective of cardiac function or filling status under constant PVR condition. However, when reduction of PVR by CPAP was taken into account, an increase in CO was expected especially in the hypervolemic and low right ventricle (RV) systolic function cases. CONCLUSIONS: CPAP would increase CO only where PVR can be reduced by CPAP therapy, especially in the case with hypervolemia and/or low RV systolic function. Understanding the underlying mechanism should help identify the patients for whom NIPPV would be effective.

Impact of Killip classification on acute myocardial infarction: data from the SAIKUMA registry.

Therapeutic devices for acute myocardial infarction (AMI) have evolved dramatically in recent years. However, the impact of the Killip classification of AMI outcomes in patients undergoing aggressive percutaneous coronary intervention remains unclear. We performed a 10-year retrospective review of 2062 patients diagnosed with AMI, and divided the data into two 5-year intervals: 2005-2009 (n = 1071), and 2010-2014 (n = 991). No difference was observed in in-hospital mortality rate between the two periods (first period, 11.5% vs second period, 9.7%; P = 0.19). The incidence of stent thrombosis was not significantly different between the two periods, and very few thrombi occurred in patients who received second-generation drug-eluting stents (DES) (0.98%: 5/511). In-hospital mortality due to stent thrombosis was high in the full cohort (15%). During the second period, in-hospital mortality was lower in Killip class 4 patients, although the difference was not significant (59.1 vs 47.5%, P = 0.07). Multivariable logistic regression identified several factors that significantly affected in-hospital mortality, including age [odds ratio (OR) 1.07], left main trunk (OR 2.47), peak CPK value above 5000 IU/L (OR 3.18), and Killip class 4 (OR 15.63). We evaluated trends in in-hospital mortality among patients with AMI over a 10-year period. New DES and the frequent use of mechanical support in patients with hemodynamic compromise tended to improve in-hospital mortality, but the effect was not significant. Notably, Killip class 4 on admission was associated with an estimated 16-fold increased risk of in-hospital death.

Adaptive servo-ventilation therapy reduces hospitalization rate in patients with severe heart failure.

INTRODUCTION: Adaptive servo-ventilation (ASV) therapy is a recently developed non-pharmacological therapy that has been reported to improve cardiac function and survival in patients with severe congestive heart failure (CHF). However, a recent large randomized study suggested that ASV does not improve survival in patients with reduced ejection fraction. It remains unclear whether ASV treatment can reduce the hospitalization rate of CHF patients. We thus examined the frequency of hospital admission before and after initiation of ASV therapy in patients with CHF. METHODS AND RESULTS: Hospitalization frequencies during the 12months before and 12months after initiation of ASV therapy (24 consecutive months) were retrospectively compared in 44 consecutive patients with severe CHF. The admission frequency decreased from 1.9±1.4 admissions in the 12months before ASV to 1.1±1.6 admissions in the 12months after ASV initiation (P<0.001). The decrease tended to be greater in those patients with more frequent hospitalizations before ASV initiation. CONCLUSION: ASV therapy reduces hospital admissions in patients with severe CHF who are receiving maximum medical treatment.

Hemodynamic response during standing test after blood donation can predict the late phase vasovagal reaction.

A major complication of blood donation is vasovagal reaction (VVR) with or without syncope. VVR occurs not only in the early phase, but also in the late phase after blood donation. We previously reported the hemodynamic characteristics of blood donors susceptible to early phase VVR. In the present study, we investigated the hemodynamic characteristics of those who developed late VVR. Ninety-six healthy volunteers donating 400 ml of whole blood were studied. After asking about their physical condition or routine questions for blood donation, blood pressure (BP) and heart rate (HR) were recorded while the donors were kept standing up for 3 min before and after blood collection. Questionnaires were distributed to all donors for reporting late VVR symptoms within 24 h. Those with younger age and lower diastolic blood pressure were more susceptible to late VVR (both p < 0.05). Furthermore, we identified the increase in HR during the standing test after blood collection as a good predictor of late VVR (odds ratio 1.063, 95 % CI 1.005-1.124; p = 0.031). Also, analysis of questions asked before donation revealed that significantly more donors considered themselves as sensitive to pain in the late VVR group (Odds ratio 0.070, 95 % CI 0.008-0.586; p = 0.014). Excessive HR response to standing after blood collection and subjective sensitivity to pain as well as younger age and lower diastolic BP may be useful to detect donors at high risk for late VVR.

