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PubMed2002

Spontaneous ischemic events in the brain and heart adapt the hearts of severely atherosclerotic mice to ischemia.

To investigate if spontaneous ischemic events in mice with severe multi-organ atherosclerosis could adapt to ischemia, apolipoprotein E/LDL receptor knockout mice were fed an atherogenic diet for 7 to 9 months. Signs of spontaneous ischemia occurred. One to two days later, hearts were excised, Langendorff-perfused with induced global ischemia, and compared with mice without signs of disease. In vivo heart or brain infarctions were verified by heart histology and/or increased serum levels of cardiac troponin T and S100B. Hearts of mice with spontaneous ischemic events had improved function and reduced Langendorff-induced infarctions. To investigate the remote preconditioning effect of brain ischemia, bilateral ligation of the internal carotid arteries was performed in C57BL6 mice. Twenty-four hours later, their isolated hearts were protected against induced global ischemia. A possible role of inducible NO synthase (iNOS) was studied in iNOS knock out mice, who were not preconditioned by induced brain ischemia. Cardiac iNOS was unchanged 24 hours after preconditioning, suggesting that NO is a trigger rather than a mediator of protection. These findings suggest that spontaneous ischemic events in the brain and heart adapt the heart to ischemia. This can be mimicked by induced brain ischemia, with iNOS as a key factor of protection.

Animals↗
PubMed2004

Effect of candesartan on cause-specific mortality in heart failure patients: the Candesartan in Heart failure Assessment of Reduction in Mortality and morbidity (CHARM) program.

BACKGROUND: Patients with heart failure are at increased risk of sudden death and death attributed to progressive pump failure. We assessed the effect of candesartan on cause-specific mortality in patients enrolled in the Candesartan in Heart failure Assessment of Reduction in Mortality and morbidity (CHARM) program. METHODS AND RESULTS: The CHARM program consisted of 3 component trials that enrolled patients with symptomatic heart failure: CHARM-Alternative (n=2028; LVEF<=40% [corrected] and ACE intolerant), CHARM-Added (n=2548; LVEF<=40%, [corrected] already on ACE inhibitors), and CHARM-Preserved (n=3023; LVEF >40%). Patients were randomized to candesartan, titrated to 32 mg QD, or placebo and were followed up for a median of 37.7 months. All deaths were reviewed by a blinded adjudication committee and categorized according to prespecified definitions on the basis of a narrative and source documentation. The number and rate of deaths by cause were calculated for each of the component trials and the overall program. Of all the patients, 8.5% died suddenly, and 6.2% died of progressive heart failure. Candesartan reduced both sudden death (HR 0.85 [0.73 to 0.99], P=0.036) and death from worsening heart failure (HR 0.78 [0.65 to 0.94], P=0.008). These reductions were most apparent in the patients with LVEF<=40% [corrected]. CONCLUSIONS: Candesartan reduced sudden death and death from worsening heart failure in patients with symptomatic heart failure, although this reduction was most apparent in patients with systolic dysfunction.

Aged↗
PubMed2000

Tumor necrosis factor-alpha is expressed in donor heart and predicts right ventricular failure after human heart transplantation.

