Congestive Heart Failure Conditions Research Articles

Association of Life’s essential 8 score with the risk of all-cause mortality and cardio-cerebrovascular mortality in patients with stroke

BackgroundA higher Life's Essential 8 (LE8)-based cardiovascular health (CVH) has been reported to be associated with a lower risk of both all-cause mortality and cardio-cerebrovascular diseases (CCVDs) related mortality in adults in the United States. At the same time, multiple studies have shown a significant negative association of CVH with the risk of stroke and CCVDs. Since no research has investigated the applicability of the LE8 in stroke patients, this study aimed to explore the association of LE8 with all-cause mortality and cardio-cerebrovascular mortality in stroke patients.MethodsData of patients were extracted from the National Health and Nutrition Examination Surveys (NHANES) database in 2007–2018 in this retrospective cohort study. Weighted univariate and multivariate COX regression analyses were utilized to investigate the associations of LE8 with all-cause mortality and cardio-cerebrovascular mortality. We further explored these relationships in subgroups of age, gender, body mass index (BMI), cancer, congestive heart failure (CHF), and coronary heart disease (CHD). The evaluation indexes were hazard ratios (HRs) and 95% confidence intervals (CIs).ResultsAmong the eligible patients, 278 died from all-cause and 89 (8.38%) of them died due to CCVDs. After adjusting for covariates, patients with LE8 score ≥ 58.75 seemed to have both lower risk of all-cause mortality (HR = 0.46, 95%CI: 0.31–0.69) and cardio-cerebrovascular mortality (HR = 0.51, 95%CI: 0.26–0.98), comparing to those with LE8 score < 48.123. Higher LE8 scores were associated with lower risk of all-cause mortality in patients aged < 65 years old, without cancer, and whatever the gender, BMI, CHF or CHD conditions (all P < 0.05). The relationships between high LE8 scores and low cardio-cerebrovascular mortality risk were only found in age < 65 years old and non-cancer subgroups (all P < 0.05).ConclusionA higher LE8 score was associated with lower risk of both all-cause mortality and cardio-cerebrovascular mortality in patients with stroke, which may provide some reference for risk management and prognosis improvement in stoke. However, more evidences are needed to verify this beneficial role of high LE8 score in stroke prognosis.

Abstract 18465: Regulation of Collagen Synthesis and Fibrosis Development in Skeletal Muscle by La-Related Protein 6 (LaRP6)

Introduction: Excessive extracellular matrix (ECM) accumulation, especially collagens, impairs muscle function in muscular dystrophies, aging and muscle trauma (fibrosis). We have found increased skeletal muscle fibrosis in congestive heart failure (CHF) conditions, likely contributing to the impaired muscle functions. Hypothesis: We hypothesized that LARP6 (La Ribonucleoprotein Domain Family Member 6), an mRNA binding protein that coordinates efficient translation of Collagen I α chains, regulates collagen synthesis during skeletal muscle fibrosis in CHF conditions. Approach: Skeletal muscle fibrosis was analyzed in two mouse models, angiotensin II (Ang II) infusion and left anterior descending artery (LAD) ligation. Expression and subcellular localization of Collagen I, Larp6 and myogenic markers (myogenin and Myh3) were analyzed by qRT-PCR, western blotting, in situ hybridization (RNAScope) and immunostaining in hindlimb muscles in vivo and primary myoblasts and fibro/adipogenic progenitor (FAP) cells in vitro . Collagen I levels were also analyzed by picrosirius red staining (PSR). These analyses were performed in a newly-generated Larp6 knockout (Larp6 -/- ) mice. Results: In both Ang II and LAD ligation models, Collagen I mRNA and protein levels were increased together with LARP6, suggesting that LARP6 may regulate Collagen I synthesis in these conditions. In cultured myoblasts and FAPs, LARP6 protein was co-localized with Col1a1 mRNA at endoplasmic reticulum (ER). TGF-β treatment increased the LARP6 and Col1a1 mRNA co-localization, associated with increased pro-collagen I protein levels. Although Larp6 deficiency did not alter basal Collagen I levels, Collagen I induction in fibrotic conditions was decreased in Larp6 -/- mice. We found that thick collagen fibers were more significantly decreased compared to intermediate or loosely-packed thin collagen fibers (PSR signal analysis under the polarized microscope). Conclusions: These data suggest that LARP6 regulates Collagen I protein synthesis and its filament assembly likely in ER by binding to Col1a1 mRNA upon fibrosis induction. Suppression of LARP6 may be a therapeutic strategy to prevent pathophysiological fibrosis development in skeletal muscle.

