A Multidisciplinary Approach to Hip Fractures: Evaluating Outcomes on Mortality and Secondary Hip Fractures.

Fracture liaison services (FLS) have been introduced in Japan and several other countries to reduce medical complications and secondary fractures. We aimed to evaluate the effects of the implementation of an FLS approach on patient outcomes during hospitalization at our hospital and over a 2-year follow-up post-injury. This retrospective cohort study included patients ≥ 60 years admitted to our hospital for hip fragility fractures between October 1, 2016, and July 31, 2020. Patient groups were defined as those treated before (control group, n=238) and after (FLS group, n=196) establishment of the FLS protocol at our institution. The two groups were compared in terms of time to surgery, length of hospital stay, and the incidence of complications after admission, including secondary hip fracture and mortality rates. The follow-up period was 24 months. FLS focuses on early surgery within 48 h of injury and assessing osteoporosis treatment before injury to guide post-discharge anti-osteoporosis medication. FLS reduced the length of hospital stay (p<0.001) and the prevalence of complications after admission (p<0.001), particularly cardiovascular disease, and it increased adherence to anti-osteoporosis medication. These FLS effects resulted in lower secondary hip fracture and mortality rates at 12 and 24 months post-injury. FLS for fragility hip fractures can improve patient outcomes during hospitalization and over a 2-year follow-up period.

Explosive sound without external stimuli following electroencephalography kappa rhythm fluctuation: A case report.

BACKGROUND: The pathology underlying exploding head syndrome, a parasomnia causing a loud sound/sense of explosion, is not well understood. Kappa rhythm is a type of electroencephalogram alpha band activity with maximum potential between contralateral temporal electrodes We report a case of preceding kappa activity before exploding head syndrome attacks. CASE REPORT: A 57-year-old woman complained of explosive sounds for 2 months; a loud sound would transpire every day before sleep onset. She was diagnosed with exploding head syndrome. During polysomnography and the multiple sleep latency test, the exploding head syndrome attacks occurred six times. A kappa wave with activity disappearing a few seconds before most exploding head syndrome attacks was observed. The alpha band power in T3-T4 derivation gradually waxed followed by termination around the attacks. CONCLUSION: This case demonstrated that the dynamics of kappa activity precede exploding head syndrome attacks. Finding ways to modulate electroencephalogram oscillation could elucidate their causality and lead to therapeutic intervention.

Treatment of an Intractable Forefoot Ulcer Using Realignment Osteotomy in a Patient with Rheumatoid Arthritis.

Forefoot deformities are common among patients with rheumatoid arthritis (RA). Herein, we describe a case of intractable ulceration on the dorsomedial aspect of the right 5th digit, secondary to forefoot deformity, in a 76-year-old woman with a 35-year history of RA. The ulcer was due to a persistent subcutaneous infection. Although the infection was controllable with antibiotics, there was concern of relapse because of the abnormal pressure on the skin due to an overlap of the 4th and 5th digits. We proceeded with surgical correction of the forefoot alignment, including shortening oblique osteotomy of metatarsals 2 through 5, rather than amputation of the 5th digit. Following surgery, targeted antibiotic treatment was provided. The postoperative course was unremarkable, and the patient recovered weight-bearing function without recurrence of pain or ulceration. Forefoot realignment is a feasible option that should be considered for treating intractable foot pain and ulceration secondary to long-lasting RA.

Hepatitis C virus relapse after successful treatment with direct-acting antivirals, followed by sarcomatous changes in hepatocellular carcinoma: a case report.

