Cardiac End Research Articles

Characterization of upper thoracic spinal neurons receiving noxious cardiac and/or somatic inputs in diabetic rats

The aim of the present study was to examine spinal processing of cardiac and somatic nociceptive input in rats with STZ-induced diabetes.Type 1 diabetes was induced with streptozotocin (50mg/kg) in 14 male Sprague–Dawley rats and citrate buffer was injected in 14 control rats. After 4–11weeks, the rats were anesthetized with pentobarbital, ventilated and paralyzed. A laminectomy enabled extracellular recording of T3 spinal cord neuronal activity. Intrapericardial administration of a mixture of algogenic chemicals (bradykinin, serotonin, prostaglandin E2 (all at 10−5M), and adenosine (10−3M)) was applied to activate nociceptors of cardiac afferent nerve endings. Furthermore, somatic receptive properties were examined by applying innocuous (brush and light pressure) and noxious (pinch) cutaneous mechanical stimuli.Diabetes-induced increases in spontaneous activity were observed in subsets of neurons exhibiting long-lasting excitatory responses to administration of the algogenic mixture.Algogenic chemicals altered activity of a larger proportion of neurons from diabetic animals (73/111) than control animals (55/115, P<0.05). Some subtypes of neurons exhibiting long-lasting excitatory responses, elicited prolonged duration and others, had a shortened latency. Some neurons exhibiting short-lasting excitatory responses in diabetic animals elicited a shorter latency and some a decreased excitatory change. The size of the somatic receptive field was increased for cardiosomatic neurons from diabetic animals. Cutaneous somatic mechanical stimulation caused spinal neurons to respond with a mixture of hyper- and hypoexcitability.In conclusion, diabetes induced changes in the spinal processing of cardiac input and these might contribute to cardiovascular autonomic neuropathy in patients with diabetes.

649 Non-invasive assessment of metabolic substrate selection in the failing heart using hyperpolarized 13C magnetic resonance

Disordered metabolic substrate utilisation has been implicated in the pathogenesis of heart failure (HF). Hyperpolarised (HYP) 13C magnetic resonance, a technique in which the fate of 13C-labelled metabolites can be followed using MR imaging (MRI) or spectroscopy (MRS), has enabled non-invasive assessment of metabolism. The aim of this study was to monitor carbohydrate metabolism alongside cardiac structure, function, and energetics, throughout HF progression. HF was induced in pigs (n = 5) by right ventricular pacing at 188 bpm for 5 weeks. Pigs were examined at weekly time points: cine MRI assessed cardiac structure and function, HYP 13C2-pyruvate was administered intravenously and 13C MRS was used to assess 13C-glutamate production via Krebs cycle, 31P MRS assessed myocardial energetics, and HYP 13C1-pyruvate was administered to enable MRI of H13CO3- production from pyruvate dehydrogenase (PDH). At baseline, pigs had a normal left ventricular (LV) cardiac index (CI) and end diastolic volume (EDVi). The PCr/ATP was 2.3 ± 0.2. The 13C-glutamate/13C2-pyruvate was 4.3 ± 0.9%, and the H13CO3-/13C1-pyruvate ratio was 1.6 ± 0.2%. After 1-2 weeks of pacing, CI decreased to 3.3 ± 0.5 l/min/m2, PCr/ATP decreased to 1.7 ± 0.1, and 13C-glutamate/13C2-pyruvate decreased to 2.1 ± 0.6%. With the onset of HF, EDVi increased to 140.3 ± 14.1 ml/m2 and H13CO3-/13C1-pyruvate decreased to 0.5 ± 0.2%. In the pacing induced HF model, we observed an early defect in Krebs' cycle that occurred alongside impaired cardiac energetics and function. Carbohydrate oxidation via PDH was maintained until the onset of HF. These results suggest the use of metabolic therapies may delay/prevent the onset of heart failure.

Dihydroergotoxine-induced bradycardia in rats.

Dihydroergotoxine (0.01-0.3 mg kg-1 i.v.) decreased heart rate in pentobarbitone-anaesthetized rats. The bradycardia was reduced but not blocked by pre-treatment with guanethidine, yohimbine, propranolol or pithing. It was not prevented by bivagotomy, atropine, sulpiride or haloperidol. Dihydroergotoxine failed to affect, either the bradycardia produced by electrical stimulation of the vagus, or the cardioacceleration induced by i.v. isoprenaline. The increase in heart rate elicited in pithed rats by electrical stimulation of the spinal cord was reduced by dihydroergotoxine; this effect being inhibited by yohimbine but not by sulpiride. In conclusion, the main mechanism by which dihydroergotoxine (i.v.) induces bradycardia in the rat involves stimulation of alpha 2-adrenoceptors located predominantly at the cardiac sympathetic nerve endings.

