In vivo data have been unable to provide conclusive results with regard to the relative impact of circumferential and longitudinal shortening on stroke volume. The objective of the present study was to assess the relative contribution of circumferential and longitudinal myocardial shortening to left ventricular stroke volume and ejection fraction, and to evaluate the effect of left ventricular hypertrophy. A two-shell, three-dimensional mathematical model was used to assess the individual contributions of longitudinal and midwall circumferential shortening (or strain) to stroke volume and ejection fraction. Reducing either circumferential or longitudinal shortening resulted in a reduced ejection fraction and stroke volume. The stroke volume fell by 43% when circumferential strain was reduced from −20% to −5%, but only by 19% when longitudinal strain was similarly reduced. The sole contribution of circumferential and longitudinal shortening to stroke volume was 67% and 33%, respectively. These proportions were independent of wall thickness. The present study demonstrated that both longitudinal and midwall circumferential shortening contribute to different extents depending on the degree of abnormality of myocardial shortening. Contrary to most previous studies, the present study shows that circumferential shortening has a relatively greater contribution to stroke volume (ie, two-thirds) and ejection fraction than longitudinal shortening. These observations have important clinical and research implications in the assessment of left ventricular function.

Diabetes mellitus encompasses a group of chronic metabolic conditions associated with cardiovascular complications such as atherosclerosis, cardiomyopathy and nephropathy. In the present study, the authors investigated the beneficial effects of swertiamarin in diabetes and its associated cardiovascular complications in Zucker fa/fa rats. Six male Zucker fa/fa rats in each group were treated for 28 days with swertiamarin (75 mg/kg/day, intraperitoneally) or pioglitazone (30 mg/kg orally). Blood samples were collected and evaluated for several parameters. Elevated serum glucose, triglyceride, nonesterified free-fatty acid and cholesterol levels were found in untreated Zucker fa/fa rats. Serum matrix metalloproteinase (MMP)-9 and MMP-3 levels were also found to be significantly higher in untreated Zucker fa/fa rats. Treatment with swertiamarin significantly (P<0.05) reduced serum glucose, triglyceride, nonesterified free-fatty acid and cholesterol levels, and also reduced serum MMP-9 and MMP-3 levels compared with untreated rats. Swertiamarin also significantly (P<0.05) decreased serum levels of urea compared with untreated Zucker fa/fa rats. Overall, the data suggest that swertiamarin produced beneficial effects with respect to diabetes-induced cardiovascular complications such as atherosclerosis and nephropathy. A swertiamarin-induced decrease in serum MMP-9 and MMP-3 levels is one of the possible mechanisms responsible for improvement of these complications.

A history of severe allergic reaction to iodine contrast leading to anaphylactic shock presents a dilemma in patients requiring cardiac catheterization. As an alternative, gadolinium has been an interesting and potentially useful agent. However, gadolinium produces poor image quality and has been associated with significant arrhythmias in small case series. Furthermore, there is no consensus about the maximal allowable dose that can be administered to a patient. In the present report, a successful combination of gadolinium contrast with a power injector that produced adequate image quality in a patient with severe allergy to iodine contrast is described. The case was complicated by the occurrence of ventricular fibrillation when damping occurred during injection of contrast into the right coronary artery. This complication has been reported previously with intracoronary gadolinium injection. The report is followed by a brief literature review.

BACKGROUND:

Studies have shown that rheumatoid arthritis (RA) patients are two to five times more likely to develop premature cardiovascular disease, thus shortening their life expectancy by five to 10 years. This risk has risen to approximately 12.6% in the urban population and 7.4% in the rural population of India. The Framingham risk score (FRS) identifies patients at increased cardiovascular risk and helps determine the need for preventive interventions. An investigation of the patients’ coronary arteries and coronary artery calcification (CAC) – a measure of atherosclerotic plaque – has been found to be a strong predictor of cardiovascular disease.