Abstract 18748: Prevention of Skeletal Muscle Atrophy and Fibrosis in Congestive Heart Failure by Skeletal Myoblast-Targeted Overexpression of Angiotensin II Type 2 Receptor

Introduction: We have previously shown that angiotensin II (Ang II) type 2 receptor (AT2R) positively regulates skeletal myoblast differentiation. Systemic angiotensin II (Ang II) increase or congestive heart failure suppress AT2R expression, likely contributing to the development of skeletal muscle atrophy and fibrosis associated with these conditions. Hypothesis: We hypothesized that AT2R overexpression in skeletal myoblasts could prevent skeletal muscle atrophy and fibrosis associated with congestive heart failure (CHF). Approach: Two mouse models, systemic Ang II infusion and left anterior descending coronary artery (LAD) ligation were used in this study. Myoblast differentiation, muscle atrophy and muscle fibrosis were assessed by analyzing gene expressions (e.g. myogenin and atrogin-1), myofiber cross sectional area, and the collagen deposition (picrosirius red staining). Primary myoblasts were isolated from mouse hindlimb muscles. Myoblast-specific AT2R-overexpressing transgenic mice were generated by crossing Pax7 CreER/+ mice (tamoxifen-inducible cre recombinase is expressed under Pax7 promoter) and CAG-stop flox -AT2R mice (AT2R is expressed under CMV early enhancer element, chicken β-actin gene promoter upon cre-mediated excision of floxed stop codon). Results: AT2R expression was robustly increased during myoblast differentiation both in vitro and in vivo . siRNA-mediated AT2R knockdown significantly suppressed myoblast differentiation in vitro and skeletal muscle regeneration in vivo . In both Ang II infusion and LAD ligation models, AT2R induction during myoblast differentiation was significantly suppressed, associated with reduced muscle regeneration and increased atrophy and fibrosis. Myoblast-specific AT2R overexpression in vivo restored muscle regenerative capacity, and prevented muscle atrophy and fibrosis. Conclusions: AT2R induction in skeletal myoblast is suppressed in CHF, possibly via increased Ang II. Decreased AT2R expression and its downstream signaling in myoblast lead to lowered muscle regenerative capacity and increased muscle atrophy and fibrosis. Restoration of myoblast AT2R expression could lead to a novel therapy to prevent muscle atrophy and fibrosis in CHF condition.

Impact of continuous-flow mechanical circulatory support on cerebrospinal fluid motility.

Mechanical circulatory support (MCS), including ventricular assist devices (VADs), have emerged as promising therapeutic alternatives for end-stage congestive heart failure (CHF). The latest generation of these devices are continuous flow (CF) blood pumps. While there have been demonstrated benefits to patient outcomes due to CF-MCS, there continue to be significant clinical challenges. Research to-date has concentrated on mitigating thromboembolic risk (stroke), while the downstream impact of CF-MCS on the cerebrospinal fluid (CSF) flow has not been well investigated. Disturbances in the CSF pressure and flow patterns are known to be associated with neurologic impairment and diseased states. Thus, here we seek to develop an understanding of the pathophysiologic consequences of CF-MCS on CSF dynamics. We built and validated a computational framework using lumped parameter modeling of cardiovascular, cerebrovascular physics, CSF dynamics, and autoregulation. A sensitivity analysis was performed to confirm robustness of the modeling framework. Then, we characterized the impact of CF-MCS on the CSF and investigated cardiovascular conditions of healthy and end-stage heart failure. Modeling results demonstrated appropriate hemodynamics and indicated that CSF pressure depends on blood flow pulsatility more than CSF flow. An acute equilibrium between CSF production and absorption was observed in the CF-MCS case, characterized by CSF pressure remaining elevated, and CSF flow rates remaining below healthy, but higher than CHF states. This research has advanced our understanding of the impact of CF-MCS on CSF dynamics and cerebral hemodynamics.

Optimal Classification of Atrial Fibrillation and Congestive Heart Failure Using Machine Learning.

Cardiovascular disorders, including atrial fibrillation (AF) and congestive heart failure (CHF), are the significant causes of mortality worldwide. The diagnosis of cardiovascular disorders is heavily reliant on ECG signals. Therefore, extracting significant features from ECG signals is the most challenging aspect of representing each condition of ECG signal. Earlier studies have claimed that the Hjorth descriptor is assigned as a simple feature extraction algorithm capable of class separation among AF, CHF, and normal sinus rhythm (NSR) conditions. However, due to noise interference, certain features do not represent the characteristics of the ECG signals. This study addressed this critical gap by applying the discrete wavelet transform (DWT) to decompose the ECG signals into sub-bands and extracting Hjorth descriptor features and entropy-based features in the DWT domain. Therefore, the calculation of Hjorth descriptor and entropy-based features performed on each sub-band will produce more detailed information of ECG signals. The optimization of various classifier algorithms, including k-nearest neighbor (k-NN), support vector machine (SVM), random forest (RF), artificial neural network (ANN), and radial basis function network (RBFN), was investigated to provide the best system performance. This study obtained an accuracy of 100% for the k-NN, SVM, RF, and ANN classifiers, respectively, and 97% for the RBFN classifier. The results demonstrated that the optimization of the classifier algorithm could improve the classification accuracy of AF, CHF, and NSR conditions, compared to earlier studies.