Pattern and presentation of carcinoma stomach.

To determine the clinical profile of carcinoma stomach. A case series. A single unit of the Department of General Surgery, Dow University of Health Sciences and Civil Hospital, Karachi, from April 2006 to April 2010. Patients with gastric cancer confirmed on histopathology were included in the study. Patients diagnosed with acid peptic disease and benign gastric ulcer were excluded. Variables studied were, age, gender, mode of presentation, presenting complain, endoscopy findings, palpable supraclavicular lymph node, histopathology, stage and treatment. Data was analyzed for descriptive statistics. Total number of patients were 15, include 9 males (60%) and 6 females (40%); male female ratio was 1.5:1. Mean age was 48.6, ± 4.47 years, ranging from 26-65 years. Majority of the patients (n=9, 60%) were presented through outpatient department, while the rest presented through emergency. Common presenting complains were vague upper abdominal pain, mass, ascites, peritonitis and hematemesis. On endoscopy tumour was found at the cardiac end in 5 patients (33%), at pylorus and antrum in 6 patients (40%), linitis plastica in 2 patients (13.3%), only body and body and pylorus were involved in 1 patient (6.7%) each. Ten patients (66.6%) presented at stage IV and 3 patients (20%) in stage III. Surgical resection was possible in 5 patients (33.3%). Total gastrectomy was performed in one patient (6.7%), while subtotal gastrectomy was undertaken in 4 patients (26.7%). Palliative gastrojejunostomy was performed in 4 (26.7%) and feeding gastrostomy and endoscopic stenting in 2 patients (13.3%) each. Chemotherapy was given to 8 patients (53.3%) patients while radiotherapy to 2 patients (13.3%). Histopathological diagnosis was diffuse infiltrating adenocarcinoma in 10 (66.6%), infiltrating intestinal type in 3 (20%) and gastric lymphoma in 2 (13.3%) patients. Mortality was 13.3%. Majority of the patients with gastric carcinoma were young males, presenting with advanced stage disease. Only 33% tumours were resectable while 53.3% tumours were managed by palliative treatment. Overall mortality was 13.3%.

Hybrid Management Strategy for Percutaneous Fontan Completion Without Surgery: Early Results

We report early results of surgical preparation and subsequent percutaneous Fontan completion strategy for the treatment of single-ventricle defects. Two hundred twenty-seven patients underwent bidirectional cavopulmonary connection (BDCPC) between 2002 and 2007. Thirty-four patients had lateral tunnel created at time of BDCPC, fenestrated with 10 to 14 mm openings with the cardiac superior vena cava end patched to maintain BDCPC physiology. At second stage, Fontan circulation was established by superior vena cava patch perforation, tunnel dilatation, and stenting plus fenestration device closure. Thirty-four patients underwent Fontan preparation with BDCPC. Median age was 7.7 months (5 to 51) and 29 patients (85%) had previous palliation. Mean bypass and ischemic times were 141 and 72 minutes, respectively. Median ventilation, intensive care, and hospital stay durations were 1, 5, and 10 days, respectively. There was one early death and two take-downs. Twenty-eight patients underwent Fontan procedure: surgical (n = 3), percutaneous (n = 25). None of the patients who underwent percutaneous Fontan completion required inotropes, chest tube insertion, or mechanical ventilation. Median intensive care and hospital stay durations were 1 and 6 days, respectively. There were no early mortalities after percutaneous Fontan but one late death and one surgical revision. Overall survival after BDCPC with Fontan preparation was 77%. Despite longer bypass and ischemic times, Fontan preparation at time of BDCPC is feasible and associated with encouraging early outcomes. Percutaneous Fontan completion is associated with short recovery, low morbidity and excellent early dynamics, and echocardiographic and clinical outcomes. Further follow-up is needed to confirm those favorable results.