BACKGROUND: Combination therapy of interferon and ribavirin has traditionally been used to eradicate hepatitis C virus. The sustained virologic response achieved with interferon-related therapy is persistent, and late relapses after achieving sustained virologic response at 24 weeks using this therapy are reportedly rare (< 1%). In 2014, interferon-free therapy with direct-acting antivirals was developed, and the rate of sustained virologic response was improved. However, the persistence thereof remains uncertain, and the appropriate follow-up period for hepatitis C virus-positive patients is under discussion. CASE PRESENTATION: A 74-year-old Japanese man who had hepatitis C virus-related hepatocellular carcinoma and was successfully treated with radiofrequency ablation four times underwent direct-acting antiviral therapy with daclatasvir and asunaprevir; sustained virologic response at 24 weeks was confirmed. However, although he had no high risk factors for reinfection, hepatitis C virus ribonucleic acid was detected again 6 months after achieving sustained virologic response at 24 weeks. Moreover, he developed active hepatitis with an increased viral load. Five months after development of hepatitis, recurrent hepatocellular carcinoma emerged in segment II, where we had performed radiofrequency ablation 17 months previously. The recurrent hepatocellular carcinoma enlarged quite rapidly and induced multiple peritoneal disseminations and lung metastases. He died 3 months after the abrupt recurrence. A sarcomatous change in the hepatocellular carcinoma was identified during the autopsy. CONCLUSIONS: Although sustained virologic response at 24 weeks has generally been regarded to denote complete eradication of hepatitis C virus, we present a patient in whom hepatitis C virus recurred 6 months after achieving sustained virologic response at 24 weeks with direct-acting antiviral therapy. In addition, a sarcomatous change in hepatocellular carcinoma emerged 5 months after active hepatitis developed due to late hepatitis C virus relapse in this case. The sarcomatous change in hepatocellular carcinoma is generally thought to be related to anticancer therapies, such as radiofrequency ablation. However, in this case, late viral relapse and active hepatitis in addition to the previous radiofrequency ablation could have been the trigger. There may be a need for follow-up of hepatitis C virus ribonucleic acid beyond sustained virologic response at 24 weeks with direct-acting antiviral therapy, owing to the possibility of late viral relapse and tumorigenesis.

Paraneoplastic dermatomyositis appearing after nivolumab therapy for gastric cancer: a case report.

BACKGROUND: While dermatomyositis is often associated with malignancy, several autoimmune diseases like myositis can be caused by immune checkpoint inhibitors. Differentially diagnosing malignancy-associated dermatomyositis or myositis caused by immune checkpoint inhibitors is sometimes difficult, particularly when a patient with malignancy shows the symptoms of myositis after checkpoint inhibitor administration. We experienced such a case in which we had difficulties in diagnosing paraneoplastic dermatomyositis or drug-associated myositis. In this case, all of our team initially assumed that the diagnosis was myositis caused by immune checkpoint inhibitors. However, it turned out finally that the diagnosis was paraneoplastic dermatomyositis. Because the diagnosis was unexpected, we report here. CASE PRESENTATION: We report the case of a 71-year-old Japanese man who developed clinical symptoms of myositis, such as muscle aches and weakness, after initiation of nivolumab therapy for his gastric cancer. He was initially diagnosed with nivolumab-induced myositis, because the myositis symptoms appeared after nivolumab administration, and nivolumab is known to trigger various drug-associated autoimmune diseases. However, according to his characteristic skin lesions, the type of muscle weakness, his serum marker profiles, electromyography of his deltoid muscle, and magnetic resonance imaging, he was finally diagnosed as having paraneoplastic dermatomyositis. Accordingly, treatment with intravenously administered corticosteroid pulse treatment, immunoglobulin injection, and tacrolimus was applied; his symptoms subsequently improved. However, to our regret, at day 142 after administration, he died due to rapid worsening of his gastric cancer. CONCLUSION: Differentially diagnosing paraneoplastic dermatomyositis or drug-associated myositis caused by immune checkpoint inhibitors is difficult in some cases. The differential diagnosis is crucial because it influences the decision regarding the appropriateness of the use of immunosuppressive treatment against the autoimmune diseases as well as the decision regarding the appropriateness of the continuous use of immune checkpoint inhibitors against the primary cancers. Because subclinical autoimmune disease may become overt after administering immune checkpoint inhibitors, non-apparent autoimmune diseases, which have already existed, should also be considered to avoid the delay of appropriate treatment, when symptoms of autoimmune diseases are recognized.