Comprehensive electrocardiographic diagnosis based on deep learning.

Cardiovascular disease (CVD) is the leading cause of death worldwide, and coronary artery disease (CAD) is a major contributor. Early-stage CAD can progress if undiagnosed and left untreated, leading to myocardial infarction (MI) that may induce irreversible heart muscle damage, resulting in heart chamber remodeling and eventual congestive heart failure (CHF). Electrocardiography (ECG) signals can be useful to detect established MI, and may also be helpful for early diagnosis of CAD. For the latter especially, the ECG perturbations can be subtle and potentially misclassified during manual interpretation and/or when analyzed by traditional algorithms found in ECG instrumentation. For automated diagnostic systems (ADS), deep learning techniques are favored over conventional machine learning techniques, due to the automatic feature extraction and selection processes involved. This paper highlights various deep learning algorithms exploited for the classification of ECG signals into CAD, MI, and CHF conditions. The Convolutional Neural Network (CNN), followed by combined CNN and Long Short-Term Memory (LSTM) models, appear to be the most useful architectures for classification. A 16-layer LSTM model was developed in our study and validated using 10-fold cross-validation. A classification accuracy of 98.5% was achieved. Our proposed model has the potential to be a useful diagnostic tool in hospitals for the classification of abnormal ECG signals.

Chronic Kidney Disease (CKD) in U.S. Adults with Self-Reported Cardiovascular Disease (CVD)—A National Estimate of Prevalence by KDIGO 2012 Classification

Overall prevalence of CKD in the U.S. adult general population was estimated to be 14.8%. But data on the prevalence of CKD among CVD population are limited. Using the NHANES 2007-2014 data, we conducted a cross-sectional analysis of an adult sample with self-reported CVD (n=2325), aged ≥18 years, to assess prevalence of CKD in U.S. adults with CVD using KDIGO 2012 classification. Participants with CVD were identified based on self-reported personal interview data on a broad range of health conditions—congestive heart failure, coronary heart disease, angina, stroke, or heart attack. Appropriate sample weights were used to provide a national estimate. Results of prevalence of CKD in U.S. adults with self-reported CVD are presented in Table 1. The prevalence of moderately to severely decreased renal impairment based on eGFR below 60 ml/min/1.73m2 was 24.9%: 14.1% with Stage 3a, 7.8% with Stage 3b, and 3.0% with Stage 4 or 5. The prevalence of mildly decreased renal impairment (stage 2, eGFR=60-90 ml/min/1.73m2) was 45.2%: 36.8% with UACR&amp;lt;30 mg/g (normal to mildly increased albuminuria), 7.4% with UACR≥ 30-300 mg/g (moderately increased albuminuria) and 1.1% with UACR &amp;gt;300mg/g (severely increased albuminuria). This study confirms the high prevalence of CKD in CVD, and provides insights into distribution by CKD categories based on the KDIGO 2012 classification. Disclosure T. Wang: Employee; Self; Merck &amp; Co., Inc.. Stock/Shareholder; Self; Merck &amp; Co., Inc.. Employee; Spouse/Partner; Janssen Pharmaceuticals, Inc.. Y. Xi: None. R.N. Lubwama: None. C. Koro: Employee; Self; Merck &amp; Co., Inc.. Stock/Shareholder; Self; GlaxoSmithKline plc..

Congestive Cardiac Heart failure patients in the community: successfully managing complexity and polypharmacy

