Mechanisms In Congestive Heart Failure Research Articles

Novel biomarkers in cats with congestive heart failure due to primary cardiomyopathy

The pathogenesis of feline cardiomyopathy and congestive heart failure (CHF) requires further understanding. In this study, we assessed serum proteome change in feline CHF, aiming to identify novel biomarker for both research and clinical use. The study comprised 15 cats in CHF, 5 cats in preclinical cardiomyopathy and 15 cats as healthy controls. Serum proteome profiles were obtained by tandem mass tag labelling followed by mass spectrometry. Protein concentrations in CHF cats were compared with healthy controls. Western blot was performed for proteomic validation. Correlations were assessed between the altered proteins in CHF and clinical variables in cats with cardiomyopathy to evaluate protein-cardiac association. Bioinformatic analysis was employed to identify pathophysiological pathways involved in feline CHF. Sixteen serum proteins were significantly different between CHF and healthy control cats (P < .05). These included serine protease inhibitors, apolipoproteins and other proteins associated with inflammation and coagulation. Clinical parameters from cats with cardiomyopathy significantly correlated with the altered proteins (P < .05). Bioinformatic analysis identified 13 most relevant functional profiles in feline CHF, which mostly associated with extracellular matrix organization and metabolism.Data are available via ProteomeXchange with identifier PXD017761. SignificanceCardiomyopathies affect both cats and humans, and they can cause serious consequence such as congestive heart failure (CHF). To date, the pathophysiological mechanism of CHF is not fully understood. In this study, for the first time, we used a proteomic approach combined with bioinformatic analysis to evaluate serum protein change in cats with CHF. Results indicate systemic inflammation, coagulation protein changes, innate immunity and extracellular matrix remodeling are involved in feline CHF, which are largely comparable with findings in previous human studies. Our study provides new insights into CHF and cardiomyopathy in cats, and the identified novel biomarkers and pathophysiological pathways provide valuable information for future studies.

Rimeporide as a first- in-class NHE-1 inhibitor: Results of a phase Ib trial in young patients with Duchenne Muscular Dystrophy

Rimeporide, a first-in-class sodium/proton exchanger Type 1 inhibitor (NHE-1 inhibitor) is repositioned by EspeRare for patients with Duchenne Muscular Dystrophy (DMD). Historically, NHE-1 inhibitors were developed for cardiac therapeutic interventions. There is considerable overlap in the pathophysiological mechanisms in Congestive Heart Failure (CHF) and in cardiomyopathy in DMD, therefore NHE-1 inhibition could be a promising pharmacological approach to the cardiac dysfunctions observed in DMD. Extensive preclinical data was collected in various animal models including dystrophin-deficient (mdx) mice to characterise Rimeporide’s anti-fibrotic and anti-inflammatory properties and there is evidence that NHE-1 inhibitors could play a significant role in modifying DMD cardiac and also skeletal pathologies, as the NHE-1 isoform is ubiquitous. We report here the first study with Rimeporide in DMD patients. This 4-week treatment, open label phase Ib, multiple oral ascending dose study, enrolled 20 ambulant boys with DMD (6–11 years), with outcomes including safety, pharmacokinetic (PK) and pharmacodynamic (PD) biomarkers. Rimeporide was safe and well-tolerated at all doses. PK evaluations showed that Rimeporide was well absorbed orally reaching pharmacological concentrations from the lowest dose, with exposure increasing linearly with dose and with no evidence of accumulation upon repeated dosing. Exploratory PD biomarkers showed positive effect upon a 4-week treatment, supporting its therapeutic potential in patients with DMD, primarily as a cardioprotective treatment, and provide rationale for further efficacy studies.

The function and significance of SERA2a in congestive heart failure: an analysis of gene therapy trials.