Clinical Perspective on the Management of Hypertension

Hypertension is an important medical and public health issue all over the world. It is one of the most prevalent conditions seen today by clinicians in both developed and developing countries. Depending upon progression of systolic and diastolic blood pressure it is classified into stage 1, 2 and 3 hypertension. Life style modifications may be helpful in initial stage but pharmacological treatment is necessary when it become difficult to control it. In routine practice, pharmacological treatment is being selected from diuretics, β-blockers, calcium channel blockers and renin angiotensin system inhibitors either alone or in combination for both initial and maintenance therapy. Choice of drug depends upon favourable effects in specific clinical setting. Thiazide type diuretics are being preferred for most patients with uncomplicated hypertension whereas β-blockers show strong benefits in patients with a variety of cardiovascular complications. ACE-Inhibitors and ARBs are superior to other class in patients with multiple risk factors like obesity, insulin resistance or diabetes. CCBs compared with other class of hypertensive drugs demonstrate similar blood pressure lowering effects and similar reductions in cardiovascular morbidity and mortality but higher incidence of heart failure and fatal myocardial infarction in some patients. Despite the continued decrease in mortality and morbidity rate by these antihypertensive drugs, some documented increasing prevalence of cardiac failure and end stage renal disease remains to be explained.

Valvular Regurgitation Impact on Left Ventricular 2-Dimensional and Doppler Echocardiographic Indices in Patients With Essential Hypertension

BackgroundBlacks have both a higher hypertension prevalence and accelerated cardiac end organ damage. Because blacks also have a higher prevalence of valvular heart disease, which occurs at a younger age than for whites, we further examined the contribution of valvular regurgitation to the severity of hypertensive heart disease in Nigerians. MethodsWe evaluated and compared echocardiograph-ic indexes in 75 essential hypertensive Nigerians with (n = 48) and without (n = 27) valvular regurgitations. Demographic and echocardiographic indices, as well as the types and severity of valvular lesions were compared between the groups using bivariate logistic regression and analysis of variance. ResultsThe 2 groups were of similar demographics, but those with regurgitations had larger cardiac size (p < .05), greater mass (147 ± 31 vs 122 ± 32 g/m2, p = .01) higher volume (p < .01), and left atrial size (35.6 ± 4.6 vs 33.3 ± 4.6 mm, p < .05). Atrial size, cardiac volume, and dimension were independent correlates/predictors of regurgitation occurrence. Relative wall thickness of at least 0.6 was more common in regurgitation patients. Cardiac mass was correlated to increasing age (r = 0.23, p = .043). The valvular lesions frequencies were aortic regurgitation, 8; mitral regurgita-tion, 22; and mixed, 18. The aortic orifice dimension was significantly different among the regurgitant cases, highest in aortic regurgitation (p = .001). Aortic orifice dimension increased with hypertension duration (p = .028). ConclusionsRegurgitant lesions are common and occur early in hypertensive Africans. Apparently mild valvular regurgitation may accentuate preclinical concentric hypertrophy in hypertensive blacks.

Cell therapy for heart failure: the need for a new therapeutic strategy

Improvements in the treatment of ischemic heart disease have led to a significant growth in the numbers of patients with systolic heart failure secondary to myocardial injury. Current therapies fail to address the loss of contractile tissue due to myocardial injury. Cell therapy is singular in its promise of primarily treating this underlying issue through salvage of viable myocardium or generation of new contractile tissue. Multiple cell types have been used to target acute myocardial infarction, chronic ischemic heart disease and heart failure due to infarction. Bone marrow mononuclear cells have been used to increase myocardial salvage after acute infarction. Randomized trials of over 800 patients have demonstrated no safety issues, and meta-analyses have suggested an improvement in left ventricular function in treated patients with trends toward improvements in hard cardiac end points. Cell therapy for chronic ischemic heart disease with bone marrow angiogenic progenitors has shown similar safety and trends toward improvement in function. While these therapies have targeted patients with viable myocardium, myoblasts have been used to treat patients with left ventricular dysfunction secondary to transmural infarction. Cell types with cardiomyogenic potential, including induced pluripotent stem cells and cardiac progenitor cells, offer the promise of true myocardial regeneration. Future studies with these cells may open the door for true myocardial regeneration.