An introduction: (comprising context and problem statement) Congestive heart failure (CHF) is a chronic progressive condition that affects the pumping power of heart muscles which results in fluid builds up around the heart and causes it to pump inefficiently. Patients who develop decompensated CHF need to attend daily clinics in the hospital and are frequently admitted to hospital for periods of at least 2 days. Short description of practice change implemented: In consultation with nurse specialists, consultant cardiologist and the Community Intervention Team (CIT) a care pathway is developed for the patient’s treatment in the community, supported by electronic health records. Sample case study to highlight practice change: Patient prescribed intravenous (IV) frusemide in Outpatients. Referral and prescription electronically sent to CIT. IV medication is administered in patients’ home 2 days a week. Only 1 visit per week is now required to the CHF clinic. Patient is monitored and educated on the efficiency of the medication. Patient and family / carers are educated in what to look for in case of worsening symptoms. There is frequent feedback from the CIT to the hospital on the patient’s condition. Achieving the objectives: Safe management of CHF patients in the community: Symptoms that previously required admission to the acute setting are observed earlier in the home and acted upon thus reducing the opportunity for problems to build up. Consequent reduction in admissions to acute settings: Quality of patients’ life improved significantly, measured by the reduction of IV treatment, massive reduction of oedema and related discomfort; independence gained in activities of daily living (ADL’s). Aim and theory of change: The close IT-enabled communication between hospital and community ensures that all clinicians involved with the patients’ treatment are aware of changes in condition and treatment. This holistic approach avoids admission to hospital. Targeted population and stakeholders: CHF patient population deemed suitable for management in the community as identified by cardiologist and CHF nurse. Stakeholders: Primary: community intervention team (CIT), GP, public health etc. Secondary: Cardiac Failure Nurse specialists, outpatient departments, consultants etc. Highlights: (innovation, Impact and outcomes) The integrated care approach for a CHF patient is the first of its kind in this community, with high patient and clinician satisfaction. CHF patients are often referred to as palliative as their medical condition is irreversible. However quality of life and longevity can be achieved on this programme through the close monitoring of the patient at home, compatibility with other medication, reduced chance of the patient acquiring hospital infection superimposing on top of their CHF condition thus weakening overall health This intervention is both sustainable and transferable to other CHF patients throughout the country. Discussion and conclusion: Problems arising from CHF are multi-faceted as they vary from shortness of breath, reduced mobility, to fatigue etc. Managing this complexity in the community requires excellent integrated care between primary and secondary providers. Lessons Learned: Communication between primary and secondary healthcare professionals is essential to keeping patients in the community.

When to Suspect Sleep Apnea and What to Do About It

Obstructive sleep apnea (OSA), which is characterized by recurrent upper airway obstruction during sleep with resultant hypoxia-reoxygenation and sleep fragmentation, is prevalent among patients with cardiovascular disease. Refractory hypertension, nocturnal angina or arrhythmias, and stroke in particular should prompt consideration of OSA. The symptoms of OSA include snoring and excessive daytime sleepiness; risk factors include obesity and reduced upper airway dimensions. Up to 50% of patients with congestive heart failure (CHF) may manifest OSA, central sleep apnea-Cheyne-Stokes respiration (CSA-CSR), or both. Patients with CSA-CSR may present with fatigue, disrupted sleep, and paroxysmal nocturnal dyspnea. Objective sleep recording is required to document the nature and severity of sleep apnea. The gold standard is in-laboratory overnight polysomnography (PSG), including monitoring of electroencephalography and other signals to determine sleep-wake state, and recording of body position, airflow, respiratory effort, and pulse oximetry. Portable cardiorespiratory recorders are now approved for diagnosis in patients without comorbidities. Full PSG is recommended for diagnosis in all other cases, although OSA and CSA-CSR can be identified from portable recorders in some patients with CHF and other conditions. The objectives of treatment are to improve symptoms, quality of life, and cardiovascular outcomes. The mainstay of treatment for moderate-to-severe OSA is positive airway pressure (PAP). Automated PAP devices may be used in uncomplicated OSA, whereas continuous fixed PAP is the treatment of choice for other patients with OSA, and may also treat a proportion of patients with CSA-CSR. A form of bi-level PAP known as adaptive servoventilation is effective in treating a majority of patients with CSA-CSR.

Potentially avoidable hospital admissions in Germany: an analysis of factors influencing rates of ambulatory care sensitive hospitalizations.

The concept of ambulatory care sensitive hospitalization (ACSH) is based on the assumption that hospitalization for certain conditions might have been avoided by the timely provision of appropriate care outside the hospital. As preventive care and early treatment are often carried out in the ambulatory setting, ACSH have come to be viewed as an indicator of quality for this sector of the health-care system. Factors potentially influencing the regional distribution of ACSH were examined for four conditions-congestive heart failure, angina pectoris, arterial hypertension, and diabetes mellitus-with separate analyses for men and women. A regression analysis was performed on the basis of German nationwide data for the year 2008 (hospital statistics and population statistics). The data covered all areas of Germany. Each rise in the density of practice based specialists by 1 per 100,000 inhabitants was associated with a 0.1% reduction of ACSH in general and with a 0.3% reduction of ACSH for diabetes among men. A corresponding rise in the density of general practitioners was associated with reductions of ACSH among men by 0.1% for heart failure and by 0.5% for hypertension, yet also with increases of ACSH for angina pectoris (0.2% rise) and for diabetes (0.4% rise). Unemployment, residency in a rural area, and the number of hospital beds available locally were all positively correlated with small rises the ACSH rate. An age of 65 years and older was associated with the highest ACSH rates (0.7% to 3.6%). Overall, the analyzed variables were only weakly associated with the frequency of ambulatory care sensitive hospitalization. Future studies should consider further aspects such as the quality of care, comorbidities, and participation in healthcare programs.