BACKGROUND-Myocardial failure is an important problem after heart transplantation. Right ventricular (RV) failure is most common, although its mechanisms remain poorly understood. Inflammatory cytokines play an important role in heart failure. We studied the expression of tumor necrosis factor (TNF)-alpha and other cytokines in donor myocardium and their relationship to the subsequent development of RV failure early after transplantation. METHODS AND RESULTS-Clinical details were obtained, and ventricular function was assessed by transesophageal echocardiography in 26 donors before heart retrieval. A donor RV biopsy was obtained immediately before transplantation, and each recipient was followed for the development of RV failure. Reverse transcriptase-polymerase chain reaction was performed to detect TNF-alpha, interleukin-2, interferon-gamma, and inducible nitric oxide synthase expression. Eight of 26 recipients (30.8%) developed RV failure. Seven of these 8 (87.5%) expressed TNF-alpha, but only 4 of the 18 (22.2%) who did not develop RV failure expressed TNF-alpha (P<0.005). As a predictor of RV failure, TNF-alpha mRNA had a sensitivity of 87.5%, a specificity of 83.3%, a positive predictive value of 70%, and a negative predictive value of 93.7%. Western blotting demonstrated more TNF-alpha protein in the myocardium of donor hearts that developed RV failure (658+/-60 versus 470+/-57 optical density units, P<0.05). Immunocytochemistry localized TNF-alpha expression to cardiac myocytes. Reverse transcriptase-polymerase chain reaction detected interferon-gamma in 2 (7.7%), interleukin-2 in 1 (3.8%), and inducible nitric oxide synthase mRNA in 1 (3.8%) of the 26 donor hearts, none of which developed RV failure. CONCLUSIONS-TNF-alpha expression in donor heart cardiac myocytes seems to predict the development of RV failure in patients early after heart transplantation.

Adolescent↗
PubMed2000

Heart cell transplantation improves heart function in dilated cardiomyopathic hamsters.

BACKGROUND: Little is known about the effect of heart cell transplantation into the dilated cardiomyopathic myocardium. This study was designed to evaluate the effect of heart cell transplantation into dilated cardiomyopathic hamsters. METHODS AND RESULTS: Ventricular heart cells were isolated from 4-week-old BIO 53. 58 hamsters and cultured for 2 weeks before transplantation. The cells were labeled with bromodeoxyuridine (BrdU) before transplantation for identification. Adult hamsters (17 weeks old) were used as recipients. Heart cells (4 x 10(6) cells) or culture medium was transplanted into the left ventricular free wall (transplantation and control groups, respectively, n=12 each). Sham-operated hamsters (n=12) underwent the surgery but not the transplantation. Cyclosporine A was administered subcutaneously to all hamsters daily after the operation. Four weeks after the transplantation, heart function was evaluated with the use of a Langendorff preparation. Histology showed severe focal myocardial necrosis in all groups. BrdU-stained tissue was found at the cell transplantation sites. The transplanted hearts had greater (P:<0. 001) developed pressures at all balloon volumes and improved dP/dt (transplantation 915+/-253 versus control 453+/-120 and sham 530+/-187 mm Hg/s, P:<0.001, balloon volume of 15 microL). No differences in ventricular function were found between control and sham-operated hamsters. CONCLUSIONS: The transplanted ventricular heart cells formed cardiac-like tissue in cardiomyopathic myocardium and improved its contractile function.

Animals↗
PubMed1994

Reduced heart rate variability and mortality risk in an elderly cohort. The Framingham Heart Study.

BACKGROUND: The prognostic implications of alterations in heart rate variability have not been studied in a large community-based population. METHODS AND RESULTS: The first 2 hours of ambulatory ECG recordings obtained on original subjects of the Framingham Heart Study attending the 18th biennial examination were reprocessed to assess heart rate variability. Subjects with transient or persistent nonsinus rhythm, premature beats > 10% of total beats, < 1 hour of recording time, processed time < 50% of recorded time, and those taking antiarrhythmic medications were excluded. The associations between heart rate variability measures and all-cause mortality during 4 years of follow-up were assessed. There were 736 eligible subjects with a mean age (+/- SD) of 72 +/- 6 years. The following five frequency domain measures and three time domain measures were obtained: very-low-frequency power (0.01 to 0.04 Hz), low-frequency power (0.04 to 0.15 Hz), high-frequency power (0.15 to 0.40 Hz), total power (0.01 to 0.40 Hz), the ratio of low-frequency to high-frequency power, the standard deviation of total normal RR intervals, the percentage of differences between adjacent normal RR intervals that are > 50 milliseconds, and the square root of the mean of the squared differences between adjacent normal RR intervals. During follow-up, 74 subjects died. In separate proportional hazards regression analyses that adjusted for relevant risk factors, very-low-frequency power (P < .0001), low-frequency power (P < .0001), high-frequency power (P = .0014), total power (P < .0001), and the standard deviation of total normal RR intervals (P = .0019) were significantly associated with all-cause mortality. When all eight heart rate variability measures were assessed in a stepwise analysis that included other risk factors, low-frequency power entered the model first (P < .0001); thereafter, none of the other measures of heart rate variability significantly contributed to the prediction of all-cause mortality. A 1 SD decrement in low-frequency power (natural log transformed) was associated with 1.70 times greater hazard for all-cause mortality (95% confidence interval of 1.37 to 2.09). CONCLUSIONS: The estimation of heart rate variability by ambulatory monitoring offers prognostic information beyond that provided by the evaluation of traditional risk factors.