A lotus root-like appearance in both the left anterior descending and right coronary arteries.

A 60-year-old man was referred to our hospital because of dyspnea on exertion. He was diagnosed with heart failure due to an old myocardial infarction. Myocardial stress perfusion scintigraphy revealed inducible myocardial ischemia. Coronary angiography revealed hazy slit lesions in both the left anterior descending (LAD) and right coronary arteries (RCA). We first performed percutaneous coronary intervention (PCI) on the LAD lesion. Subsequently, we performed PCI for the RCA lesion using multiple imaging modalities. We observed a lotus root-like appearance in both the LAD and RCA, and PCI was successful for both vessels. We describe this rare case in detail.

Inadvertent consequences of percutaneous coronary intervention to treat unstable spontaneous coronary artery dissection.

We present two cases of spontaneous coronary artery dissection (SCAD), which were diagnosed and treated with emergent percutaneous coronary intervention (PCI). Patients with ongoing ischemia due to SCAD need emergent coronary revascularization with PCI or coronary artery bypass grafting. We discuss the difficulties of PCI to bail out unstable SCAD regardless of the modern techniques and modalities. Brief reviews of the literature with relevance are included. .

Patient factors against stable control of warfarin therapy for Japanese non-valvular atrial fibrillation patients.

INTRODUCTION: Effectiveness and safety of warfarin therapy for non-valvular atrial fibrillation (NVAF) patients are strongly associated with its stability presented such as time in therapeutic range (TTR) of PT-INR. However, the factors that affect TTR have not been fully elucidated in Japan where majority of patients are controlled within the range of 1.6-2.6 of PT-INR irrespective of the age. METHODS: We retrospectively analyzed 163 NVAF patients taking warfarin to determine the factors that affect TTR including metabolic enzymes polymorphisms after TTR calculation with both the standard PT-INR range and the actual control range of 1.6-2.6. RESULTS: Overall TTR calculated using Japanese Guideline was 69.7 ± 25.1% (<70 and ≥ 70 years; 49.6 ± 24.8% and 77.8 ± 20.3%, respectively). After confirming that PT-INR values in patients < 70 years distributed in the same range as in those ≥ 70 years, as in a Japanese large cohort, we recalculated TTR of those < 70 years with 1.6-2.6 of PT-INR and found that it was 79.5 ± 20.1%. Poor control of this new TTR were significantly associated with the lower height, the higher serum creatinine, the lower creatinine clearance, female gender, and presence of congestive heart failure, (p<0.05 respectively). Multivariate analysis revealed female gender and presence of congestive heart failure as independent predictor of the lower TTR (p<0.05, p<0.01, respectively). Polymorphism of CYP2C9 and VKORC1 were related to the dosage of warfarin but not determinant of TTR. CONCLUSIONS: When evaluated using a range of PT-INR actually used in Japan, TTR is generally well controlled and female gender and presence of congestive heart failure significantly affected the poorer TTR control.

Mediastinal leiomyosarcoma concurrent with intra-aortic thrombosis.

We report a case of a large intra-aortic thrombosis in an 83-year-old woman concurrent with metastatic mediastinal leiomyosarcoma. Imaging studies incidentally detected a mediastinal malignant tumour metastasising to bilateral adrenals and an extensive intra-aortic mass that was suspected to be intra-aortic thrombosis. One month later massive embolism developed in the lower limb and her condition deteriorated rapidly resulting in death. Autopsy revealed diffused proliferation of highly pleomorphic atypical cells accompanied by necrosis in the mediastinum tumours and bilateral adrenal glands. Leiomyosarcoma metastasising to bilateral adrenals was confirmed by the results of immunostaining. The intra-aortic mass suggested that the fragmented thrombus might be the cause of a sudden lower-limb embolism. Microscopic examination showed that the mass lesion in the aortic arch was composed of a blood clot containing neutrophils. We report this case because leiomyosarcoma arising from the mediastinum and, especially, associated with an extraordinarily large intra-aortic thrombosis is very rare.

Enhancement of cardiac performance by bilevel positive airway pressure ventilation in heart failure.