Longer-Term Assessment of Trastuzumab-Related Cardiac Adverse Events in the Herceptin Adjuvant (HERA) Trial

We investigated the incidence of cardiac adverse events in patients with early breast cancer in the Herceptin Adjuvant (HERA) trial who were treated with 1 year of trastuzumab after completion of (neo)adjuvant chemotherapy. The HERA trial is a three-group, randomized trial that compared 1 year or 2 years of trastuzumab with observation in women with human epidermal growth factor receptor-2 (HER2) -positive early breast cancer. Eligible patients had normal left ventricular ejection fraction (LVEF; >or= 55%) after completion of (neo)adjuvant chemotherapy with or without radiotherapy. Cardiac function was monitored throughout the trial. This analysis considers patients randomly assigned to 1 year of trastuzumab treatment or observation. There were 1,698 patients randomly assigned to observation and 1,703 randomly assigned to 1 year of trastuzumab treatment; 94.1% of patients had been treated with anthracyclines. The incidence of discontinuation of trastuzumab because of cardiac disorders was low (5.1%). At a median follow-up of 3.6 years, the incidence of cardiac end points remained low, though it was higher in the trastuzumab group than in the observation group (severe CHF, 0.8% v 0.0%; confirmed significant LVEF decreases, 3.6% v 0.6%) In the trastuzumab group, 59 of 73 patients with a cardiac end point reached acute recovery; of these 59 patients, 52 were considered by the cardiac advisory board (CAB) to have a favorable outcome from the cardiac end point. The incidence of cardiac end points remains low even after longer-term follow-up. The cumulative incidence of any type of cardiac end point increases during the scheduled treatment period of 1 year, but it remains relatively constant thereafter.

Early involvement of sympathetic cardiac nerve endings in a patient with rem sleep behaviour disorders

Background REM sleep behaviour disorder (RBD) is a parasomnia characterized by suppression of muscular atonia and abnormal, often violent, motor behaviours during REM sleep. RBD can be either idiopathic or associated with degenerative disorders, such as dementia with Lewy bodies (LBD), multiple system atrophy (MSA), progressive sopranuclear paralysis (PSP) or Parkinson’s disease (PD). Myocardial 123Metaiodiobenzylguanidine (MIBG) enables the assessment of postganglionic sympathetic cardiac never terminals. Reduced myocardial MIBG uptake of the tracer suggests cardiac sympathetic denervation. MIBG uptake allows a differentiation between Lewy body disease and taupathies and other parkinsonisms. Indeed cardiac innervation is impaired in nearly all patients with PD and LBD, while it is preserved in patients with parkinsonisms, such as MSA and PSP. Recently, decreased MIBG uptake has been also described in patients with RBD.

Time to collapse following slaughter without stunning in cattle

Time to physical collapse was examined in 174 cattle which were restrained in the upright position and then released immediately from the restraint following the halal cut. The frequencies of swelling and false aneurysm in the cephalic and cardiac severed ends of the arteries were recorded. Fourteen percent of the cattle collapsed and stood up again before finally collapsing. The average time to final collapse for all the cattle was 20s (sd+/-33). In 8% of the animals time to final collapse was 60s. Seventy-one percent of the cattle that took more than 75s to collapse had false aneurysms in the cardiac ends of the severed carotid arteries. The frequency of swelling at the cephalic severed ends of the carotid arteries in 129 cattle was 7%. Failure to collapse within 60s was associated with swelling of the cephalic ends of the carotid arteries.

Bradykinin and thromboxane A2reciprocally interact to synergistically stimulate cardiac spinal afferents during myocardial ischemia

Myocardial ischemia is a complex process leading to the simultaneous release of a number of mediators, including thromboxane A(2) (TxA(2)) and bradykinin (BK), that activate cardiac spinal afferents. The present study tested the hypothesis that TxA(2) and BK reciprocally interact to excite ischemically sensitive cardiac afferents. Nerve activity of single cardiac afferent units was recorded from the left sympathetic chain or rami communicantes (T(2)-T(5)) of anesthetized cats. Fifty-two ischemically sensitive afferents (conduction velocity = 0.27-3.35 m/s, 7 Adelta-fibers and 45 C-fibers) were identified. Repeated injections (1 microg) of BK into the left atrium (LA) 4 min after the administration of U-46619 (5 microg into the LA), a TxA(2) mimetic, induced a significantly larger cardiac afferent response than the first response to BK (0.61 +/- 0.14 to 1.95 +/- 0.29 vs. 0.66 +/- 0.09 to 2.75 +/- 0.34 impulses/s, first injection vs. second injection, n = 8). Conversely, blockade of TxA(2) receptors with BM-13,177 (30 mg/kg iv) attenuated the responses of eight other afferents to BK (1 microg into the LA) by 45%. In contrast, repeated BK (1 microg into the LA) induced consistent discharge activity in six separate afferents. We then observed that the coadministration of U-46619 (5 microg) and BK (1 microg into the LA) together caused a total response that was significantly higher than the predicted response by the simple addition of the individual responses. BK (1 microg) facilitated eight cardiac afferent responses to U-46619 (5 microg into the LA) by 64%. In contrast, repeated U-46619 (5 microg into the LA) without intervening BK stimulation evoked consistent responses in seven other ischemically sensitive afferents. Finally, inhibition of cyclooxygenase with indomethacin (5 mg/kg iv) eliminated the potentiating effects of BK on the cardiac afferent response to U-46619 (5 microg into the LA) but did not alter the afferent response to U-46619. These data suggest that BK and TxA(2) reciprocally interact to stimulate ischemically sensitive cardiac afferent endings leading to synergistic afferent responses and that the BK sensitization effect is mediated by cyclooxygenase products.