Aged↗
PubMed1982

Mechanical interactions between four heart chambers with and without the pericardium in canine hearts.

By using excised postmortem hearts obtained from 15 mongrel dogs with the pericardium intact, we investigated mechanical interactions between the four heart chambers from the standpoint of ventricular pressure-volume relationships. The interactions investigated were those between (1) the atrium and the ventricle, (2) the right ventricle and left ventricles, (3) the atrium and one ventricle vs. the other ventricle, and finally (4) the left and right atrium and the right ventricle vs. the left ventricle. For these purposes, we inserted compliant balloons into the four heart chambers without injuring the pericardium, i.e., we incised the base of the atria which was not covered with the pericardium. We obtained the right and/or left ventricular pressure-volume relationships under a constant pressure in three other heart chambers by changing the height of the reservoir connected to each balloon. As a result, both ventricular pressure-volume relationships were hardly affected by an increase in the atrial pressure ranging from 5 to 30 cm H2O with the pericardium removed, although the ventricle became less compliant due to an increase of the same magnitude of the opposite ventricular pressure. On the other hand, the effect of an increase in atrial pressure was distinct with the pericardium intact. Also, all mechanical interactions were enhanced dramatically with the intact pericardium. Thus, the pericardium plays an important role in these mechanical interactions, especially when the filling pressures of all heart chambers increase simultaneously. Clinically, these findings may be important to understanding ventricular functions as related to various heart disease-especially acute heart failure.

Animals↗
PubMed2006

Optimizing engineered heart tissue for therapeutic applications as surrogate heart muscle.

BACKGROUND: Cardiac tissue engineering aims at providing heart muscle for cardiac regeneration. Here, we hypothesized that engineered heart tissue (EHT) can be improved by using mixed heart cell populations, culture in defined serum-free and Matrigel-free conditions, and fusion of single-unit EHTs to multi-unit heart muscle surrogates. METHODS AND RESULTS: EHTs were constructed from native and cardiac myocyte enriched heart cell populations. The former demonstrated a superior contractile performance and developed vascular structures. Peptide growth factor-supplemented culture medium was developed to maintain contractile EHTs in a serum-free environment. Addition of triiodothyronine and insulin facilitated withdrawal of Matrigel from the EHT reconstitution mixture. Single-unit EHTs could be fused to form large multi-unit EHTs with variable geometries. CONCLUSIONS: Simulating a native heart cell environment in EHTs leads to improved function and formation of primitive capillaries. The latter may constitute a preformed vascular bed in vitro and facilitate engraftment in vivo. Serum- and Matrigel-free culture conditions are expected to reduce immunogenicity of EHT. Fusion of single-unit EHT allows production of large heart muscle constructs that may eventually serve as optimized tissue grafts in cardiac regeneration in vivo.

Animals↗
PubMed1999

Neurologic status of newborns with congenital heart defects before open heart surgery.