OBJECTIVE:

To identify important biological markers for easy and non-invasive identification of cardiovascular disease in RA patients, and to investigate whether there is a relationship between the FRS and coronary artery atherosclerosis in RA patients.

METHODS:

The present study included 43 established RA patients and 50 healthy individuals (controls). Traditional and nontraditional risk factors were studied and compared with the control group. Insulin resistance was assessed using the homeostasis model of assessment of insulin resistance (HOMA-IR) and the homeostasis model of assessment of beta cell function. The FRS and the 10-year cardiovascular risk were compared between RA patients and controls. The presence of CAC was determined using electron-beam computed tomography, and the association between the FRS and CAC was examined.

RESULTS:

Significant differences in body mass index, waist circumference, rheumatoid factors (immunoglobulin [Ig]G, IgM and IgA) and inflammatory markers – C-reactive protein and erythrocyte sedimentation rate – were noted. There was significant correlation between HOMA-IR and body mass index, hypertension and C-reactive protein, but no correlation was seen with the homeostasis model of assessment of beta cell function. Significant differences were observed in the nontraditional biomarkers in RA patients, thus supporting their importance. Calcium deposition was observed in only seven RA patients.

CONCLUSIONS:

RA patients with increased C-reactive protein levels and erythrocyte sedimentation rates showed an increase in serum insulin levels and significant differences in HOMA-IR, thus indicating insulin resistance, which could lead to underlying progression of artherosclerosis. Significant differences were observed in the nontraditional risk factors, which could be chosen as biomarkers for endothelial dysfunction. There was a significant correlation between calcium score and the FRS in seven patients, suggestive of an underlying risk of atherosclerosis.

BACKGROUND:

Hypertrophic cardiomyopathy (HCM) is a disease of the heart muscle, with an autosomal dominant mode of inheritance. It is also known as the ‘disease of the sarcomere’, and is a major cause of morbidity and mortality worldwide. Mutations in the sarcomeric genes have been largely implicated in the manifestation of HCM. Modifier genes and environmental factors, along with causative mutation, add to the cumulative effect of the disease.

METHODS:

In the present study, the role of the cardiac actin gene and the cardiac muscle LIM protein as contributors to HCM – through genetic variation – has been elucidated by screening the entire coding region in 100 control and 100 HCM subjects through polymerase chain reaction-based single-strand conformation polymorphism analysis and direct sequencing.

RESULTS:

The authors could not find any novel or reported exonic variations in any of the genes in the studied population; however, intronic variations were revealed in the cardiac actin gene through direct sequencing. A case of compound heterozygosity was observed in a patient with a variation in intron 1, along with a novel heterozygous mutation in exon 7 (S215L) of α-tropomyosin.

CONCLUSIONS:

The particular genes are highly conserved, and account for only 1.5% of HCM cases. They do not seem to play a major role in the genesis of HCM in the present population, thus confirming earlier reports of conserved sequences and ethnicity.

BACKGROUND:

Several allelic variants of matrix γ-carboxyglutamic acid protein (MGP) can differentially affect the development of certain forms of ischemic heart disease depending on specific characteristics of each population.

OBJECTIVE:

To study the distribution of allelic variants of MGP promoter T−138→C (rs1800802) and G−7→A (rs1800801), and Thr83→Ala exon 4 (rs4236) polymorphisms in a Ukrainian population of patients with acute coronary syndrome (ACS).

METHODS:

Polymerase chain reaction and restriction fragment length polymorphism (RFLP) analysis were used to detect the above-mentioned variants of the MGP gene in 115 patients with ACS and in 140 essentially healthy individuals.