A polymorphism in CCR1/CCR3 is associated with narcolepsy.

Etiology of narcolepsy-cataplexy involves multiple genetic and environmental factors. While the human leukocyte antigen (HLA)-DRB1*15:01-DQB1*06:02 haplotype is strongly associated with narcolepsy, it is not sufficient for disease development. To identify additional, non-HLA susceptibility genes, we conducted a genome-wide association study (GWAS) using Japanese samples. An initial sample set comprising 409 cases and 1562 controls was used for the GWAS of 525,196 single nucleotide polymorphisms (SNPs) located outside the HLA region. An independent sample set comprising 240 cases and 869 controls was then genotyped at 37 SNPs identified in the GWAS. We found that narcolepsy was associated with a SNP in the promoter region of chemokine (C-C motif) receptor 1 (CCR1) (rs3181077, P=1.6×10(-5), odds ratio [OR]=1.86). This rs3181077 association was replicated with the independent sample set (P=0.032, OR=1.36). We measured mRNA levels of candidate genes in peripheral blood samples of 38 cases and 37 controls. CCR1 and CCR3 mRNA levels were significantly lower in patients than in healthy controls, and CCR1 mRNA levels were associated with rs3181077 genotypes. In vitro chemotaxis assays were also performed to measure monocyte migration. We observed that monocytes from carriers of the rs3181077 risk allele had lower migration indices with a CCR1 ligand. CCR1 and CCR3 are newly discovered susceptibility genes for narcolepsy. These results highlight the potential role of CCR genes in narcolepsy and support the hypothesis that patients with narcolepsy have impaired immune function.

New susceptibility variants to narcolepsy identified in HLA class II region.

Narcolepsy, a sleep disorder characterized by excessive daytime sleepiness, cataplexy and rapid eye movement sleep abnormalities, is tightly associated with human leukocyte antigen HLA-DQB1*06:02. DQB1*06:02 is common in the general population (10-30%); therefore, additional genetic factors are needed for the development of narcolepsy. In the present study, HLA-DQB1 in 664 Japanese narcoleptic subjects and 3131 Japanese control subjects was examined to determine whether HLA-DQB1 alleles located in trans of DQB1*06:02 are associated with narcolepsy. The strongest association was with DQB1*06:01 (P = 1.4 × 10(-10), odds ratio, OR = 0.39), as reported in previous studies. Additional predisposing effects of DQB1*03:02 were also found (P = 2.5 × 10(-9), OR = 1.97). A comparison between DQB1*06:02 heterozygous cases and controls revealed dominant protective effects of DQB1*06:01 and DQB1*05:01. In addition, a single-nucleotide polymorphism-based conditional analysis controlling for the effect of HLA-DQB1 was performed to determine whether there were other independent HLA associations outside of HLA-DQB1. This analysis revealed associations at HLA-DPB1 in the HLA class II region (rs3117242, P = 4.1 × 10(-5), OR = 2.45; DPB1*05:01, P = 8.1 × 10(-3), OR = 1.39). These results indicate that complex HLA class II associations contribute to the genetic predisposition to narcolepsy.

[Diagnosis and treatment in circadian rhythm sleep disorders].

Circadian rhythm sleep disorders (CRSD) are characterized by misalignment between major sleep episode and desired sleep phase, or symptoms associated with internal desynchronization between endogenous circadian rhythm and overt sleep-wake rhythm. Endogenous circadian rhythm is mainly regulated by master circadian clock located in the suprachiasmatic nucleus. Light entrains the circadian clock according to a phase-response curve. Furthermore, social time cue affects human sleep-wake rhythm. Instructions concerning sleep hygiene including light environment play fundamental role for the treatment in CRSD. In addition, light therapy and oral melatonin administration have application to delayed sleep phase type. Diagnostic classification and treatment in each types of CRSD are reviewed in this article.