UNLABELLED: Controversy exists regarding the integrity of the nervous system in the newborn with a congenital heart defect who must undergo corrective or palliative open heart surgery. Neurodevelopmental sequelae have been primarily attributed to surgical procedures without standardized evaluation of the preoperative neurologic status. OBJECTIVE: To determine whether newborns with congenital heart defects demonstrate abnormalities in neurobehavioral status before surgery. STUDY DESIGN: In this prospective study, a standardized neonatal neurobehavioral assessment and a neurologic examination were conducted independently in a consecutive series of 56 neonates referred to our hospital for investigation of open heart surgery. RESULTS: Neurobehavioral and neurologic abnormalities were documented in greater than half of the cohort and included hypotonia, hypertonia, jitteriness, motor asymmetries, and absent suck. Poor state regulation (62%) and feeding difficulties (34%) also were commonly observed. Furthermore, 3 subjects had seizures, 35.7% were microcephalic, and 12.5% were macrocephalic. The overall likelihood of neurobehavioral abnormalities was not enhanced by indicators of cardiorespiratory compromise. Interestingly, newborns with acyanotic congenital heart defects were more likely to demonstrate neurologic compromise than were those with cyanotic defects. CONCLUSIONS: Findings suggest that the prevalence of neurobehavioral abnormalities before surgery in newborns with congenital heart defects has been underappreciated and would indicate that factors other than intraoperative procedures should be considered in the genesis of brain injury in this population.congenital heart defects, neurologic examination, newborn.

Heart Defects, Congenital↗
PubMed2001

Impaired capsaicin-induced decrease in heart rate and coronary flow in isolated heart of diabetic rats.

The effect of capsaicin (0.1 microM) on heart rate and coronary flow was studied in Langendorff-perfused heart from streptozotocin-induced (50 mg/kg i.v.) diabetic rats where sensory neuropathy developed. In hearts from animals 4- and 8-week diabetes baseline heart rate and coronary flow decreased from 317.9 +/- 2.9 b.p.m. and 13.4 +/- 0.7 m/min to 255.1 +/- 12.7 and 219.8 +/- 2.8 b.p.m. and 8.9 +/- 0.6 and 10.0 +/- 0.1 ml/min (P<0.05), respectively. Capsaicin significantly decreased both variables in either normal or 4-week diabetic animals its effects, however, on coronary flow or heart rate were missing in preparations from 8-week diabetic rats. Endothelin-1 (0.1 nM), the putative mediator of the capsaicin effect, significantly decreased heart rate and coronary flow irrespective of the presence or absence of diabetes. In the femoral nerve of streptozotocin-treated animals conduction velocity involving both fast conducting A- and slow-conducting C-fibres was decreased proportional to the duration of the pre-existing diabetic state. It is concluded that in insulin deficient diabetes the diminished responses evoked by capsaicin on heart rate and coronary flow are signs of sensory neuropathy. This is related to a feeble endothelin release from sensory nerve endings without changes in post-receptor mechanisms mediating the endothelin effects.

Animals↗
PubMed2002

Heart rate recovery after exercise: relations to heart rate variability and complexity.

Physical exercise is associated with parasympathetic withdrawal and increased sympathetic activity resulting in heart rate increase. The rate of post-exercise cardiodeceleration is used as an index of cardiac vagal reactivation. Analysis of heart rate variability (HRV) and complexity can provide useful information about autonomic control of the cardiovascular system. The aim of the present study was to ascertain the association between heart rate decrease after exercise and HRV parameters. Heart rate was monitored in 17 healthy male subjects (mean age: 20 years) during the pre-exercise phase (25 min supine, 5 min standing), during exercise (8 min of the step test with an ascending frequency corresponding to 70% of individual maximal power output) and during the recovery phase (30 min supine). HRV analysis in the time and frequency domains and evaluation of a newly developed complexity measure - sample entropy - were performed on selected segments of heart rate time series. During recovery, heart rate decreased gradually but did not attain pre-exercise values within 30 min after exercise. On the other hand, HRV gradually increased, but did not regain rest values during the study period. Heart rate complexity was slightly reduced after exercise and attained rest values after 30-min recovery. The rate of cardiodeceleration did not correlate with pre-exercise HRV parameters, but positively correlated with HRV measures and sample entropy obtained from the early phases of recovery. In conclusion, the cardiodeceleration rate is independent of HRV measures during the rest period but it is related to early post-exercise recovery HRV measures, confirming a parasympathetic contribution to this phase.