RESULTS:

The distribution of homozygous carriers of a major allelic variant, and heterozygous and homozygous minor allele variants of the T−138→C MGP promoter polymorphism in patients with ACS were 59.8%, 32.7% and 7.5%, respectively. The corresponding distributions of variants in the control group were 54.0%, 41.0% and 5.0%, respectively (P>0.05 [χ2 test]). With respect to the G−7→A polymorphism, the respective distributions were 42.1%, 45.6% and 12.3%, compared with 50.7%, 45.0% and 4.3% in the control group, respectively (P<0.05). Finally, the respective distributions according to the Thr83→Ala exon 4 polymorphism were 42.6%, 43.5% and 13.9%, respectively, compared with 45.3%, 43.0% and 11.7% in the control group. Using logistic regression analysis, it was estimated that the A/A genotype (G−7→A polymorphism) was significantly (P=0.02) associated with ACS (OR 4.302 [95% CI 1.262 to 14.673]).

CONCLUSION:

The allelic A/A promoter variant of MGP G−7→A polymorphism can be considered a risk factor for ACS in the Ukrainian population.

BACKGROUND:

An inflammatory response and systemic oxidative stress are directly caused by coronary artery bypass grafting (CABG) surgery. Cytokines, such as interleukin (IL) 1β, IL-6 and tumour necrosis factor-α (TNF-α), can also be stimulated. Reducing the release of pro-inflammatory cytokines plays an important role in limiting the postoperative inflammatory response. Silymarin has strong anti-inflammatory, antioxidant and cytoprotective properties.

OBJECTIVE:

To investigate the protective anti-inflammatory and antioxidant properties of silymarin against the inflammation and oxidative stresss inherent to CABG surgery.

METHODS:

Of the 102 patients undergoing elective first-time CABG surgery that were recruited, 50 (49.02%) received silymarin treatment and 52 (50.9%) were controls. Plasma cytokine levels (IL-1β, IL-6 and TNF-α) were measured preoperatively, 6 h and 24 h after CABG surgery. C-reactive protein (CRP) levels, trolox equivalent antioxidant capacity (TEAC) and glutathione (GSH) and malondialdehyde (MDA) levels were analyzed.

RESULTS:

Postoperative cytokine levels in the silymarin group were significantly lower compared with preoperative levels, and were significantly lower compared with postoperative control group levels. The area under the curve for cytokines and CRP for the silymarin group were significantly lower compared with preoperative levels, and were significantly lower compared with postoperative control group levels. Postoperative levels of TEAC and MDA in the silymarin-treated group were significantly lower than in the control group. GSH levels were significantly elevated in the silymarin group compared with control. No side effects or mortality were associated with the use of silymarin.

CONCLUSION:

The anti-inflammatory and antioxidant effects of silymarin treatment provided protection against reperfusion injury and inflammation after CABG surgery.

Cardiac angiosarcomas are rare, rapidly progressive tumours that often present as diagnostic dilemmas resulting in delayed diagnosis. They should be considered in patients with recurrent pericardial effusions.

A 33-year-old man presented for evaluation of a recurrent pericardial effusion. Infectious and rheumatological workups were negative. Pericardial fluid cytology and pericardial biopsy were unremarkable. Imaging, including echocardiogram and magnetic resonance imaging, were nondiagnostic.

While awaiting surgical intervention, the patient developed respiratory failure requiring urgent intubation. Intraoperatively, he experienced significant hemorrhage from the myocardium. Hemostasis could not be achieved and the patient expired. Pathology reports revealed metastatic angiosarcoma.

The present case illustrates a rare case of primary cardiac angiosarcoma posing a diagnostic dilemma in a young man. The authors present the challenges in diagnosis, and review the most current diagnostic and therapeutic strategies in the care of patients with this condition.

For many years, ergotamine has been used for the acute treatment of migraine. Ergotamine may produce coronary vasospasm, which is often associated with ischemic electrocardiography changes and angina pectoris. A 62-year-old woman who was admitted to the emergency department because of chest pain is described. She had a history of severe migraine attacks and started to use ergotamine tartrate 0.75 mg daily the day before. Electrocardiography revealed sinus tachycardia with left anterior hemiblock and T wave inversion in the precordial leads. Cardiac biomarker levels were elevated. After discontinuation of the drug and initiation of vasodilator treatment, her chest pain resolved. Patients with migraine may have an underlying vasospastic disorder predisposing them to coronary artery spasm. Physicians should be alerted to potential cardiac vasospastic effects of low-dose ergotamine in the treatment of migraine.