A before and after comparison of the effects of forest walking on the sleep of a community-based sample of people with sleep complaints.

BACKGROUND: Sleep disturbance is a major health issue in Japan. This before-after study aimed to evaluate the immediate effects of forest walking in a community-based population with sleep complaints. METHODS: Participants were 71 healthy volunteers (43 men and 28 women). Two-hour forest-walking sessions were conducted on 8 different weekend days from September through December 2005. Sleep conditions were compared between the nights before and after walking in a forest by self-administered questionnaire and actigraphy data. RESULTS: Two hours of forest walking improved sleep characteristics; impacting actual sleep time, immobile minutes, self-rated depth of sleep, and sleep quality. Mean actual sleep time estimated by actigraphy on the night after forest walking was 419.8 ± 128.7 (S.D.) minutes whereas that the night before was 365.9 ± 89.4 minutes (n = 42). Forest walking in the afternoon improved actual sleep time and immobile minutes compared with forest walking in the forenoon. Mean actual sleep times did not increase after forenoon walks (n = 26) (the night before and after forenoon walks, 380.0 ± 99.6 and 385.6 ± 101.7 minutes, respectively), whereas afternoon walks (n = 16) increased mean actual sleep times from 342.9 ± 66.2 to 475.4 ± 150.5 minutes. The trend of mean immobile minutes was similar to the abovementioned trend of mean actual sleep times. CONCLUSIONS: Forest walking improved nocturnal sleep conditions for individuals with sleep complaints, possibly as a result of exercise and emotional improvement. Furthermore, extension of sleep duration was greater after an afternoon walk compared to a forenoon walk. Further study of a forest-walking program in a randomized controlled trial is warranted to clarify its effect on people with insomnia.

Chronic electrical stimulation of the carotid sinus baroreflex improves left ventricular function and promotes reversal of ventricular remodeling in dogs with advanced heart failure.

BACKGROUND: Autonomic abnormalities exist in heart failure and contribute to disease progression. Activation of the carotid sinus baroreflex (CSB) has been shown to reduce sympathetic outflow and augment parasympathetic vagal tone. This study tested the hypothesis that long-term electric activation of the CSB improves left ventricular (LV) function and attenuates progressive LV remodeling in dogs with advanced chronic heart failure. METHODS AND RESULTS: Studies were performed in 14 dogs with coronary microembolization-induced heart failure (LV ejection fraction ≈25%). Eight dogs were chronically instrumented for bilateral CSB activation using the Rheos System (CVRx Inc, Minneapolis, Minn) and 6 were not and served as controls. All dogs were followed for 3 months, and none received other background therapy. During follow-up, treatment with CSB increased LV ejection fraction 4.0±2.4% compared with a reduction in control dogs of −2.8±1.0% (P<0.05). Similarly, treatment with CSB decreased LV end-systolic volume -2.5±2.7 mL compared with an increase in control dogs of 6.7±2.9 mL (P<0.05). Compared with control, CSB activation significantly decreased LV end-diastolic pressure and circulating plasma norepinephrine, normalized expression of cardiac ß(1)-adrenergic receptors, ß-adrenergic receptor kinase, and nitric oxide synthase and reduced interstitial fibrosis and cardiomyocyte hypertrophy. CONCLUSIONS: In dogs with advanced heart failure, CSB activation improves global LV function and partially reverses LV remodeling both globally and at cellular and molecular levels.

Sleep, mental health status, and medical errors among hospital nurses in Japan.

Medical error involving nurses is a critical issue since nurses' actions will have a direct and often significant effect on the prognosis of their patients. To investigate the significance of nurse health in Japan and its potential impact on patient services, a questionnaire-based survey amongst nurses working in hospitals was conducted, with the specific purpose of examining the relationship between shift work, mental health and self-reported medical errors. Multivariate analysis revealed significant associations between the shift work system, General Health Questionnaire (GHQ) scores and nurse errors: the odds ratios for shift system and GHQ were 2.1 and 1.1, respectively. It was confirmed that both sleep and mental health status among hospital nurses were relatively poor, and that shift work and poor mental health were significant factors contributing to medical errors.