Congestive heart failure (CHF) is a widespread disease that has a negative impact on health, worldwide. Despite advances in therapies, morbidity, mortality and hospital discharges due to CHF remain high. Advances in the understanding of the pathophysiological mechanisms of CHF and the development of gene transfer technology have made gene therapy a realistic potential therapeutic method for CHF. Among the various potential targets, sarco-endoplasmic reticulum Ca²⁺-ATPase 2a (SERCA2a), which is an important protein in the regulation of Ca²⁺ cycling, has piqued the interest of many researchers. Restoring decreased SERCA2a activity in CHF could improve cardiac contractions and energetics, as well as reduce myocardial fibrosis and ventricular arrhythmias, and these benefits have been confirmed by studies using both in vivo and in vitro models. Following these promising preclinical results, SERCA2a gene therapy advanced to clinical trials. However, results of the clinical trials were controversial, leading some to question whether SERCA2a is the right target for CHF treatment. In this review, we illustrate the function and significance of SERCA2a in CHF, and more importantly, analyze possible causes of the controversial clinical trials results, with the aim of stimulating future research on the relationship between SERCA2a and CHF.

Analysis of Gene Expression During the Development of Congestive Heart Failure After Myocardial Infarction in Rat Models.

Our study aimed to investigate the gene expression at different myocardial infarction (MI) phases and to understand the development mechanisms of congestive heart failure (CHF) after MI. Dataset GSE1957 including 24 samples of rat left ventricles at 1-day post MI or sham operation and 7-day post MI or sham operation was downloaded from Gene Expression Ominibus. The data were normalized with an affyPLM package and differentially expressed genes (DEGs) were identified with a Linear Models for Microarray Data package. Heat maps of the DEGs were constructed using Cluster 3.0. GO (Gene Ontology) enrichment analysis of the DEGs was performed in Database for Annotation, Visualization, and Integrated Discovery. A protein-protein interaction (PPI) network was constructed by Biomolecular Interaction Network Database and visualized by Cytoscape, and a subnetwork was analyzed using plugin ClusterONE in Cytoscape. A total of 5 DEGs at 1-day post-MI, 5 DEGs at 7-day post-MI, and 7 DEGs between the MI and sham groups at 1-day and 7-day post-MI were identified. For the GO category analysis, DEGs at 1-day post-MI were enriched in response to cytokine stimulus. DEGs at 7-day post-MI were enriched in response to inorganic substance and chemical homeostasis. DEGs between 1-day and 7-day post-MI including CDK2 and CDC20 were significantly enriched in mitosis. CDK2, ANXA1, CDC20, and AQP2 were included in the PPI network, and CDK2 was the only DEG included in the subnetwork. In conclusion, the induction of DEGs at 7-day post-MI might participate in the response to a hormone and endogenous stimulus to regulate the development of CHF after MI.

Usefulness of Running Wheel for Detection of Congestive Heart Failure in Dilated Cardiomyopathy Mouse Model

BackgroundInherited dilated cardiomyopathy (DCM) is a progressive disease that often results in death from congestive heart failure (CHF) or sudden cardiac death (SCD). Mouse models with human DCM mutation are useful to investigate the developmental mechanisms of CHF and SCD, but knowledge of the severity of CHF in live mice is necessary. We aimed to diagnose CHF in live DCM model mice by measuring voluntary exercise using a running wheel and to determine causes of death in these mice.Methodology/Principal FindingsA knock-in mouse with a mutation in cardiac troponin T (ΔK210) (DCM mouse), which results in frequent death with a t1/2 of 70 to 90 days, was used as a DCM model. Until 2 months of age, average wheel-running activity was similar between wild-type and DCM mice (approximately 7 km/day). At approximately 3 months, some DCM mice demonstrated low running activity (LO: <1 km/day) while others maintained high running activity (HI: >5 km/day). In the LO group, the lung weight/body weight ratio was much higher than that in the other groups, and the lungs were infiltrated with hemosiderin-loaded alveolar macrophages. Furthermore, echocardiography showed more severe ventricular dilation and a lower ejection fraction, whereas Electrocardiography (ECG) revealed QRS widening. There were two patterns in the time courses of running activity before death in DCM mice: deaths with maintained activity and deaths with decreased activity.Conclusions/SignificanceOur results indicate that DCM mice with low running activity developed severe CHF and that running wheels are useful for detection of CHF in mouse models. We found that approximately half of ΔK210 DCM mice die suddenly before onset of CHF, whereas others develop CHF, deteriorate within 10 to 20 days, and die.