Recent advances in diagnosis, surgery and interventional management have significantly changed the quality of life of patients with congenital heart disease. Historically, congenital heart disease patients with multiple cardiac lesions have been referred for surgery; however, with the advent of newer technologies and expertise, transcatheter treatment has evolved as an alternative option. A series of patients who underwent interventional procedures for multiple congenital heart disease lesions with excellent procedural and medium-term outcomes is reported.

BACKGROUND:

Coronary artery disease (CAD) occurs at an earlier age in South Asians compared with other ethnic groups. Infection and inflammation show a positive association with the disease.

OBJECTIVE:

To investigate the association of infection and inflammatory markers with premature CAD in the Indian Atherosclerosis Research Study population.

METHODS:

Antibody titres for Chlamydia pneumoniae, cytomegalovirus (CMV), Helicobacter pylori, herpes simplex virus and levels of interleukin-6 (IL-6), high-sensitivity C-reactive protein (hsCRP), fibrinogen and secretory phospholipase A2, were measured in 866 individuals (433 CAD patients and matched controls). All individuals were followed-up for recurrent cardiac events for four years. ANOVA was used to study the association of infection and inflammation with CAD.

RESULTS:

The present study found that the odds of CAD occurrence was 2.42 (95% CI 1.26 to 4.64; P<0.008), with all four infections and increased in the presence of hsCRP (OR 4.67 [95% CI 1.43 to 15.25]); P=0.011). Only anti-CMV antibody levels were a significant risk factor for CAD occurrence (OR 2.23 [95% CI 1.20 to 4.15]; P=0.011) and recurrent cardiac events (OR 1.94 [95% CI 0.85 to 4.45]; P=0.015). Mean values of the inflammatory biomarkers IL-6 (P=0.035), fibrinogen (P=0.014), hsCRP (P=0.010) and secretory phospholipase A2 (P=0.002) increased with CMV antibody levels. Incorporating hsCRP and IL-6 in the risk prediction models significantly increased the OR to 2.56 (95% CI 1.16 to 5.63; P=0.019) with a c statistic of 0.826.

CONCLUSIONS:

Pathogen burden, especially CMV infection in combination with inflammatory markers, is a significant predictor of CAD risk in the young Indian population.

Coronary artery aneurysms are rare malformations caused by atherosclerosis, connective tissue disease or vasculitides, and are usually discovered incidentally with invasive coronary angiography. A case involving a 58-year-old male presenting with an acute coronary syndrome who was found on invasive angiogram to have a giant aneurysm of the left anterior descending coronary artery is described. The incidence, pathophysiology and management of giant aneurysms in the context of an acute coronary syndrome are reviewed.

Acute ST-elevation myocardial infarction (STEMI) is a well recognized manifestation of severe coronary artery spasm. Although there are many recognized triggers, hypovolemia has not been previously described. The present report describes a case of acute STEMI that occurred four days following major colonic surgery in a severely dehydrated patient. Coronary angiography revealed underfilled coronary arteries with severe multifocal spasm, which largely resolved with aggressive fluid repletion and intracoronary nitrate.

Lung tumours are the leading metastatic cancers that spread to the heart through direct invasion, and rarely extend into the chambers of the left side of the heart via pulmonary veins. A case of primary lung sarcoma involving a patient who presented with dyspnea and fatigue is reported. This sarcoma extended from the lung into the left atrium via (a/the) pulmonary vein. Chemotherapy and radiotherapy were recommended. Surgery was not considered due to high risk and the advanced stage of the tumour.