Effects of Tolvaptan on Systemic and Renal Hemodynamic Function in Dogs with Congestive Heart Failure

We investigated the effects of tolvaptan, a vasopressin V(2)-receptor antagonist, on diuretic response and systemic and renal hemodynamic characteristics in conscious dogs with congestive heart failure (CHF). We also compared these effects with those of furosemide, a loop diuretic. CHF was induced by rapid right-ventricular pacing at 260 beats/min for at least 3 weeks, and maintained with a pacing rate of 220-240 beats/min. CHF dogs were orally given tolvaptan (10 mg/kg), furosemide (10 mg/kg) and vehicle in random order during the stable CHF state. Urine excretion, systemic and renal hemodynamic parameters, and plasma hormone levels were measured over 6-hour periods after drug administration. Tolvaptan induced aquaresis with an increase in free water clearance, resulting in a significant increase in serum sodium concentrations and a decrease in cumulative water balance. Tolvaptan also decreased pulmonary capillary wedge pressure without affecting systemic vascular resistance, glomerular filtration rate or renal blood flow. Tolvaptan tended to increase plasma arginine vasopressin concentrations but did not affect plasma renin activity. In contrast, furosemide induced clear saluresis with increased electrolyte excretion, resulting in decreased pulmonary capillary wedge pressure. However, furosemide also decreased serum potassium concentration and increased plasma arginine vasopressin concentrations and plasma renin activity. Tolvaptan elicited a potent aquaretic response and reduced the cardiac preload without unfavorable effects on systemic or renal hemodynamics, the renin-angiotensin-aldosterone system, or the sympathetic nervous system in CHF dogs. Thus, tolvaptan may offer a novel approach to remove excess water congestion from patients with CHF.

Different Factors Affecting Human ANP Amyloid Aggregation and Their Implications in Congestive Heart Failure

AimsAtrial Natriuretic Peptide (ANP)-containing amyloid is frequently found in the elderly heart. No data exist regarding ANP aggregation process and its link to pathologies. Our aims were: i) to experimentally prove the presumptive association of Congestive Heart Failure (CHF) and Isolated Atrial Amyloidosis (IAA); ii) to characterize ANP aggregation, thereby elucidating IAA implication in the CHF pathogenesis.Methods and ResultsA significant prevalence (85%) of IAA was immunohistochemically proven ex vivo in biopsies from CHF patients. We investigated in vitro (using Congo Red, Thioflavin T, SDS-PAGE, transmission electron microscopy, infrared spectroscopy) ANP fibrillogenesis, starting from α-ANP as well as the ability of dimeric β-ANP to promote amyloid formation. Different conditions were adopted, including those reproducing β-ANP prevalence in CHF. Our results defined the uncommon rapidity of α-ANP self-assembly at acidic pH supporting the hypothesis that such aggregates constitute the onset of a fibrillization process subsequently proceeding at physiological pH. Interestingly, CHF-like conditions induced the production of the most stable and time-resistant ANP fibrils suggesting that CHF affected people may be prone to develop IAA.ConclusionsWe established a link between IAA and CHF by ex vivo examination and assessed that β-ANP is, in vitro, the seed of ANP fibrils. Our results indicate that β-ANP plays a crucial role in ANP amyloid deposition under physiopathological CHF conditions. Overall, our findings indicate that early IAA-related ANP deposition may occur in CHF and suggest that these latter patients should be monitored for the development of cardiac amyloidosis.

Automated Cardiac Drug Infusion System Using Adaptive Fuzzy Neural Networks Controller

This paper presents a fuzzy neural network (FNN) control system to automatically manage the hemodynamic variables of patients with hypertension and congestive heart failure (CHF) via simultaneous infusion of cardiac drugs such as vasodilators and inotropic agents. The developed system includes two FNN sub-controllers for regulating cardiac output (CO) and mean arterial pressure (MAP) by cardiac drugs, considering interactive pharmacological effects. The adaptive FNN controller was tested and evaluated on a cardiovascular model. Six short-term therapy conditions of hypertension and CHF are presented under different sensitivities of a vasodilator drug. The results of the automated system showed that root mean square errors were ≤ 5.56 mmHg and ≤ 0.22 L min-1 for regulating MAP and CO, respectively, providing short settling time responses of MAP (≤ 10.9 min) and CO (≤ 8.22 min) in all therapy conditions. The proposed FNN control scheme can significantly improve the performance of cardiac drug infusion System.