Abnormal regional left ventricular systolic and diastolic function in patients with coronary artery disease undergoing percutaneous coronary intervention: clinical significance of post-ischemic diastolic stunning.

OBJECTIVES: This study was designed to characterize both regional left ventricular (LV) systolic and diastolic function after percutaneous coronary intervention by using strain imaging (SI) derived from 2-dimensional speckle-tracking echocardiography. BACKGROUND: Ischemic insult after coronary occlusion affects not only regional LV systolic but also diastolic function. METHODS: Regional LV transverse peak strain and strain changes during the first one-third of diastole duration (strain imaging diastolic index [SI-DI]) were monitored in at-risk segments after percutaneous coronary intervention in 30 patients with coronary artery disease. The segments were divided into proximal and distal. Strain data in the at-risk segments were compared with values derived from remote nonischemic segments. RESULTS: Coronary occlusion induced a marked reduction in the systolic strain in both proximal and distal at-risk segments (from 36.9 +/- 6.0% to 12.0 +/- 3.9% and from 31.9 +/- 5.6% to 6.2 +/- 3.3%, respectively, p < 0.0001). Concomitantly, SI-DI values decreased (from 76.6 +/- 5.3% to -21.2 +/- 9.1% and from 72.5 +/- 5.9% to -48.7 +/- 20.8%, respectively, p < 0.0001). Upon reperfusion, systolic deformation parameters returned to near-normal pre-occlusion values. However, SI-DI values in the both proximal and distal at-risk segments decreased (43.2 +/- 9.5%, p < 0.01, and -17.3 +/- 11.1%, p < 0.0001, respectively) 30 min after reperfusion and were still lower (51.5 +/- 9.9%, p < 0.01) in the distal at-risk segment 24 h after reperfusion. CONCLUSIONS: SI analysis provides detailed mechanical characterization of regions with myocardial ischemic insult and can demonstrate post-ischemic diastolic stunning despite complete systolic functional recovery after reperfusion.

Exercise-induced post-ischemic left ventricular delayed relaxation or diastolic stunning: is it a reliable marker in detecting coronary artery disease?

OBJECTIVES: The aim of this study was to determine whether post-ischemic left ventricular (LV) delayed relaxation could be detected by using strain imaging (SI) derived from 2-dimensional speckle-tracking echocardiography in patients with stable effort angina. BACKGROUND: Regional LV delayed relaxation during early diastole is a sensitive sign of acute myocardial ischemia and may persist beyond recovery of exercise-induced ischemia. METHODS: Regional LV transverse strain changes during the first one-third of diastole duration (strain imaging diastolic index [SI-DI]) were determined at baseline and 5 and 10 min after the exercise test in 162 patients with stable effort angina. The ratio of SI-DI before and after exercise (SI-DI ratio) was used to identify regional LV delayed relaxation. RESULTS: A total of 117 patients had significant (> or =50% of luminal diameter) coronary stenoses. The mean SI-DI decreased from 78.0 +/- 9.7% to 27.6 +/- 16.0% (p < 0.0001) in 191 territories perfused by coronary arteries with significant stenoses 5 min after the treadmill exercise, whereas it remained unchanged in 280 territories perfused by arteries with nonsignificant stenoses. Ten minutes after exercise, regional delayed relaxation was still observed in 85% of territories perfused by stenotic coronary arteries. An SI-DI ratio with a cutoff value of 0.74 had a sensitivity of 97% and a specificity of 93% to detect significant coronary stenosis in the receiver-operator characteristic curve. CONCLUSIONS: Detection of post-ischemic regional LV delayed relaxation or diastolic stunning after treadmill exercise using SI is a sensitive and reliable method for the detection of coronary artery disease.

Darbepoetin-alpha prevents progressive left ventricular dysfunction and remodeling in nonanemic dogs with heart failure.