The presence of coronary ectasias in otherwise normal epicardial coronary arteries are an infrequent angiographic finding. Coronary ectasia is not a benign condition and has been associated with a high risk of coronary events. In the present case, a patient with left dominant coronary artery ectasia who developed ventricular fibrillation during coronary angiography is described. This event was unexpected, and has not been previously reported.

Left ventricular noncompaction is a condition characterized by prominent ventricular trabeculations, often accompanied by systolic dysfunction. The present case involves an adult with a small ventricular septal defect, initially exhibiting mild systolic dysfunction and slightly prominent left ventricular trabeculations progressing over 13 years to severe dilated cardiomyopathy and overt noncompaction. The present case strongly suggests a correlation between the extent of noncompaction and the degree of systolic dysfunction. The initial presence of a small ventricular septal defect and mild trabeculations highlights the genetic determinants of non-compaction and the importance of closely following patients with mild noncompaction due to the possibility of progression. More sensitive diagnostic criteria are needed to avoid overlooking mild cases, which may show prominent trabeculations without reaching a requisite ratio of compacted to noncompacted tissue.

BACKGROUND:

The critical role of microRNAs (miRNAs) in the global control of gene expression in the heart has recently been postulated; however, the mechanisms of miRNA regulation in cardiac pathology are not clear.

OBJECTIVE:

To evaluate the levels of miR-1, miR-208a and miR-29a expressed in neonatal rat cardiomyocytes during anoxia-reoxygenation (AR).

METHODS:

Reverse transcription coupled with real-time polymerase chain reaction was used to evaluate the level of mature and immature miRNAs in cardiomyocyte culture during AR.

RESULTS:

The initial levels of the mature and immature miRNAs were different: mature – miR-1 7.46±4.440, miR-208a 0.02±0.015 and miR-29a 5.60±2.060; immature – miR-1 0.02±0.007, miR-208a 0.05±0.029 and miR-29a 0.01±0.008. The most prominent changes were observed for immature miRNAs during AR, with immature miR-1 and miR-29a expressed at significantly higher levels during remote reoxygenation (AR [0.5 h/24 h]) compared with control, while the level of expressed immature miR-208a was significantly decreased during acute reoxygenation (AR [0.5 h /1 h]) and returned to control levels during remote reoxygenation (AR [0.5h /24 h]). Also, the ratios of mature to immature miRNAs were significantly increased during acute reoxygenation for miR-1 and miR-208a, returning to control levels during remote reoxygenation, while for miR-29a, this ratio had the progressive tendency to decrease under AR.

CONCLUSION:

The discordance between the estimated levels of mature and immature miRNA during AR supports the hypothesis that transcriptional and post-transcriptional regulatory mechanisms at the miRNA level play a role in the response of cardiomyocytes to AR, and could be a contributing factor in the differential resistance of cardiomyocytes to AR.

In 2003, cardiovascular disease was the most costly disease in Canada, and it is still on the rise. The loss of properly functioning cardiomyocytes leads to cardiac impairment, which is a consequence of heart failure. Therefore, understanding the pathways of cell death (necrosis and apoptosis) has potential implications for the development of therapeutic strategies. In addition, the role of B-cell lymphoma-2 family members is discussed and the importance of mitochondria in directing cell death mechanisms.

Cardiac disease is a global epidemic that is on the rise, despite the recent advances in cardiovascular research. Once the myocardium is injured, it has a limited capacity to activate reparative mechanisms to restore proper cardiac function, leading to the development of systemic heart failure. Autophagy, under certain conditions, may result in cell death, further emphasizing the controversial issues regarding the autophagic process as an adaptive or maladaptive biological response. Although significant progress in understanding the signalling mechanisms of cell death in myocytes has been made, the role of apoptotic cell death and programmed necrosis during heart failure is not completely understood. Insight to how myocytes determine whether to activate apoptotic or programmed necrosis signalling machinery remains under current investigation because it is a major problem for both scientists and clinicians in treating heart failure patients. Herein, the different modes of cell death implicated in heart failure are highlighted, as well as the role of B-cell lymphoma-2 family members and how mitochondria act as central organelles in directing such cell death mechanisms.