Proteomic Profiling Implies Mitochondrial Dysfunction in Tachycardia-Induced Heart Failure

Background/ObjectivesMolecular mechanisms of congestive heart failure as reflected by alterations of protein expression patterns are still incompletely analyzed. We therefore investigated intraventricular (ie, left ventricular congestive heart failure [LV-CHF] vs. LV-control [CTRL], and right ventricular [RV]-CHF vs. RV-CTRL) and interventricular (ie, LV-CHF vs. RV-CHF, and LV-CTRL vs. RV-CTRL) protein expression differences in an animal model. MethodsThe model of rapid ventricular pacing in rabbits was combined with a proteomic approach using 2-dimensional gel electrophoresis. Identification of proteins was done by matrix-assisted laser desorption/ionization-tandem mass spectrometry (MALDI-MS/MS). ResultsRapid ventricular pacing-induced heart failure was characterized by LV dilatation, dysfunction, and hypotension as well as by increased BNP gene expression. By comparing LV-CHF vs. LV-CTRL, proteins were found to be underexpressed at 3 crucial points of cellular energy metabolism. In RV-CHF vs. RV-CTRL, proteins belonging to respiratory chain complexes were underexpressed, but additionally a disturbance in the nitric oxide–generating enzymatic apparatus was seen. Regarding the interventricular analyses, a stronger expression of energetic pathways was accompanied by an underexpression of contractile and stress response proteins in failing left vs. right ventricles. Finally, significant protein expression differences were found in LV-CTRL vs. RV-CTRL reflecting a higher expression of contractile, stress response, and respiratory chain proteins in LV tissue. ConclusionsIn tachycardia-induced heart failure, significant inter- and intraventricular protein expression patterns were found with a predominance of proteins, which are involved in cellular energy metabolism.

A new model of congestive heart failure in rats

Current rodent models of ischemia/infarct or pressure-volume overload are not fully representative of human heart failure. We developed a new model of congestive heart failure (CHF) with both ischemic and stress injuries combined with fibrosis in the remote myocardium. Sprague-Dawley male rats were used. Ascending aortic banding (Ab) was performed to induce hypertrophy. Two months post-Ab, ischemia-reperfusion (I/R) injury was induced by ligating the left anterior descending (LAD) artery for 30 min. Permanent LAD ligation served as positive controls. A debanding (DeAb) procedure was performed after Ab or Ab + I/R to restore left ventricular (LV) loading properties. Cardiac function was assessed by echocardiography and in vivo hemodynamic analysis. Myocardial infarction (MI) size and myocardial fibrosis were assessed. LV hypertrophy was observed 4 mo post-Ab; however, systolic function was preserved. LV hypertrophy regressed within 1 mo after DeAb. I/R for 2 mo induced a small to moderate MI with mild impairment of LV function. Permanent LAD ligation for 2 mo induced large MI and significant cardiac dysfunction. Ab for 2 mo followed by I/R for 2 mo (Ab + I/R) resulted in moderate MI with significantly reduced ejection fraction (EF). DeAb post Ab + I/R to reduce afterload could not restore cardiac function. Perivascular fibrosis in remote myocardium after Ab + I/R + DeAb was associated with decreased cardiac function. We conclude that Ab plus I/R injury with aortic DeAb represents a novel model of CHF with increased fibrosis in remote myocardium. This model will allow the investigation of vascular and fibrotic mechanisms in CHF characterized by low EF, dilated LV, moderate infarction, near-normal aortic diameter, and reperfused coronary arteries.