Adult↗
PubMed1987

Interrelationships between the heart and central nervous system: localization of neuro-transmitters and imaging of their associated nuclei, including the raphe nuclei & the locus coeruleus, as well as the imaging of the heart and its representation areas in slices of the human central nervous system using the "Bi-Digital O-Ring Test" imaging method.

Using microscopic slides of specific tissues from the human body or pure substances including neuro-transmitters such as serotonin, dopamine, norepinephrine, etc., as reference control substances in the Bi-Digital O-Ring Test Molecular Identification Method, the author was able to localize and image normal and abnormal internal organs, and to localize and trace the distribution of neurotransmitters in the different parts of the central nervous system. Using microscopic slides of different parts of the heart, we were able to image the outline of the heart as well as the SA node, AV node, tricuspid valve, mitral valve, aortic valve, pulmonary valve, coronary arteries, and aorta and its branches, including the vertebral arteries, without using any bulky or expensive imaging instruments. Using serotonin as a reference control substance on the different parts of the central nervous system, it was possible to demonstrate the 6 well-known raphe nuclei and the locus coeruleus (which contains serotonin & norepinephrine), as well as the distribution of serotonin in the cerebrum and the cerebellum, all of which closely resembled previously published well-known neuroanatomical structures and distributions of neurotransmitters. As an extension of this work, possible representations of different internal organs on the central nervous system were examined using microscopic slides of different internal organs as reference control substances. The results indicated that the entire heart is represented primarily in the medulla oblongata, and that the SA node and the upper half of the left atrium are represented in the caudal end of the pons; the right side of the heart (i.e. R-atrium, AV node, tricuspid valve, R-ventricle) is represented on the right side of the medulla oblongata, and the left side of the heart (i.e. lower half of the L-atrium, mitral valve, L-ventricle) is represented on the left side of the medulla oblongata, and the upper half of the left atrium is represented in the caudal end of the left side of the pons. The bottoms of the ventricles are located near the spinal cord. Furthermore, the right and the left sides of the heart are represented in specific areas of each side of the right and left hemispheres of the cerebral cortex, and there are connecting pathways between the representation areas of identical parts of the heart, through the corpus callosum and other neuro-pathways.

Central Nervous System↗
PubMed2001

[Anesthesia for a patient with alcoholic heart disease and transient complete heart block].

A 70-year-old man who had been drinking a bottle of whisky each day was scheduled for laser resection of a tongue tumor. His electrocardiogram showed sinus bradycardia (heart rate was 35-40 bpm), and transient complete heart block was observed. Echocardiography showed hypertrophic cardiomyopathy. After a temporary transvenous pacemaker had been inserted, anesthesia was induced with thiopental and vecuronium bromide, and maintained with sevoflurane and fentanyl. Heart rate was 45.min-1 before the induction of anesthesia, and after the induction increased to 70-80.min-1. Analysis of heart rate variability suggested that the increase in heart rate was due to augmentation of sympathetic nervous activity after intubation and operation stress. After the operation his bradycardia improved gradually, and after 3 months heart rate settled at about 55.min-1. Cadiomyopathy is known to be one of the complications of alcoholism. It was reported that alcoholic heart disease was improved promptly by abstinence from alcohol. During his long hospitalization, abstinence might have improved his severe bradycardia. Thiopental is useful for induction of anesthesia in a patient with severe bradycardia from alcoholic cadiomyopathy.

Aged↗
PubMed2002

[Experience of coronary artery bypass grafting on the beating heart with right heart bypass; 3 cases of octogenarian].

Right heart bypass (RHB) yields more stable hemodynamics by increasing left ventricular preload and collapse right ventricular chamber during the displacement of the heart on beating heart coronary artery bypass grafting (CABG). Recently beating heart CABG gaining popularity, and the indications for CABG have increasingly expanded to elderly person. Using RHB while exposing posterior branches by displacing the beating heart, we have attempted to make total revascularization in beating heart CABG. We performed beating heart CABG with RHB in 3 cases of octogenarian. All patients had left main trunk lesion and needed revascularization of posterior vessels. Introduction of RHB enabled us to approach to posterior target vessels in better exposure and under greater hemodynamic stability. All three patients had no complications postoperatively. Strictly speaking CABG with RHB is not off-pump CABG, but RHB system does not include either artificial lung or manipulation of the aorta. Therefore we think it is very effective support system which enables multiple coronary revascularization for elderly person.