A “love triangle” elicited by electrochemistry: complex interactions among cardiac sympathetic afferent, chemo-, and baroreflexes

there are three major cardiovascular reflexes: the baroreflex, chemoreflex, and cardiac sympathetic afferent reflex (CSAR). This commentary provides a brief overview of these three reflexes and also discusses the interplay among them. In addition, it outlines the potential centrally integrative

Novel roles of a local angiotensin‐generating system in the carotid body

The carotid body is a highly vascularized network of chemoreceptor cells, which are located at the bifurcation of the internal and external carotid arteries arising from the common carotid artery. Carotid body chemoreceptors, called glomus (type 1, catechol-secreting) cells release dopamine in response to rapid changes in arterial PO2, PCO2 and pH, thus increasing carotid body sinus nerve activity and provoking centrally mediated cardiopulmonary responses (Gonzalez et al. 1994). The endocrine (circulating) renin–angiotensin system (RAS) plays a role in regulating the blood pressure, electrolyte and fluid homeostasis. The aspartyl protease renin cleaves the precursor of the system, angiotensinogen, to yield angiotensin I, which is subsequently cleaved by angiotensin converting enzyme (ACE) to yield the physiologically active octapeptide angiotensin II (Ang II). Pressor responses to Ang II are largely mediated through activation of the type 1 receptor (AT1R). It is now recognized that the RAS exists in diverse mammalian cells and organs, where it plays diverse roles in their respective tissues and organs. Apart from the haemodynamic function, they include, but are not limited to, cell proliferation, apoptosis, oxidative stress and inflammatory as well as fibrotic actions. This so-called local RAS which adds to and/or differs from the circulating RAS, frequently operated in a paracrine and/or autocrine manner (Lavoie & Sigmund, 2003). Newly discovered functions of locally generated Ang II in tissues and organs are of particular interest in the physiological and pathophysiological aspects. Such a system has recently been proposed to exist in the carotid body: here, key RAS components (including angiotensinogen, ACE, AT1R and AT2R) are expressed in the absence of renin, suggesting the existence of a renin-independent biosynthetic pathway for Ang II or an intrinsic angiotensin-generating system in the carotid body (Lam & Leung, 2002). This system may play a key role in modulating the carotid body response to hypoxia. Ang II itself increases carotid body efferent activity, presumably via AT1R activation (Allen, 1998). Meanwhile, chronic hypoxia up-regulates several key RAS components in the carotid body, including a time-course-dependent activity of ACE (Lam & Leung, 2003; Lam et al. 2004). Specifically, expression of the AT1R on glomus cells is enhanced, consistent with increased expression of the AT1R at gene and protein level (Leung et al. 2000). Chronic hypoxia thus enhances AT1R-mediated efferent activity (Leung et al. 2000). In addition, AT1R activation increases intracellular calcium levels in dissociated glomus cells, an effect which is enhanced three-fold by chronic hypoxaemia (Fung et al. 2002). Taken together, all data suggest that chronic hypoxia is a major factor that increases AT1R expression and function in the carotid chemoreceptor, with likely changes in cardiopulmonary function. Thus the excitatory action of Ang II on the glomus cells may increase the chemosensitivity of the carotid body and may counteract the blunting effect of chronic hypoxia. Notwithstanding this involvement of a local angiotensin-generating system in the carotid body, details of the molecular and cellular mechanisms underlying the modulation require extensive study. A paper by Li & Schultz (2006) in this issue of The Journal of Physiology adds valuable data to this story. Using a rabbit model of congestive heart failure (CHF), the authors demonstrate a role for local glomus Ang II/AT1R signalling in increasing the sensitivity of Kv channels to hypoxia. High concentrations of Ang II (> 1 nm) directly inhibit Kv currents (Ik) while changes in Kv channel protein expression may contribute to the suppression of Ik and enhanced sensitivity of Ik to hypoxia in the CHF state. This study has two significant implications: Ang II can enhance the oxygen sensitivity of Kv channels via the mediation of AT1R and the cellular Ang II–AT1R pathway is functional in carotid glomus cells of CHF but not normal animals. In spite of this solid evidence, the precise mechanism by which CHF up-regulates the Ang II–AT1R and its function in the carotid body have yet to be resolved. In this regard, chronically impaired cardiac output resulting from CHF might be sufficient to render a prolonged deprivation of oxygen delivery to carotid glomus cells, a state akin to chronic hypoxia, thus leading to activation of its cellular RAS pathway. These data indicate a paracrine/autocrine role of Ang II in the modulation of enhanced carotid chemoreceptor sensitivity to chronic hypoxia characterized in chronic heart failure. In summary, the carotid body is the major organ central to the physiological responses to various forms of hypoxic stress: acute, chronic and intermittent hypoxia. Thus, activation of the RAS by hypoxia might be commonly associated with chronic cardiopulmonary diseases and sleep apnoea. Of great interest in this context is the emerging data of evidence for the existence of a local carotid angiotensin-generating system, which is up-regulated by chronic hypoxia to alter carotid chemoreceptor sensitivity. The data of Li and Schultz thus support this concept.