In anemic patients with heart failure (HF), erythropoietin-type drugs can elicit clinical improvement. This study examined the effects of chronic monotherapy with darbepoetin-alpha (DARB) on left ventricular (LV) function and remodeling in nonanemic dogs with advanced HF. HF [LV ejection fraction (EF) approximately 25%] was produced in 14 dogs by intracoronary microembolizations. Dogs were randomized to once a week subcutaneous injection of DARB (1.0 microg/kg, n=7) or to no therapy (HF, n=7). All procedures were performed during cardiac catheterization under general anesthesia and under sterile conditions. LV end-diastolic volume (EDV), end-systolic volume (ESV), and EF were measured before the initiation of therapy and at the end of 3 mo of therapy. mRNA and protein expression of caspase-3, hypoxia inducible factor-1alpha, and the bone marrow-derived stem cell marker c-Kit were determined in LV tissue. In HF dogs, EDV and ESV increased and EF decreased after 3 mo of followup. Treatment with DARB prevented the increase in EDV, decreased ESV, and increased EF. DARB therapy also normalized the expression of HIF-1alpha and active caspase-3 and enhanced the expression of c-Kit. We conclude that chronic monotherapy with DARB prevents progressive LV dysfunction and dilation in nonanemic dogs with advanced HF. These results suggest that DARB elicits beneficial effects in HF that are independent of the presence of anemia.

Interhemispheric EEG asymmetries during unilateral bright-light exposure and subsequent sleep in humans.

We tested whether evening exposure to unilateral photic stimulation has repercussions on interhemispheric EEG asymmetries during wakefulness and later sleep. Because light exerts an alerting response in humans, which correlates with a decrease in waking EEG theta/alpha-activity and a reduction in sleep EEG delta activity, we hypothesized that EEG activity in these frequency bands show interhemispheric asymmetries after unilateral bright light (1,500 lux) exposure. A 2-h hemi-field light exposure acutely suppressed occipital EEG alpha activity in the ipsilateral hemisphere activated by light. Subjects felt more alert during bright light than dim light, an effect that was significantly more pronounced during activation of the right than the left visual cortex. During subsequent sleep, occipital EEG activity in the delta and theta range was significantly reduced after activation of the right visual cortex but not after stimulation of the left visual cortex. Furthermore, hemivisual field light exposure was able to shift the left predominance in occipital spindle EEG activity toward the stimulated hemisphere. Time course analysis revealed that this spindle shift remained significant during the first two sleep cycles. Our results reflect rather a hemispheric asymmetry in the alerting action of light than a use-dependent recovery function of sleep in response to the visual stimulation during prior waking. However, the observed shift in the spindle hemispheric dominance in the occipital cortex may still represent subtle local use-dependent recovery functions during sleep in a frequency range different from the delta range.

Detection of postischemic regional left ventricular delayed outward wall motion or diastolic stunning after exercise-induced ischemia in patients with stable effort angina by using color kinesis.

To determine whether postischemic diastolic stunning could be detected using color kinesis, we evaluated regional left ventricular (LV) diastolic wall motion in 36 patients with stable effort angina and a coronary stenosis (> or = 70% of luminal diameter), and in 30 control subjects. Regional LV filling fraction in the short-axis view during the first 30% of the LV filling time (color kinesis diastolic index) was determined before, 20 minutes, 1 hour, and 24 hours after the treadmill exercise test. In 33 of the 36 patients (92%), new regional LV delayed outward motion during early diastole (color kinesis diastolic index < or = 40%) was detected at 20 minutes after exercise. The regional LV delayed diastolic wall motion showed significant improvement but persisted 1 hour afterward in 20 of 36 patients (56%), and disappeared 24 hours after exercise. Detection of regional stunned myocardium with impaired diastolic function may be a useful tool for the diagnosis of coronary artery disease.

Chronic monotherapy with rosuvastatin prevents progressive left ventricular dysfunction and remodeling in dogs with heart failure.