Facilitatory Interactions between 5‐HT and Thromboxane A2 in Stimulation of Ischemically Sensitive Cardiac Sympathetic Afferents

We have demonstrated that the endogenously produced mediators serotonin (5‐HT) and thromboxane A2 (TxA2) contribute to activation of cardiac afferents during ischemia. In the present study we hypothesized facilitatory interactions between these two metabolites in stimulation of cardiac afferents during ischemia. Nerve activity of single cardiac afferent units was recorded from the left sympathetic chain or rami communicantes (T2 ‐ T5) of anesthetized cats. Twenty ischemically sensitive afferents (CV= 0.28 ‐ 3.62 m/s, 4 Ad‐ and 16 C‐fibers) were identified. We observed that a repeat injection of 5‐HT (40 μg/kg) into left atrium (LA), 4 min after LA 2.5 μg of U46619, a TxA2 mimetic, induced a significantly larger cardiac afferent response than the first 5‐HT response (0.46±0.08 to 1.06±0.11 vs.0.45±0.13 to 1.90±0.18 imp/s, first vs. second injection, n=3). In a control group, repeated 5‐HT (40 μg/kg, LA) evoked consistent responses in three other ischemically sensitive afferents. Furthermore, LA administration of 5‐HT (40 μg/kg) and U46619 (2.5 μg) caused a larger response than simple addition of the individual responses (n=5). Additionally, the responses of three cardiac afferents to repeat U46619 (2.5 μg, LA) were enhanced compared with the U46619 response before 5‐HT, while the responses of three other cardiac afferents to repeated U46619 stimulation were consistent. Finally, blockade of the 5‐HT3 receptors with tropisetron (200 μg/kg, iv) attenuated the responses of three cardiac afferent to U46619 (2.5 μg, LA) by 52%. These preliminary data suggest that 5‐HT and TxA2 each facilitate the responses of ischemically sensitive cardiac afferent endings to the actions of other metabolite (Supported by NIH HL66217).

Effect of fluvastatin on cardiac outcomes in kidney transplant patients with systemic lupus erythematosus: A randomized placebo‐controlled study

Patients with systemic lupus erythematosus (SLE), with or without end-stage renal failure, are at increased risk of premature cardiovascular disease. Although statin therapy has been found to reduce cardiovascular risk in the general population, its effectiveness in kidney transplant recipients with SLE has not been examined. This study was undertaken to investigate the effect of fluvastatin on cardiac end points in a randomized controlled trial of renal transplant patients with SLE. Patients with SLE were identified from among participants in the Assessment of Lescol in Renal Transplantation trial, a randomized, double-blind, placebo-controlled study of the effect of fluvastatin (40-80 mg/day) on cardiovascular outcomes in renal transplant recipients. Patients were randomized to either a group receiving fluvastatin or a placebo group for the duration of the 5-6-year trial, and then invited to continue in a 2-year open-label extension during which all participants, regardless of original group, received fluvastatin. Patients were followed up for a total of 7-8 years for assessment of the primary end point of major cardiac events, comprising nonfatal myocardial infarction, cardiac death, and coronary intervention procedures. Fluvastatin reduced low-density lipoprotein cholesterol levels by 29.2% (95% confidence interval [95% CI] 18.3-40%), from a mean +/- SD of 4.0 +/- 0.9 mmoles/liter to 2.8 +/- 1.1 mmoles/liter, and total cholesterol by 19.6% (95% CI 11.7-27.5%), from 6.4 +/- 0.9 mmoles/liter to 5.1 +/- 1.1 mmoles/liter. Compared with placebo-treated patients, patients randomized to receive fluvastatin exhibited a 73.4% reduction in the risk of major cardiac events (relative risk 26.6 [95% CI 5.9-119.4], P = 0.064). Our results indicate that the effect of fluvastatin on cardiac events in renal transplant recipients with SLE is similar to that observed with statin therapy in the renal transplant population as a whole.