Mind-Body Medicine in Chronic Heart Failure

The connection between the mind and body has often been regarded by Western medicine as something ascribed to the mystical and a topic residing outside the scope of scientific thought. However, it has been a long-term integral tenet in the medical practice of many other cultures.1 It could be argued that the reliance of Western thought on the concept of dualism in which Plato, Aristotle, and other classical philosophers separated the body as a physical entity from the mind as a “spiritual” force has ultimately discouraged health care professionals from serious consideration of what has appeared to be a vague and even mysterious connection between the mind and body.2 Nevertheless, a growing body of research has progressively identified the mechanistic building blocks that demystify the reciprocal mind-body interaction and show that it is clearly a physical rather than mystical connection. Descriptions of neurovisceral changes in which readily demonstrated structural alterations in the brain, heart, and other organ systems arise in response to stress and a variety of emotional states provide further demonstration of the true organic mind-body connection. Perhaps the most abundant mechanistic data pertain to the brain-heart interaction under both conditions of health and a variety of cardiovascular disease states. The increasing body of evidence for these important interactions has in fact led to the call for dedicated integrated fields such as neurocardiology or behavioral cardiology.3–5 It is therefore important to examine the current state of our understanding of mind-body interactions including the experimental evidence identifying the physiological basis for these interactions and their impact on clinical outcomes. As will be shown, there is a significant overlap between the pathophysiologic mechanisms of congestive heart failure and the major effectors of mind-body connections. This provides the basis for potential new therapies that incorporate mind-body medicine. …

Acute Myocardial Infarction in the Evening Has a Worse Prognosis. Circadian Rhythm, Does It Matter?

Refer to the page 616-624 Recently Bae et al.1) reported that hospital presentation of patients with acute myocardial infarction (AMI) in the evening was linked to a higher rate of mortality for twelve months. In addition, congestive heart failure (CHF) was more prevalent in the evening onset of AMI. Therefore, it was concluded that the evening onset of AMI was indirectly related to a worse prognosis due to poor baseline left ventricular (LV) function. A finding consistent with previous reports was that the proportion of diabetes patients was higher in the evening onset of ST segment elevation myocardial infarction (STEMI).2) Since the mode of onset as the dependent variable in the baseline data was not considered, statistical analyses on factors related to evening onsets similar to the previous study were not available.2-4) LV function is the strongest prognostic factor in AMI. It is critical to ascertain the factors which are associated with depressed LV function at the time of hospital presentation.5) Consequently, symptom to door (STD) time or door to balloon time (DBT) should be the first theoretical reference for AMI. However, it is very difficult to define the real onset of AMI using chest pain as an indicator because the elderly, patients with diabetes and females have blunted or atypical symptoms. In this study, an important finding on the quality of care was addressed. DBT was longer in the evening or during off-duty hours. A worse outcome of pre-hospital delay or longer DBT was not observed, even with a higher proportion of STEMI in this study. This is because the effect can be diluted by patients with a very long STD time. STD time, which is pre-hospital time delay in STEMI was 419±573 minutes, which is better compared to the previous result of 699±144 minutes.4) However the large standard deviation is still challenging and the factors related to the pre-hospital time delay in Korea need to be further investigated. The natural course of AMI is inevitably followed by LV failure within a couple of days. As with the progression of infarction, increased wall tension and ischemia may allow the provocation of angina by a vulnerable myocardium resulting in a delayed presentation in the evening. Asymptomatic or neglected onset of AMI in the morning can present as CHF in the evening. Recurrent and gradual or slowly progressive ischemia in the morning may also result in AMI with CHF in the evening. As a pathophysiological perspective, Tanaka et al.6) suggested patients with non-plaque rupture are more likely to present in the evening. Nonetheless, an evening onset of AMI is not necessarily a delayed manifestation by a new onset of LV dysfunction from the morning since pre-existing LV dysfunction or ischemia could provoke ischemic symptoms in the evening. With overtime work, mental stress may aggravate pre-existing CHF in patients who have critical stenosis in the coronary vessel. Consequently, they would suffer from chest pain with a recumbent position in the evening. Other factors associated with an evening onset of AMI such as the reluctance to visit the hospital, poor social or familial support and behavioral factors such as smoking and drinking may be associated with CHF.7) History of CHF and Non-Q wave MI are well known factors linked to the evening onset of AMI.2) In the early 1990s, Kim et al.8) also reported that history of CHF is more frequently noted in the evening onset of AMI in Korean patients. In patients with pre-existing heart failure, limited duration of heart failure medications could also unveil ischemic symptoms in the evening. On the other hand, aspirin or beta-blockers may blunt the symptoms in the morning, potentially leading to pre-hospital delay.2) Hence, from the clinical viewpoint, AMI in the evening warrants a more sophisticated strategy to cope with all of these associated clinical problems. CHF was present in 20-40% of AMI patients on admission and pre-existing heart failure was present in approximately 10% of patients.5) Considering the mechanism of CHF at the onset of AMI and the prognosis, multi-vessel disease with single culprit lesion causing AMI is of particular interest. The net results of revascularization treatment are decided by the summation of the infarcted myocardium and the saved ischemic myocardium. Therefore, not only the quality of care for the culprit lesion but also the results of revascularization on non-culprit vessels may be important for long-term prognosis. As the optimal revascularization strategy for the non-culprit lesions in AMI patients with depressed LV function, outcome of percutaneous coronary intervention versus coronary artery bypass graft needs further study. Unlike previous studies in Western countries, a majority of Asian studies showed a clear double peak circadian rhythm in AMI.3),7),9),10) It is important to investigate whether this difference is due to racial/biologic factors or to socioeconomic factors in order to provide appropriate interventions.