OBJECTIVES: This study examined the effects of long-term monotherapy with rosuvastatin (RSV) on the progression of left ventricular (LV) dysfunction and remodeling in dogs with heart failure (HF). BACKGROUND: 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors or "statins" possess other noncholesterol-lowering properties that include inhibiting proinflammatory cytokines, attenuating LV hypertrophy, and stimulating the release of bone marrow-derived stem cells (BMSCs). METHODS: Twenty-one dogs with microembolization-induced HF were randomized to 3 months oral monotherapy with low-dose (LD) RSV (0.5 mg/kg once daily, n = 7), high-dose (HD) RSV (3.0 mg/kg once daily, n = 7), or to no therapy (control group, n = 7). The change (Delta) from pre- to post-therapy (treatment effect) in LV end-diastolic volume (EDV) and end-systolic volume (ESV) and ejection fraction (EF) was measured. Protein level of tumor necrosis factor (TNF)-alpha in LV tissue and the number of circulating Sca-1-positive BMSCs was also determined. Blood and LV tissue from 6 normal dogs was obtained and used for comparison. RESULTS: There were no differences in DeltaEDV, DeltaESV, and DeltaEF between control group and LD RSV. In contrast, DeltaEDV and DeltaESV were significantly lower, and DeltaEF was significantly higher in HD RSV compared with control group. High-dose, but not LD, RSV also normalized protein levels of TNF-alpha and was associated with a significant increase in the number of circulating BMSCs. CONCLUSIONS: In dogs with HF, chronic therapy with HD RSV prevents progressive LV dysfunction and dilation. This benefit may be partly derived from normalization of TNF-alpha expression and partly from increased mobilization of BMSCs.

Therapy with cardiac contractility modulation electrical signals improves left ventricular function and remodeling in dogs with chronic heart failure.

OBJECTIVES: This study examined the effects of long-term delivery of cardiac contractility modulation (CCM) electric signals on left ventricular (LV) function and global, cellular, and molecular remodeling in dogs with chronic heart failure (HF). BACKGROUND: Acute studies in dogs with experimentally induced HF showed that CCM signals applied to the failing myocardium during the absolute refractory period improved LV function without increasing myocardial oxygen consumption. METHODS: In one study, dogs with intracoronary microembolization-induced HF were randomized to 3 months of active CCM monotherapy or to a sham-operated control group. In another study, 19 HF dogs were randomized to 3 months chronic monotherapy with extended release metoprolol succinate (MET-ER), MET-ER with CCM, or no therapy at all (control group). RESULTS: In CCM-only treated dogs, LV ejection fraction (EF) increased (27 +/- 1% vs. 33 +/- 1%, p < 0.0001) compared with a decrease in sham-operated control animals (27 +/- 1% vs. 23 +/- 1%, p < 0.001). The increase in EF seen with CCM-treated dogs was accompanied by reduced LV volumes, improved myocardial structure, reversal of the maladaptive fetal gene program, and an improvement in sarcoplasmic reticulum calcium cycling proteins. Dogs treated with a combination of MET-ER and CCM showed a greater increase in LV EF and a greater reversal of LV global, structural, and biochemical remodeling compared with dogs treated with MET-ER alone. CONCLUSIONS: In dogs with HF, long-term CCM therapy improves LV systolic function. The improvements are additive to those seen with beta-blockers. These findings are further strengthened by the concomitant benefits of CCM therapy on LV global, cellular, and biochemical remodeling.

Left atrial reverse remodeling in dogs with moderate and advanced heart failure treated with a passive mechanical containment device: an echocardiographic study.