BACKGROUND: Recent studies have reported the clinical usefulness of positive airway pressure ventilation therapy with various kinds of pressure support compared with simple continuous positive airway pressure (CPAP) for heart failure patients. However, the mechanism of the favorable effect of CPAP with pressure support can not be explained simply from the mechanical aspect and remains to be elucidated. METHODS AND RESULTS: In 18 stable chronic heart failure patients, we performed stepwise CPAP (4, 8, 12 cm H(2)O) while the cardiac output and intracardiac pressures were continuously monitored, and we compared the effects of 4 cm H(2)O CPAP with those of 4 cm H(2)O CPAP plus 5 cm H(2)O pressure support. Stepwise CPAP decreased cardiac index significantly in patients with pulmonary arterial wedge pressure (PAWP) <12 mm Hg (n = 10), but not in those with PAWP ≥12 mm Hg (n = 8). Ventilation with CPAP plus pressure support increased cardiac index slightly but significantly from 2.2 ± 0.7 to 2.3 ± 0.7 L min(-1) m(-2) (P = .001) compared with CPAP alone, regardless of basal filling condition or cardiac index. CONCLUSIONS: Our results suggest that CPAP plus pressure support is more effective than simple CPAP in heart failure patients and that the enhancement might be induced by neural changes and not simply by alteration of the preload level.

Recombinant mitochondrial transcription factor A protein inhibits nuclear factor of activated T cells signaling and attenuates pathological hypertrophy of cardiac myocytes.

The overexpression of mitochondrial transcription factor A (TFAM) attenuates the decrease in mtDNA copy number after myocardial infarction, ameliorates pathological hypertrophy, and markedly improves survival. However, non-transgenic strategy to increase mtDNA for the treatment of pathological hypertrophy remains unknown. We produced recombinant human TFAM protein (rhTFAM). rhTFAM rapidly entered into mitochondria of cultured cardiac myocytes. rhTFAM increased mtDNA and abolished the activation of nuclear factor of activated T cells (NFAT), which is well known to activate pathological hypertrophy. rhTFAM attenuated subsequent morphological hypertrophy of myocytes as well. rhTFAM would be an attractive molecule in attenuating cardiac pathological hypertrophy.

Diagnostic performance of cardiac fusion images from myocardial perfusion imaging and multislice computed tomography coronary angiography for assessment of hemodynamically significant coronary artery lesions: an observational study.

BACKGROUND: In detecting coronary artery disease (CAD), fusion images obtained by combining myocardial perfusion imaging (MPI) and computed tomography coronary angiography (CTCA) have shown a higher accuracy and clinical usefulness than these modalities used separately or a simple comparison of individual images. However, the clinical use of fusion images has been restricted by the necessity of obtaining images with an integral type device or with devices made by the same manufacturer. Thus, we evaluated the detection of hemodynamically significant CAD by fusion images created with a newly developed general-purpose application that can be used with any type of device. METHODS AND RESULTS: In 49 patients, MPI during exercise and at rest and CTCA were obtained separately and combined into fusion images using the new application. As the reference standard, a comparative interpretation of MPI and the conventional coronary arteriography (CAG) was adopted. Hemodynamically significant CAD were diagnosed when MPI showed a reversible perfusion defect in a region with greater than 50% luminal stenosis on CAG. The capability of fusion images to detect CAD was compared with that of CTCA images alone. Fusion images showed a higher ability to detect CAD (sensitivity 80%, specificity 94%, positive predictive value 77%, and negative predictive value 95%) than CTCA alone (77, 77, 46, and 93%, respectively; fusion vs. CTCA: specificity P=0.0002, positive predictive value P=0.0001). CONCLUSION: Fusion images obtained with a general-purpose application were superior to CTCA images alone for detecting hemodynamically significant CAD.

Experience of step-wise protocol using noninvasive positive pressure ventilation for treating cardiogenic pulmonary edema.

Initiating and weaning procedure of noninvasive positive pressure ventilation (NIPPV) on acute cardiogenic pulmonary edema (ACPE) has been determined empirically, and the total time of its use has been sometimes prolonged unnecessarily. A simple protocol for its use may facilitate initiation and avoids prolongation of the NIPPV treatment. We designed a step-wise protocol for NIPPV use and retrospectively examined the clinical outcome of our protocol for initiation and weaning of NIPPV in 45 patients with ACPE. Almost all patients recovered from respiratory distress successfully. There was no intubation nor complication related to NIPPV. In most of the cases, maximal-end expiratory pressure was less than 7-cm H2O. The mean duration of NIPPV was 19.5±28.0 h and the median duration was 8.0 h (interquartile range=14.0 h). This simple step-wise NIPPV protocol for ACPE can facilitate quick and safe initiation and termination of the treatment.