Differences in the Incidence of Congestive Heart Failure by Ethnicity

The relationship between incident congestive heart failure (CHF) and ethnicity as well as racial/ethnic differences in the mechanisms leading to CHF have not been demonstrated in a multiracial, population-based study. Our objective was to evaluate the relationship between race/ethnicity and incident CHF. The Multi-Ethnic Study of Atherosclerosis (MESA) is a cohort study of 6814 participants of 4 ethnicities: white (38.5%), African American (27.8%), Hispanic (21.9%), and Chinese American (11.8%). Participants with a history of cardiovascular disease at baseline were excluded. Cox proportional hazards models were used for data analysis. During a median follow-up of 4.0 years, 79 participants developed CHF (incidence rate: 3.1 per 1000 person-years). African Americans had the highest incidence rate of CHF, followed by Hispanic, white, and Chinese American participants (incidence rates: 4.6, 3.5, 2.4, and 1.0 per 1000 person-years, respectively). Although risk of developing CHF was higher among African American compared with white participants (hazard ratio, 1.8; 95% confidence interval, 1.1-3.1), adding hypertension and/or diabetes mellitus to models including ethnicity eliminated statistical ethnic differences in incident CHF. Moreover, African Americans had the highest proportion of incident CHF not preceded by clinical myocardial infarction (75%) compared with other ethnic groups (P = .06). The higher risk of incident CHF among African Americans was related to differences in the prevalence of hypertension and diabetes mellitus as well as socioeconomic status. The mechanisms of CHF also differed by ethnicity; interim myocardial infarction had the least influence among African Americans, and left ventricular mass increase had the greatest effect among Hispanic and white participants.

The Future of Cardiovascular Imaging in the Diagnosis and Management of Heart Failure, Part 1

Radiographic, ultrasound, nuclear, and magnetic resonance methods have become indispensable in the management of heart failure (HF). Imaging is widely used in decision making in HF, not only in relation to left ventricular (LV) systolic and diastolic function but also in the selection of medical, device, and surgical therapy in HF and valvular heart disease. Future developments in the care of advanced heart disease, including stem cell therapy, device therapy to control remodeling, and percutaneous valve interventions, as well as the need to identify subclinical heart disease, are likely to expand this use. Moreover, the epidemic of diabesity (diabetes and obesity) will augment the existing epidemic of HF just when it appeared to have peaked.1 Large numbers of patients will need information from imaging to guide clinical decision making (Table 1). The sources of this information will need to be expeditious, inexpensive, and preferably objective and quantitative.2 View this table: Table 1. Established HF: What the Clinician Needs Although some of the measurements in HF patients are structural (LV mass and geometry), the main components of an imaging assessment in HF will continue to be primarily functional (LV ejection fraction, size, filling pressures, filling characteristics, and right ventricular [RV] function). A number of new technologies will enhance the future accuracy and reliability of these measures. ### LV Volumes and Ejection Fraction Routine techniques (contrast ventriculography, 2D echocardiography) provide real-time imaging in standard imaging planes. The only traditional method that has escaped this limitation has been radionuclide ventriculography, in which the ejection fraction is calculated from scintigraphic counts, but this introduces the separate potential problems of attenuation and overlying chambers. #### Limitations of 2D Imaging Two-dimensional imaging approaches require expert acquisition and observers and have limited reliability in obtaining appropriate cut planes in sequential studies. The limitation of requiring imaging planes in the correct axis is particularly an issue for 2D echocardiography, which …