This article highlights the important scientific contributions of Dr Pawan Singal in the area of cardiomyocyte necrosis such as the importance of intracellular Ca2+ overloading in mediating cell injury and the pathogenic role of oxidative stress. Parallel to Dr Singal’s findings, the authors also present their own research on a mitochondriocentric signal-transducer-effector pathway to cardiomyocyte necrosis. Understanding these pathogenic origins and pathophysiological expressions of congestive heart failure is paramount to developing medical management strategies.

Congestive heart failure (CHF), a common clinical syndrome, has reached epidemic proportions. Its disabling symptoms account for frequent hospitalizations and readmissions. Pathophysiological mechanisms that lead to CHF and account for its progressive nature are of considerable interest. Important scientific observations obtained from Dr Pawan K Singal’s laboratory in Winnipeg, Manitoba, have provided crucial insights to our understanding of the pathophysiological factors that contribute to cardiomyocyte necrosis (the heart is a postmitotic organ incapable of tolerating an ongoing loss of these cells without adverse functional consequences). This increment in knowledge and the mechanistic insights afforded by Dr Singal and his colleagues have highlighted the role of excessive intracellular calcium accumulation and the appearance of oxidative stress in CHF, in which the rate of reactive oxygen species generation overwhelms their rate of detoxification by antioxidant defenses. They have shown that this common pathophysiological scenario applies to diverse entities such as ischemia/reperfusion and hypoxia/reoxygenation forms of injury, myocardial infarction and the cardiomyopathies that accompany diabetes and excess levels of catecholamines and adriamycin. The authors are honoured to be invited to contribute to the present focus issue of Experimental & Clinical Cardiology in recognizing Dr Singal’s numerous scholarly accomplishments. The present article reviews the authors’ recent work on a mitochondriocentric signal-transducer-effector pathway to cardiomyocyte necrosis found in rats with either an acute stressor state that accompanies isoproterenol administration or a chronic stressor state manifested after four weeks of aldosterone/salt treatment.

Ventricular fibrillation (VF) is the main cause of sudden cardiac death; therefore, understanding the mechanisms responsible for the onset and maintenance of VF is essential, along with investigating the factors that might affect defribrillation threshold and VF termination. It has been previously suggested that connexin-43 (Cx43) facilitates the development of malignant arrhythmias, and the hypothesis is that VF deteriorates Cx43 and, thus, hampers cardioversion into sinus rhythm. This study examined whether myocardial expression and phosphorylation status of Cx43 is altered due to VF and during sinus rhythm restoration in 10-month-old Wistar rats.

Ventricular fibrillation (VF) is a life-threatening arrhythmia, whose occurrence precedes the development of myocardial arrhythmogenic substrate resulting from either chronic or acute pathophysiological conditions. The authors’ previous and current studies suggest that downregulated and/or heterogeneously distributed cell-to-cell coupling protein – connexin-43 (Cx43) – facilitates the development of malignant arrhythmias. It was hypothesized that VF itself deteriorates Cx43, and may hamper cardioversion into sinus rhythm. The purpose of the present study was to examine whether myocardial expression and the phosphorylated status of Cx43 is altered due to VF and during sinus rhythm restoration. Experiments were performed using 10-month-old male and female Wistar rats. Isolated Langendorff-mode-perfused rat hearts were subjected to the following events: basal condition, electrically induced VF lasting 2 min, electrically induced VF lasting 10 min, and sustained VF followed by spontaneous sinus rhythm restoration due to transient stop perfusion. The hearts were snap frozen at each event; ventricular tissue was sent for Cx43 immunoblotting using rabbit antiCx43 polyclonal antibody to detect phosphorylated (P-Cx43) as well as unphosphorylated (noP-Cx43) forms of Cx43, and mouse antiCx43 monoclonal antibody to detect noP-Cx43 only. Compared with basal conditions, total Cx43 expression did not change during experiments in either male or female rat hearts. However, P-Cx43 and the ratio of P-Cx43 to total Cx43 decreased significantly due to VF lasting 2 min and 10 min in male rat hearts only. In parallel, there was a significant increase in noP-Cx43 due to VF lasting 2 min and 10 min in male rat hearts only. Surprisingly, an enhancement of noP-Cx43 linked with suppression of P-Cx43 was detected during stop perfusion-induced termination of VF lasting 2 min, followed by sinus rhythm restoration in both male and female rat hearts. Sinus rhythm was not restored after 10 min of VF, which caused pronounced Cx43 dephosphorylation. In conclusion, there is a downregulation of Cx43 due to sustaining of VF, and it occurs earlier in male rat hearts compared with female rat hearts. It appears that transient no-flow-related inhibition of cell-to-cell coupling, as indicated by an increase in nonP-Cx43, can terminate VF followed by sinus rhythm restoration depending on the degree of previous Cx43 downregulation.