Effects of the L/N-type calcium channel antagonist cilnidipine on morning blood pressure control and peripheral edema formation.

The L/N-type calcium channel blocker cilnidipine has unique effects including sympathetic nerve suppression and the balanced vasodilatation of arteries and veins that may alleviate morning hypertension (MHT) or peripheral edema caused by calcium channel antagonists. We used ambulatory blood pressure monitoring (ABPM) and a unique peripheral edema measurement to evaluate the effect of morning and bedtime cilnidipine in patients with MHT. Forty-three patients with MHT (60 ± 12 years) were randomly assigned to a morning or bedtime cilnidipine (10-20 mg/day). MHT was defined as a mean systolic blood pressure (SBP) ≥ 135 mm Hg by ABPM within 2 hours after awaking. After 3 months, greater SBP reductions were observed in the bedtime administration group (versus the morning administration group) at 3:30-6:00 AM (-24 ± 20 mm Hg vs. -10 ± 4 mm Hg; P < .05) and at 6:30-9:00 AM (-26 ± 15 mm Hg vs. -14 ± 17 mm Hg; P < .05). Although physical examinations showed leg edema in 16% of the patients, quantitative evaluations did not reveal significant volume gains. Cilnidipine had a greater effect on MHT, without causing significant leg edema, when administered at bedtime.

Instantaneous restoration of cardiac output by noninvasive positive pressure ventilation in a patient with obesity hypoventilation syndrome.

We report a 30-year-old man with severe obesity hypoventilation syndrome (OHVS) complicated by right-sided heart failure. Polysomnography revealed severe obstructive sleep apnea with apnea-hypopnea index (AHI) 70.4/h and gradual decrease in minimum oxygen saturation (SpO2) from 86% before sleep to 36% during sleep. Cardiac output (CO) was suppressed from 3.9 L/min before sleep to 2.5 L/min during sleep. Noninvasive positive pressure ventilation (NPPV) treatment drastically restored CO to the level before sleep, and improved AHI to 9.4/h and minimum SpO2 to 87%. NPPV may provide rapid and powerful symptom relief in patients with OHVS complicated with right sided heart failure.

Time-dependent changes of myocardial and systemic oxidative stress are dissociated after myocardial infarction.

Reactive oxygen species (ROS) is increased in myocardium after myocardial infarction (MI), which may play a causal role in cardiac remodelling. However, there is scant direct and longitudinal evidence that systemic oxidative stress is enhanced accompanying an increase of ROS in myocardium. The authors conducted a comprehensive investigation of ROS markers by simultaneously sampling urine, blood and myocardium and in vivo ESR for the heart at different stages of post-MI cardiac remodelling in mouse with permanent occlusion of left coronary artery. Systemic oxidative markers increased at early days after MI and were normalized later. In contrast, TBARS and 4-hexanoyl-Lys staining were increased in non-infarct myocardium at day 28. The enhancement of ESR signal decay of methoxycarbonyl-PROXYL measured at the chest was associated with the progression of left ventricle dilatation and dysfunction. This study provided the direct evidence that redox alteration and production of ROS occurred in myocardium during the progression of cardiac remodelling and failure; however, ROS marker levels in blood and urine do not reflect the production of ROS from failing myocardium.

Reverse of age-dependent memory impairment and mitochondrial DNA damage in microglia by an overexpression of human mitochondrial transcription factor a in mice.

Mitochondrial DNA (mtDNA) is highly susceptible to injury induced by reactive oxygen species (ROS). During aging, mutations of mtDNA accumulate to induce dysfunction of the respiratory chain, resulting in the enhanced ROS production. Therefore, age-dependent memory impairment may result from oxidative stress derived from the respiratory chain. Mitochondrial transcription factor A (TFAM) is now known to have roles not only in the replication of mtDNA but also its maintenance. We herein report that an overexpression of TFAM in HeLa cells significantly inhibited rotenone-induced mitochondrial ROS generation and the subsequent NF-kappaB (nuclear factor-kappaB) nuclear translocation. Furthermore, TFAM transgenic (TG) mice exhibited a prominent amelioration of an age-dependent accumulation of lipid peroxidation products and a decline in the activities of complexes I and IV in the brain. In the aged TG mice, deficits of the motor learning memory, the working memory, and the hippocampal long-term potentiation (LTP) were also significantly improved. The expression level of interleukin-1beta (IL-1beta) and mtDNA damages, which were predominantly found in microglia, significantly decreased in the aged TG mice. The IL-1beta amount markedly increased in the brain of the TG mice after treatment with lipopolysaccharide (LPS), whereas its mean amount was significantly lower than that of the LPS-treated aged wild-type mice. At the same time, an increased mtDNA damage in microglia and an impaired hippocampal LTP were also observed in the LPS-treated aged TG mice. Together, an overexpression of TFAM is therefore considered to ameliorate age-dependent impairment of the brain functions through the prevention of oxidative stress and mitochondrial dysfunctions in microglia.