Prognostic value of interleukin-6, plasma viscosity, fibrinogen, von Willebrand factor, tissue factor and vascular endothelial growth factor levels in congestive heart failure.

Congestive heart failure (CHF) carries a poor prognosis with a high mortality rate, frequent hospitalizations and increased risk of thrombotic complications such as stroke. Cytokines may contribute to the progression and prothrombotic state of CHF, including the pro-inflammatory interleukin-6 (IL-6) and the pro-angiogenic vascular endothelial growth factor (VEGF), both of which are raised in CHF. The procoagulant properties of both cytokines may be mediated via tissue factor (TF), a potent clotting activator. We hypothesized that plasma levels of these markers, as well as levels of plasma viscosity, fibrinogen, soluble P-selectin and von Willebrand factor (markers of abnormal rheology, clotting, platelet activation, and endothelial damage, respectively) will be useful in predicting morbidity and mortality in chronic stable CHF. One hundred and twenty consecutive out-patients with chronic stable CHF (92 males; mean [SD] age 64 [11] years, mean [SD] left ventricular ejection fraction of 29 [6]%) were recruited and followed for 2 years during which 42 patients reached a clinical end-point of all-cause mortality and cardiovascular hospitalizations, including stroke and myocardial infarction. Plasma IL-6 (P=0.003) and TF (P=0.013) levels, but not other research indices, were higher in those who suffered events compared with those without events. Predictors of end-points were high (> or =median) TF (P=0.011), and IL-6 (P=0.023) levels, as well as the lowest quartile of a left ventricular ejection fraction (P=0.007). A strong correlation was present between TF and IL-6 levels (r=0.59; P<0.0001) and with VEGF levels (r=0.43; P<0.0001). IL-6 and TF are predictors of poor prognosis in chronic CHF, raising the hypothesis that IL-6 may contribute to the progression and thrombotic complications of CHF via its actions on TF expression. Although VEGF did not independently predict outcome in chronic CHF, the possibility arises that it may act with IL-6 to induce TF expression.

Low molecular weight heparin (bemiparin sodium) and the coagulation profile of patients with heart failure

Background Congestive heart failure (CHF) is associated with a hypercoagulable state. Patients and Methods A single-center, randomized, double-blind, placebo-controlled trial was performed to test the hypothesis that a prophylactic dose of low molecular weight heparin (bemiparin sodium 3500 IU/daily subcutaneously) will modify a hypercoagulable state in CHF. This study included 100 patients with CHF (New York Heart Association classification II to IV). All patients underwent 3 blood tests, at baseline (before randomization), 24 hours after randomization, and before hospital discharge or within 10 days from randomization. Results In comparison of baseline bemiparin sodium 3500 IU/daily subcutaneously with after 24 hours, there was a significant decrease in plasma levels of D-dimer (−13.8 ng/mL; P = .01) and prothrombin fragments 1 and 2 (−0.11 nmol/L; P = .01), whereas protein C was significantly increased (+3.5%; P = .03). In comparison of baseline bemiparin sodium 3500 IU/daily subcutaneously with after 4 to 10 days of therapy, there were significantly decreased plasma levels for factor VII:c (−3.0%; P = .01), D-dimer (−44.0 ng/mL; P = .002), and thrombin-antithrombin complex (−0.7 μg/L; P = .0001), whereas protein C was significantly increased (+16.0%; P = .03). On the other hand, in the group of patients treated with placebo after 24 hours, a significant decrease was observed of protein C (−4.0%; P = .04). After 24 hours, the changes from baseline were significantly different for some of the hemostatic factors in comparison of bemiparin sodium 3500 IU/daily and placebo (factor VII:c: −1.7 versus 0.0%; P = .04; D-dimer: −14 versus +24.3 ng/mL; P = .009; prothrombin fragments 1 and 2: −0.11 versus +0.11 nmol/L; P = .01; protein C: +3.5 versus −4.0%; P = .01). Also at discharge, the changes from baseline were different for some of the markers in comparison of bemiparin sodium with placebo (D-dimer: −44 versus 3.8 ng/mL; P = .002; thrombin-antithrombin complex: −0.70 versus +0.14 μg/L; P = .002; protein C: +16.0 versus +0.5%; P = .02). Conclusion Our findings suggest that a hypercoagulable state in heart failure can be modified with bemiparin sodium therapy. (Am Heart J 2002;143:e3.)