Aged↗
PubMed1992

Myocardial creatine kinase-MB concentration in normal and explanted human hearts and released from hearts of patients with acute myocardial infarction.

Using an enzyme immunoassay of creatine kinase (CK)-MB concentration commercially available for diagnosis of acute myocardial infarction (AMI), we studied CK-MB concentrations in myocardium of subjects who died from noncardiac causes and in cardiac explants of patients with either coronary heart disease or cardiomyopathy who underwent cardiac transplantation. Secondly, CK-MB concentrations were measured in serial plasma samples of 93 patients with AMI. By calculation of cumulatively released amounts of CK-MB and cumulatively released activities of CK, aspartate aminotransferase (AST) and alpha-hydroxybutyrate dehydrogenase (HBDH), we obtained values of the proportions in which these quantities were released from the myocardium. Taking a myocardial HBDH activity of 152 U/g as a reference value, the released activities of CK and AST, and the released mass of CK-MB per gram of myocardium were calculated. These values were compared to the corresponding quantities in myocardium of normal hearts and in explanted myocardium. Normal hearts differ from explanted myocardium and from "infarcted" hearts with respect to CK-MB concentration, but not with respect to CK, AST and HBDH activities. The wide range of CK-MB concentrations in normal hearts (1-515 micrograms/g) suggests variable expression of the CK-MB gene. The presence of CK-MB is not confined to cardiac tissue. CK-MB concentration in 12 samples of human skeletal muscle equalled 27 +/- 1 micrograms/g (2.1 +/- 0.5% of total CK activity). In conclusion, the mean concentration of CK-MB in normal hearts is low (139 micrograms/g) with a high variation coefficient (127%), but is high (369 micrograms/g) with a small variation coefficient (31%) in explanted hearts.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed2005

[Study on cardiac gene expression microarray and recipe for activating blood circulation and supplementing qi on heart of rats with post-infarction heart failure].

OBJECTIVE: To observe the effect of recipe for activating blood circulation and supplementing Qi (RAS) on cardiac functional structure in rats with post-infarction heart failure (PIHF). METHODS: Rat model of PIHF was established by left coronary artery ligation. Left ventricular samples of model rats from infarcted or peri-infarcted area were obtained at PIHF formation stage and stable stage (10 days and 8 weeks respectively after operation), the total RNA extracted and detected using 6 pieces of rat's 40s gene microarray (4096 genes/microarray), the data were analyzed using software as Genespring, Treeview, Clustering and SOM. Besides, RAS was used to treat the model rats beginning from 4 weeks after modeling and lasted for 4 weeks, changes of heart function and cardiac coefficient before and after treatment were observed by impedance method with Captopril as positive control. RESULTS: (1) Genespring analysis showed thousands of genes differential expression (upper or down regulated), including 13 kinds of gene involving energy metabolism, myocardial cytoskeleton, fibrosis, etc. which, in the infarcted area at heart formation stage were 1086 genes and at the stable stage, 724 genes, while in the peri-infarcted area, formation stage 196 genes and stable stage 97 genes. (2) After RAS or Captopril treatment, the heart function improved significantly, with the stroke volume, cardiac output and cardiac index increased significantly (P < 0.01). RAS could also improve the cardiac coefficient of model rats, as compared with that in untreated model, P < 0.01, compared with that in the sham-operated rats, P < 0.05. CONCLUSION: PIHF is a kind of overload heart disease with multiple genes abnormality. RAS could improve the heart function and histologic indexes, so as to treat the heart failure.

Animals↗
PubMed2005

Heart disease and prevention: race and age differences in heart disease prevention, treatment, and mortality.