Proteomic Analysis Reveals Significant Alternations of Cardiac Small Heat Shock Protein Expression in Congestive Heart Failure

Background Because congestive heart failure (CHF) is a complex syndrome with many different underlying mechanisms of worsening of heart function, it is important to recognize the global alternations in protein expression associated with the processes of CHF. Methods and Results The purpose of our study was to use a proteomic approach to investigate global alternations in protein expression in tachycardia induced CHF dogs. We compared the 2-dimensional electrophoresis protein patterns of left ventricular samples from the normal with those from failing myocardium. Differentially expressed cardiac proteins showed approximately 500 cardiac protein spots. A total of 20 spots (14 increased, 6 decreased) was altered in CHF, whereas the more distinguishably increased spots in CHF were identified by using mass spectrometry as alpha B crystallin, heat shock protein (HSP) 27, and HSP20, which maintain both the morphologic and functional integrity of the cardiomyocytes and increase tolerance against various types of stress. Because phosphorylation is one of the most important posttranslational modifications, we evaluated whether or not the overexpressed small HSPs were phosphorylated in CHF. Phosphoprotein staining and Western blotting demonstrated that the phosphorylation of alpha B crystallin at serine (Ser)-59 site and of HSP27 at both Ser-78 and Ser-82 sites increased in CHF. Conclusion Proteomics studies can provide new insights into molecular mechanisms in CHF and phosphorylated small HSPs may be involved in preventing cardiac dysfunction.

Regional diastolic dysfunction in individuals with left ventricular hypertrophy measured by tagged magnetic resonance imaging—The Multi-Ethnic Study of Atherosclerosis (MESA)

Impairment of global diastolic function is considered to be the mechanism of congestive heart failure in individuals with preserved systolic left ventricular (LV) function. Left ventricular hypertrophy (LVH) is known to be a risk factor for congestive heart failure with preserved systolic function, and this process may begin as a regional process. We investigated whether regional LV diastolic function measured by magnetic resonance tagging is altered in asymptomatic participants of the MESA with LVH and preserved systolic LV function. Regional systolic and diastolic strain rates were calculated from strain data in 218 participants of the MESA study. Circumferential strain was calculated from the midwall layer of the septum, anterior, lateral, and inferior walls at mid-LV level. Global LV function measures were studied by magnetic resonance imaging in 4291 MESA participants. Left ventricular hypertrophy for men and women was defined from the MESA population using previously established Framingham criteria. Global systolic function was slightly less in the LVH (ejection fraction = 0.66 +/- 0.10) versus the non-LVH group (ejection fraction = 0.69 +/- 0.07, P < .001). Stepwise regression analyses showed a direct relationship between regional diastolic dysfunction and increasing LV mass. Regional systolic strain and strain rate measures from participants with LVH were not significantly different from those without LVH. However, regional diastolic strain rate was significantly reduced in participants with LVH (1.5 +/- 1.1 s(-1)) compared with the non-LVH group (2.2 +/- 1.1 s(-1), P < .001) regardless of age or sex. Left ventricular hypertrophy is associated with regional diastolic dysfunction in individuals without evidence of clinical cardiovascular disease and preserved systolic function. Magnetic resonance imaging tagging provides detailed quantification of regional diastolic function noninvasively.

A Polymorphism of the Gene Encoding AMPD1: Clinical Impact and Proposed Mechanisms in Congestive Heart Failure

A vast array of gene polymorphisms have been described, and further discovery of these gene variants will continue as the human genome is defined. Therefore, selection of a single polymorphism to investigate in relation to disease evolution or outcome must be motivated by specific physiologic, pathophysiologic, or epidemiologic associations. A significant gene polymorphism may result in an alteration of protein function, or be associated with disease incidence or outcome. Prevalence of the polymorphism in the general population is of extreme importance, as it must be common enough to warrant interest in its clinical impact. The polymorphism of the gene encoding for the enzyme adenosine monophosphate deaminase 1 results in an abnormal protein necessary in skeletal muscle metabolism. While its physiologic effects are not completely understood, it has been associated with improved morbidity and mortality in patients with cardiovascular disease.