Long-term outcomes of gastric mucosa-associated lymphoid tissue lymphomas after Helicobacter pylori eradication therapy.

Mucosa-associated lymphoid tissue (MALT) lymphomas are localized primarily in the gastrointestinal tract and are characterized by an indolent nature and favorable outcome with specific therapy. Gastric MALT lymphomas are closely linked to Helicobacter pylori (H. pylori) infection, for which eradication therapy is recognized as an effective primary treatment for the disease. However, there is little information about long-term outcomes after the therapy. In the present study, we elucidated the long-term outcomes of 74 patients (70 H. pylori-positive and 4 negative cases) followed up by endoscopy at least 12 months after exclusive eradication therapy alone. The median follow-up period was 46 months. When the remission status was estimated at the time point of 12 months post-eradication, the numbers of patients with complete remission (CR), histologically residual disease with macroscopic normalization (hRD), partial remission with more than 50% tumor reduction (PR) or no response (NR) were 56, 12, 2 and 4, respectively. During follow-ups of over 12 months post-eradication, 11 of the 12 hRD cases were belatedly induced to CR but one CR case histologically relapsed into hRD. One of the 2 PR cases eventually turned into hRD 20 months later. Therefore, 66 CR, 3 hRD, 1 PR, and 4 NR cases (including 3 H. pylori-negative) were identified at the last follow-up of the present study. All 74 patients were followed up without any second-line therapies, but none exhibited disease progression. Thus, the long-term outcome of localized gastric MALT lymphoma after H. pylori eradication therapy was favorable. A watch and wait strategy may be a reasonable approach for hRD since the majority might be in the process of turning into delayed CR.

Noninvasive transcutaneous bionic baroreflex system prevents severe orthostatic hypotension in patients with spinal cord injury.

Central baroreflex failure in patients with spinal cord injury results in serious orthostatic hypotension. We examined if transcutaneous electrical stimulation regulates arterial pressure in those patients. We identified skin regions capable of increasing arterial pressure and determined respective transfer function. Using the transfer function, we designed the feedback regulator (i.e., bionic baroreflex system) to control arterial pressure. Orthostatic stress decreased arterial pressure profoundly. Activation of bionic regulator restored and maintained arterial pressure at pre-specified levels. We conclude that the transcutaneous bionic system is noninvasive and capable of stabilizing arterial pressure in patients with spinal cord injury.

Fatty acids increase the circulating levels of oxidative stress factors in mice with diet-induced obesity via redox changes of albumin.

Plasma concentrations of free fatty acids are increased in metabolic syndrome, and the increased fatty acids may cause cellular damage via the induction of oxidative stress. The present study was designed to determine whether the increase in fatty acids can modify the free sulfhydryl group in position 34 of albumin (Cys34) and enhance the redox-cycling activity of the copper-albumin complex in high-fat diet-induced obese mice. The mice were fed with commercial normal diet or high-fat diet and water ad libitum for 3 months. The high-fat diet-fed mice developed obesity, hyperlipemia, and hyperglycemia. The plasma fatty acid/albumin ratio also significantly increased in high-fat diet-fed mice. The increased fatty acid/albumin ratio was associated with conformational changes in albumin and the oxidation of sulfhydryl groups. Moreover, an ascorbic acid radical, an index of redox-cycling activity of the copper-albumin complex, was detected only in the plasma from obese mice, whereas the plasma concentrations of ascorbic acid were not altered. Plasma thiobarbituric acid reactive substances were significantly increased in the high-fat diet group. These results indicate that the increased plasma fatty acids in the high-fat diet group resulted in the activated redox cycling of the copper-albumin complex and excessive lipid peroxidation.