Myocardial Bradykinin Following Acute Angiotensin-Converting Enzyme Inhibition, AT1 Receptor Blockade, or Combined Inhibition in Congestive Heart Failure

The present study examined the effects of acute angiotensin-converting enzyme inhibition (ACEI), AT(1) receptor blockade (AT(1) block), or combined treatment on in vitro and in vivo bradykinin (BK) levels. BK levels were measured in isolated porcine myocyte preparations (n = 13) in the presence of exogenous BK (10(-8) M); with an ACEI (benezaprilat; 0.1 mM) and BK; an AT(1) block (valsartan; 10(-5) M) and BK; and combined treatment and BK. In a second study, myocardial microdialysis was used to measure porcine interstitial BK levels in both normal (n = 14) and pacing-induced congestive heart failure (CHF) (240 beats/min, 3 weeks, n = 16) under the following conditions: baseline, following ACEI (benezaprilat, 0.0625 mg/kg) or AT(1) block (valsartan, 0.1 mg/kg), and a combined treatment (benezaprilat, 0.0625 mg/kg; valsartan, 0.1 mg/kg). In the left ventricular myocyte study, BK levels increased over 93% with all treatments compared to untreated values (P < 0.05). In the in vivo study, basal interstitial BK values were lower in the CHF group than in controls (2.64 +/- 0.57 vs 5.91 +/- 1.4 nM, respectively, P < 0.05). Following acute infusion of the ACEI, BK levels in the CHF state increased from baseline (57% +/- 22; P < 0.05). Following combined ACEI/AT(1) block, BK levels increased from baseline in both control (42% +/- 11) and CHF groups (60% +/- 22; P < 0.05 for both). These findings suggest that ACEI, or combined ACEI/AT(1) block increased BK at the level of the myocyte and potentiated BK levels in the CHF myocardial interstitium.

Sympathetic and reflex abnormalities in heart failure secondary to ischaemic or idiopathic dilated cardiomyopathy

Congestive heart failure (CHF) is characterized by a sympathetic activation and a baroreflex impairment whose degree is directly related to the clinical severity of the disease. However, whether these abnormalities vary according to the ischaemic or idiopathic dilated nature of the CHF state has not been conclusively documented. In patients with a clinically stable, chronic CHF state in New York Heart Association functional class II and III, due either to ischaemic heart disease (IHD; n = 22, age 60.3±2.4 years, means±S.E.M.) or to idiopathic dilated cardiomyopathy (IDC; n = 20, age 58.9±2.8 years), and in 30 age-matched controls, we measured arterial blood pressure (using a Finapres device), heart rate (by electrocardiogram) and postganglionic muscle sympathetic nerve traffic (by microneurography) at rest and during baroreceptor manipulation induced by the vasoactive drug-infusion technique. Blood pressure values were not significantly different in CHF patients and controls. Compared with controls, heart rate was similarly increased and left ventricular ejection fraction (by echocardiography) similarly reduced in CHF patients with IHD or IDC. Muscle sympathetic nerve traffic was significantly greater in CHF patients than in controls, and did not differ between patients with IHD or IDC (67.3±4.2 and 67.8±3.8 bursts/100 heart beats respectively). This was also the case for the degree of baroreflex impairment. These data show that CHF states due to IHD or to IDC are characterized by a similar degree of peripheral sympathetic activation and by a similar impairment of the baroreflex function. Thus the neuroadrenergic and reflex abnormalities characterizing CHF are independent of its aetiology.

Sympathetic and reflex abnormalities in heart failure secondary to ischaemic or idiopathic dilated cardiomyopathy

Congestive heart failure (CHF) is characterized by a sympathetic activation and a baroreflex impairment whose degree is directly related to the clinical severity of the disease. However, whether these abnormalities vary according to the ischaemic or idiopathic dilated nature of the CHF state has not been conclusively documented. In patients with a clinically stable, chronic CHF state in New York Heart Association functional class II and III, due either to ischaemic heart disease (IHD; n=22, age 60.3+/-2.4 years, means+/-S.E.M.) or to idiopathic dilated cardiomyopathy (IDC; n=20, age 58.9+/-2.8 years), and in 30 age-matched controls, we measured arterial blood pressure (using a Finapres device), heart rate (by electrocardiogram) and postganglionic muscle sympathetic nerve traffic (by microneurography) at rest and during baroreceptor manipulation induced by the vasoactive drug-infusion technique. Blood pressure values were not significantly different in CHF patients and controls. Compared with controls, heart rate was similarly increased and left ventricular ejection fraction (by echocardiography) similarly reduced in CHF patients with IHD or IDC. Muscle sympathetic nerve traffic was significantly greater in CHF patients than in controls, and did not differ between patients with IHD or IDC (67.3+/-4.2 and 67.8+/-3.8 bursts/100 heart beats respectively). This was also the case for the degree of baroreflex impairment. These data show that CHF states due to IHD or to IDC are characterized by a similar degree of peripheral sympathetic activation and by a similar impairment of the baroreflex function. Thus the neuroadrenergic and reflex abnormalities characterizing CHF are independent of its aetiology.