Murine models for the study of congestive heart failure: Implications for understanding molecular mechanisms and for drug discovery

Congestive heart failure (CHF) is a complex illness of diverse aetiology. Despite the current multiple therapies, the prognosis for CHF patients remains poor, and new therapeutic targets need to be identified. With the advent of the genetic era, the mouse has become an increasingly valuable animal species in experimental CHF research. A large number of murine models of cardiac hypertrophy and CHF have been created by genetic engineering. Meanwhile, traditional CHF models created by coronary artery ligation, cardiac pressure, or volume overload have been adapted to mice. The present review categorises and highlights the value of these murine models of cardiac hypertrophy and CHF. These models, combined with sophisticated physiological measurements of cardiac haemodynamics, are expected to yield more and valuable information regarding the molecular mechanisms of CHF and aid in the discovery of novel therapeutic targets.

Multiscale entropy analysis: a new measure of complexity loss in heart failure

Heart failure may lead to loss of complexity in physiologic dynamics. However, conventional entropy measures yield contradictory results. We applied a recently developed method, multiscale entropy (MSE) that quantifies the regularity of physiologic signals over multiple time scales. We tested the hypothesis that the rate at which entropy varies with time scale can discriminate between healthy and different classes of con- gestive heart failure (CHF) subjects. Material and Methods: We analyzed long-term Holter re- cordings from two group of subjects: 72 records from healthy subjects aged 5512 years and 43 from patients with CHF aged 5416. The CHF group included 12 subjects in NYHA classes I-II, and 31 subjects in classes III-IV. We calculated an entropy measure (SampEn) that applies to physiologic time series plotted as a function of time scale. Next, we computed the rate of change of entropy for scales smaller and larger than approximately 5 seconds and developed clustering criteria for the different groups. Results and Conclusions: Healthy and CHF subjects have different MSE curve profiles. Further, heart rate dynamics with CHF have significantly lower multiscale entropy values com- pared with healthy subjects. A 2-dimensional scatter plot based on the rate of variation of entropy with time scale showed robust separation of healthy and all CHF classes. These findings are consistent with the basic concept of information loss in cardio- vascular regulatory mechanisms in CHF and may be useful in clinical assessment.

Usefulness of pulsed tissue Doppler imaging for evaluating systolic and diastolic left ventricular function in patients with AL (primary) amyloidosis

To clarify whether pulsed tissue Doppler imaging at multiple left ventricular LV sites could help to explain the mechanism of congestive heart failure (CHF) in patients with primary amyloidosis, we examined 86 consecutive patients with primary amyloidosis confirmed by biopsy (group I, 31 patients without cardiac involvement; group II, 31 patients with evidence of heart involvement but no CHF; and group III, 24 patients with heart involvement, clinical CHF, and normal fractional shortening >28%). Peak early diastolic myocardial velocities in group II were significantly lower than those in group I, and the values in group III were also significantly lower than those in group II at most sites. In contrast to diastolic abnormalities, peak systolic wall motion velocities in group III were significantly lower than those in group II, but there were no significant differences between groups I and II. Thus, cardiac amyloidosis is characterized by an initial impairment in early cardiac relaxation, whereas CHF is associated with an impairment of peak systolic wall motion velocities, most prominently seen in the longitudinal axis. This systolic dysfunction can be detected by pulsed tissue Doppler imaging, even when ejection fraction is in the normal range.

Neurohumoral regulation in ischemia-induced heart failure. Role of the forebrain.

Congestive heart failure (CHF) is characterized by neurohumoral excitation. Increased sympathetic drive and activation of the reninangiotensin-aldosterone system (RAAS), with vasoconstriction and volume retention, are hallmarks of the CHF syndrome. Treatment strategies have targeted the peripheral influences of these two systems, but have not addressed the central mechanisms that drive them. We monitored the development of CHF following coronary ligation in adult Sprague-Dawley rats. Left ventricular dysfunction characteristic of CHF was confirmed by echocardiography, and the CHF syndrome was validated by measurements of circulating hormones, sodium appetite, thirst, renal sodium and water retention, and renal sympathetic nerve activity (RSNA). In CHF rats, neuronal activity in the hypothalamic paraventricular nucleus (PVN), which mediates downstream effects of forebrain circumventricular organs, was increased and was inhibited by blocking components of the RAAS at the forebrain level. Forebrain (AV3V) lesions and intracarotid (forebrain directed) injections of agents (captopril, losartan, spironolactone) that block RAAS substantially attenuated the behavioral and physiological manifestations of CHF. Intravenous losartan and captopril, in doses that lower arterial pressure, increased RSNA. These findings demonstrate an important role for RAAS-activated forebrain mechanisms in CHF and suggest that the central neural mechanisms driving sympathetic nerve activity and volume retention may persist and promote the progression of CHF despite treatments directed toward the peripheral influences of RAAS.