OBJECTIVE: The objective of this study was to analyze race and age differences in the distribution of health promotion and cardiovascular screening tests, and the prevalence of serious heart disease and cardiovascular mortality in the United States. DATA SOURCES/STUDY POPULATION: Data are from 7 federal datasets represented in the first National Healthcare Quality Report and the National Healthcare Disparities Report, and include surveys, administrative and vital statistics data systems. The study analyzes blacks and whites. MEASURES: Counseling on diet and nutrition, exercise, and tobacco during an outpatient visit indicate the availability of health promotion services, and screening for high blood pressure and cholesterol represent preventive services. Hospitalizations for heart-related conditions and use of certain cardiac procedures identify serious heart disease. Deaths from coronary artery disease and stroke are the heart-related mortality measures. PRINCIPAL FINDINGS: Counseling and education services tend to occur more on outpatient visits by individuals aged 45 to 64 years than in younger age groups. Screening rates among individuals aged 45 to 64 years of approximately 90% for hypertension and 80% for high cholesterol suggest progress in early detection of cardiac risk factors. However, blacks aged 45 to 64 years are 5.6 times more likely than their white counterparts to be hospitalized for hypertension, approximately one third less likely to receive a cardiac procedure, and almost twice as likely to die of coronary heart disease. CONCLUSIONS: Although findings indicate few racial differences in health promotion services in ambulatory care or screening for cardiac risk factors, the prevalence of serious cardiovascular disease, use of cardiac procedures, and heart-related mortality suggest continuing racial disparities in heart disease.

Adolescent↗
PubMedDate not supplied

Cardioprotection by aldosterone receptor antagonism in heart failure. Part I. The role of aldosterone in heart failure.

In recent years understanding of the role of aldosterone has expanded beyond the known classic effects of promoting renal sodium retention and potassium and magnesium loss. It is now well documented that aldosterone causes myocardial and perivascular fibrosis, blocks the myocardial uptake of norepinephrine, and increases plasminogen activator inhibitor levels. In conjunction with angiotensin II, aldosterone causes vascular damage, endothelial dysfunction, and decreased vascular compliance. Therefore, the renin-angiotensin-aldosterone system (RAAS) plays a major role in the development of both hypertension and heart failure and is therefore, a key target for therapeutic interventions. Commonly prescribed medications for control of hypertension and congestive heart failure are inhibitors of the RAAS, including angiotensin converting enzyme inhibitors (ACE-I) and Angiotensin II (A-II) receptor antagonists. There is a well-documented increase in aldosterone levels that occurs over several months during chronic treatment with an ACE-I or A-II receptor antagonist. Such suppression of circulating aldosterone however, is transient, as exemplified by the term "escape" used to describe the phenomenon. This rebound of aldosterone even occurs when patients receive both an ACE-I and A-II receptor antagonist. In addition, ACE-I and A-II receptor antagonists are less effective in controlling BP in the estimated 60% of hypertensive patients who are salt (volume) sensitive and more prone to hypertension-associated morbidity such as black patients and type 2 diabetics. Thus chronic and complete blockade of aldosterone action requires an aldosterone receptor antagonist. The "Randomized Aldactone Evaluation Study" (RALES) trial results in patients with severe heart failure NYHA class III or IV and a left ventricular ejection fraction of no more than 35 percent showed that administration of a sub-hemodynamic dose of spironolactone (25 mg a day) as an add on therapy to ACE-I plus standard treatment resulted in a significant mortality reduction due both to decreased death from progressive heart failure and sudden cardiac death. These findings support the pivotal role of aldosterone in the pathophysiology of progressive heart failure. Although it is an effective antialdosterone agent, widespread use of spironolactone in humans is limited by its tendency to produce undesirable sexual side effects. At standard doses, impotence and gynaecomastia can be induced in men, whereas pre-menopausal women may experience menstrual disturbances. Data on a selective aldosterone receptor antagonist, eplerenone, appear promising for the effective blockade of aldosterone and its harmful effects without the sexual disturbances of spironolactone. Recently Eplerenone was successfully introduced for the treatment of hypertension and heart failure. Growing number of experimental studies are finding a broader role for Aldosterone in driving the pathophysiology of both heart failure and hypertension. When added to conventional therapy aldosterone receptor blockers show benefits which are in addition to those conferred by ACE-I and/or AII receptor blockers.