Prolonged hypomagnesemia (Hypo-Mg) increases cardiovascular risk of morbidity and mortality after an episode of myocardial ischemia, and is common in hospitalized patients. In rodents, Hypo-Mg leads to neurogenic inflammation associated with substance P elevations. Neutral endopeptidase is a proteolytic substance P-degrading enzyme, which is expressed on mature neutrophils. This study investigated the effects of Hypo-Mg on neutral endopeptidase activity and cell activation in male Sprague-Dawley rats that were either fed a modified Mg-deficient diet or a Mg-sufficient diet for up to five weeks.

BACKGROUND/OBJECTIVE:

Hypomagnesemia (Hypo-Mg) in rodents leads to neurogenic inflammation associated with substance P (SP) elevations; neutral endopeptidase (NEP) is a principle cell surface proteolytic enzyme, which degrades SP. The effects of chronic Hypo-Mg on neutrophil NEP activity, cell activation and the associated cardiac dysfunction were examined.

METHODS/RESULTS:

Male Sprague-Dawley rats (180 g) were fed Mg-sufficient or Mg-deficient (Hypo-Mg) diets for five weeks. Enriched blood neutrophils were isolated at the end of one, three and five weeks by step gradient centrifugation. NEP enzymatic activity decreased by 20% (P value was nonsignificant), 50% (P<0.025) and 57% (P<0.01), respectively, for week 1, 3 and 5 Hypo-Mg rats. In association, neutrophil basal superoxide (•O2−)-generating activities were elevated: 30% at week 1 (P value was nonsignificant), and fourfold to sevenfold for weeks 3 to 5 (P<0.01). Maximal phorbol myristate acetate-stimulated •O2− production by Hypo-Mg neutrophils increased twofold at week 5. Also, plasma 8-isoprostane levels were elevated twofold to threefold, and red blood cell glutathione decreased by 50% (P<0.01) after three to five weeks of chronic Hypo-Mg. When Hypo-Mg rats were treated with the SP receptor blocker (L-703,606), neutrophil NEP activities were retained at 75% (week 3) and 77% (week 5) (P<0.05); activation of neutrophil •O2− and other oxidative indexes were also significantly (P<0.05) attenuated. After five weeks, histochemical (hematoxylin and eosin) staining of Hypo-Mg-treated rat ventricles revealed significant white blood cell infiltration, which was substantially reduced by L-703,606. Echocardiography after three weeks of Hypo-Mg only showed modest diastolic impairment, but five weeks resulted in significant (P<0.05) depression in both left ventricular systolic and diastolic functions; changes in these functional parameters were attenuated by L-703,606.

CONCLUSION:

NEP activity regulates neutrophil •O2− formation by controlling SP bioavailability. When oxidative inactivation of NEP is prevented by SP receptor blockade, partial protection is afforded against cardiac contractile dysfunction.