Differentiating systolic from diastolic heart failure using impedance cardiography.

Differentiating systolic from diastolic congestive heart failure (CHF) is often difficult in the ED. Impedance cardiography (IC) allows for the noninvasive evaluation of systolic function and measurement of diastolic time intervals. This study was designed to assess the ability of IC to accurately measure isovolumic relaxation time (IVRT) and determine relative cardiac contractility, thereby differentiating systolic from diastolic mechanisms in acute CHF. In an evaluation of the technique, the average differences in the diastolic time intervals measured in normal subjects by both IC tracings and phonocardiography were compared. Likewise, the average Heather index (HI) of patients with known systolic dysfunction (ejection fraction < 30% by echo-cardiography) was compared with the mean HI measured in the normal subjects. In a retrospective analysis, the clinical performance of the method was examined by extracting the values of IVRT and HI from IC tracings of patients presenting with CHF. The determined IVRT and HI values were then correlated to clinical markers for diastolic and systolic dysfunction. Analysis of 280 IC tracings in eight healthy volunteers revealed an average difference of 0.0075 seconds (95% CI = -0.0067 to 0.0217) when IVRT intervals measured by phonocardiography and IC are compared. The HI in this normal group averaged 14.2 (95% CI = 9.4 to 19.0), contrasting to the much lower value of 2.8 (95% CI = 1.98 to 3.62) seen in eight subjects with documented systolic dysfunction. In 26 patients with decompensated CHF, there was a close correlation (r = 0.81) of the measured IVRT to left ventricular hypertrophy by voltage criteria and while a fall in the HI was correlated with intravascular volume expansion. Though there was considerable overlap (46%) in mechanisms of CHF, 35% of the patients were found to have only systolic dysfunction (HI < 5 and IVRT < 0.125), while 19% had a predominantly diastolic etiology (IVRT > 0.125 and HI > 5) for their failure. IC measures of contractility and diastolic time intervals are a potentially effective method for differentiating the dominant mechanisms of CHF in the emergent setting and categorizing CHF patients into different subsets.

Correlation of radiographic cardiothoracic ratio with cardiac function in patients with acute congestive heart failure

Objective: Plain film radiographs are routinely used as a part of the emergency department evaluation of patients with acute congestive heart failure. Determination of the cardiothoracic ratio (CT ratio) may provide insight into the severity and mechanism of the cardiac dysfunction. This study was designed to correlate the determined CT ratio with measures of systolic and diastolic function in patients with decompensated congestive heart failure (CHF). Methods: The CT ratio was retrospectively calculated from the routine upright anteroposterior plain film radiographs obtained during the evaluation of patients with acute CHF. Likewise, values for the diastolic time intervals such as isovolumic relaxation times and filling times (measures of diastolic dysfunction, IVRT, FT) and the Heather Index (a measure of systolic contractility, HI) were obtained from the tracings obtained by impedance cardiography (IC). These functional measures were then independently correlated with the CT ratio by multiple regression analysis. The degree of left ventricular hypertrophy (LVH) as determined by EKG voltage was also correlated to cardiac function measures for comparison. Results: In 45 patients there was no significant correlation (P < 0.05) of the measured IVRT and FT with the corresponding CT ratio. The HI was also significantly inversely correlated with the CT ratio (r = –0.36, P < 0.05). By comparison, the degree of LVH was not significantly related to the measures of systolic function but was highly correlated to the IVRT. Conclusion: CT ratios determined from plain film radiographs appear to correlate well with measures of cardiac systolic function and may be useful in determining the severity and mechanism of CHF in the acute setting.