BACKGROUND: Assessment of global left ventricular (LV) remodeling is important in evaluating the efficacy of pharmacologic and device therapies for the treatment of chronic heart failure (HF). The effects of pharmacologic or device therapies on global left atrial (LA) remodeling in HF, although also important, are not often examined. We showed that long-term therapy with the Acorn Cardiac Support Device (CSD), a passive mechanical ventricular containment device, prevents or reverses LV remodeling in dogs with HF. This study examined the effects of the CSD on global LA remodeling in dogs with moderate and advanced HF. METHODS AND RESULTS: Studies were performed in 24 dogs with coronary microembolization-induced HF. Of these, 12 had moderate HF (ejection fraction, EF 30% to 40%) and 12 advanced HF (EF < or = 25%). In each group, the CSD was implanted in 6 dogs and the other 6 served as controls. Dogs were followed for 3 months in the moderate group and 6 months in the advanced HF group. LA maximal volume (LAVmax), LA volume at the onset of the p-wave (LAVp), LA minimal volume (LAVmin), LA active emptying volume (LAAEV), and LA active emptying fraction (LAAEF) were measured from 2-dimensional echocardiograms obtained before CSD implantation and at the end of the treatment period. Treatment effect (delta) comparisons between CSD-treated dogs and controls showed that CSD therapy significantly decreased LA volumes (deltaLAVmax: 3.33 +/- 0.70 vs. -2.87 +/- 1.31 mL, P = .002; 7.77 +/- 1.76 versus -0.37 +/- 0.87 mL, P = .002) and improved LA function (deltaLAAEF: -6.00 +/- 1.53 versus 1.85 +/- 1.32%, P = .003; -2.39 +/- 1.10 versus 3.13 +/- 1.66%, P = .02) in the moderate HF and advanced HF groups, respectively. CONCLUSIONS: Progressive LA enlargement and LA functional deterioration occurs in untreated dogs with HF. Monotherapy with the CSD prevents LA enlargement and improves LA mechanical function in dogs with moderate and advanced HF indicating prevention or reversal of adverse LA remodeling.

Hemodynamic properties of a new-generation positive luso-inotropic agent for the acute treatment of advanced heart failure.

Currently available positive inotropic agents, such as dobutamine and milrinone, although needed as "rescue therapy" for patients with acute decompensated heart failure (ADHF), are not ideal drugs because of an inherent adverse side-effect profile. This study examined the hemodynamic effects of istaroxime, a novel agent with positive inotropic and lusitropic (luso-intropic) effects, under investigation for the treatment of ADHF. Studies were performed in 7 dogs with advanced heart failure (HF). Each dog received intravenous istaroxime or saline solution in random order 1 week apart in equal volume/volume escalating doses, with each dose maintained for 1 hour. Escalating istaroxime doses of 0.5, 1.0, 2.0, 3.0, and 5.0 microg/kg per min were used. Hemodynamic, ventriculographic, and 2-dimensional echocardiographic and Doppler indices of left ventricular (LV) systolic and diastolic function were made at baseline and at the end of each hour of each dose of istaroxime or saline solution used. Electrocardiographic results were monitored throughout the study for development of de novo arrhythmias. Results showed that saline solution had no effect on any hemodynamic, ventriculographic, echocardiographic, or Doppler indices of LV function. Compared with baseline, istaroxime had no effect on heart rate, with only a modest reduction of mean aortic pressure at high doses. Istaroxime decreased LV end-diastolic and end-systolic volumes and significantly increased LV ejection fraction in a dose-dependent manner from 0.25+/-0.01 to 0.42+/-0.02 at the highest dose (p<0.05), without increasing myocardial oxygen consumption (194+/-21 micromol/min at baseline to 144+/-20 micromol/min at the highest dose, p<0.05). In addition, istaroxime significantly reduced LV end-diastolic pressure and end-diastolic wall stress and increased deceleration time of early mitral inflow velocity. None of the doses administered were associated with the development of de novo arrhythmias. In dogs with advanced HF, istaroxime elicits potent positive luso-intropic effects. Unlike classic cyclic adenosine monophospate-dependent positive inotropic agents, istaroxime elicits its benefits without increasing myocardial oxygen consumption or heart rate. These results suggest that istaroxime may be a unique positive luso-inotropic agent for the treatment of patients with ADHF.