Animals↗
PubMed2006

[Adeno-associated viral gene transfer of SERCA2a improves heart function in chronic congestive heart failure rats].

OBJECTIVE: To study the therapy effect of adeno-associated viral gene transfer of sarcoplasmic reticulum Ca(2+)-ATPase 2a (SERCA2a) on chronic congestive heart failure (HF) in 30 days, and the possible mechanism of the therapy effect. METHODS: The rats were divided into four groups: control group, HF group, Group HF + EGFP, and Group HF + SERCA2a. HF rats were obtained by creating descending aortic constriction. 0.9% sodium chloride solution, recombinant adeno-associated virus carrying enhanced green fluorescent protein gene (rAAV2.eGFP) and recombinant adeno-associated virus carrying SERCA2a gene (rAAV2.SERCA2a), were respectively delivered to pericardium of HF rats in different groups by intrapericardial injection with a trans-diaphragmatic approach. 30 days after gene transfer, hemodynamic parameters, SERCA2a protein expression and SERCA2a activity were analyzed. The proteome difference from rat hearts between Groups HF + SERCA2a and HF was detected by expression proteomics. Electrophoretic separation and quantitation of cardiac myosin heavy chain isoforms of hearts in different groups were performed at 30 days. RESULTS: At 30 days, left ventricular function improved significantly in HF rats infected with rAAV2.SERCA2a (LVSP 146.52 +/- 13.86 vs 97.91 +/- 12.13, LVEDP 7.88 +/- 2.88 vs 21.15 +/- 3.57, LV +dp/dt 11 206.16 +/- 1730.11 vs 5948.93 +/- 1283.43, LV -dp/dt -8249.54 +/- 1076.09 vs -4497.50 +/- 652.12; P < 0.05). The recovered cardiac function in Group HF + SERCA2a rats was comparable to control rats, and had lower LV-weight/Body-weight ratio (2.46 +/- 0.17 vs 2.71 +/- 0.24, P < 0.05). Overexpression of SERCA2a increased both the protein content (0.39 +/- 0.11 vs 1.11 +/- 0.18, P < 0.05) and activity (228.62 +/- 25.11 vs 82.55 +/- 14.13, P < 0.05) up to nonfailing levels. Expressions of some energy metabolic enzymes in hearts of Group HF + SERCA2a were much higher than those of HF group. They included creatine kinase-muscle, enolase beta, fructose-bisphosphate aldolase, mitochondrial H(+)-ATP synthase alpha subunit, electron transfer flavoprotein alpha-subunit, H(+)-transporting ATP synthase and heart fatty acid binding protein. Downregulation of alpha-MHC and upregulation of beta-MHC in failing hearts were observed. Gene transfer of SERCA2a could increase the expression of alpha-MHC [(74.48 +/- 3.74)% vs (53.57 +/- 2.30)%, P < 0.05], and decrease the expression of beta-MHC [(25.52 +/- 3.74)% vs (46.43 +/- 2.30)%, P < 0.05] in HF rats. The expression profiles of alpha-MHC and beta-MHC and the ratio of alpha-MHC/beta-MHC were similar to those in controls. CONCLUSIONS: Adeno-associated viral gene transfer of SERCA2a can enhance SERCA2a functions, maintain calcium homeostasis, improve cardiac energy metabolism, and normalize the expression of cardiac myosin heavy chain isoforms in HF rats. As a result, the ventricular systolic and diastolic functions can be improved significantly, and the hypertrophy of the heart may be reduced in clinic. Adeno-associated viral gene transfer of SERCA2a demonstrated good therapy effects on HF rats.

Adenoviridae↗