Exposure to Concentrated Coarse Air Pollution Particles Causes Mild Cardiopulmonary Effects in Healthy Young Adults

BackgroundThere is ample epidemiologic and toxicologic evidence that exposure to fine particulate matter (PM) air pollution [aerodynamic diameter ≤ 2.5 μm (PM2.5)], which derives primarily from combustion processes, can result in increased mortality and morbidity. There is less certainty as to the contribution of coarse PM (PM2.5–10), which derives from crustal materials and from mechanical processes, to mortality and morbidity.ObjectiveTo determine whether coarse PM causes cardiopulmonary effects, we exposed 14 healthy young volunteers to coarse concentrated ambient particles (CAPs) and filtered air. Coarse PM concentration averaged 89.0 μg/m3 (range, 23.7–159.6 μg/m3). Volunteers were exposed to coarse CAPs and filtered air for 2 hr while they underwent intermittent exercise in a single-blind, crossover study. We measured pulmonary, cardiac, and hematologic end points before exposure, immediately after exposure, and again 20 hr after exposure.ResultsCompared with filtered air exposure, coarse CAP exposure produced a small increase in polymorphonuclear neutrophils in the bronchoalveolar lavage fluid 20 hr postexposure, indicating mild pulmonary inflammation. We observed no changes in pulmonary function. Blood tissue plasminogen activator, which is involved in fibrinolysis, was decreased 20 hr after exposure. The standard deviation of normal-to-normal intervals (SDNN), a measure of overall heart rate variability, also decreased 20 hr after exposure to CAPs.ConclusionsCoarse CAP exposure produces a mild physiologic response in healthy young volunteers approximately 20 hr postexposure. These changes are similar in scope and magnitude to changes we and others have previously reported for volunteers exposed to fine CAPs, suggesting that both size fractions are comparable at inducing cardiopulmonary changes in acute exposure settings.

Nuclear imaging in cardiac amyloidosis

Amyloidosis is a disease characterized by depositions of amyloid in organs and tissues. It can be localized (in just one organ) or systemic. Cardiac amyloidosis is a debilitating disease and can lead to arrhythmias, deterioration of heart function and even sudden death. We reviewed PubMed/Medline, without time constraints, on the different nuclear imaging modalities that are used to visualize myocardial amyloid involvement. Several SPECT tracers have been used for this purpose. The results with these tracers in the evaluation of myocardial amyloidosis and their mechanisms of action are described. Most clinical evidence was found for the use of (123)I-MIBG. Myocardial defects in MIBG activity seem to correlate well with impaired cardiac sympathetic nerve endings due to amyloid deposits. (123)I-MIBG is an attractive option for objective evaluation of cardiac sympathetic level and may play an important role in the indirect measurement of the effect of amyloid myocardial infiltration. Other, less sensitive, options are (99m)Tc-aprotinin for imaging amyloid deposits and perhaps (99m)Tc-labelled phosphate derivatives, especially in the differential diagnosis of the aetiology of cardiac amyloidosis. PET tracers, despite the advantage of absolute quantification and higher resolution, are not yet well evaluated for the study of cardiac amyloidosis. Because of these advantages, there is still the need for further research in this field.

Increased Aldosterone Levels in a Model of Type 2 Diabetes Mellitus

Aldosterone is an important mediator of cardiovascular and renal remodeling. Type II diabetes mellitus leads to renal and cardiac end organ damage. We investigated the renin-angiotensin-aldosterone system in a model of type 2 diabetes mellitus with known diabetic nephropathy and cardiac remodeling, the Zucker Diabetic Fatty rat with and without ACE-inhibition (ZDF and ZDF+ACE-I) and its control, the Zucker Lean (ZDL) rat. Male animals were studied from an age of 7-24 weeks. At ages 7, 14, 17, 20, and 23 weeks, urinary excretion of aldosterone-glucuronide and potassium was assessed. ACE-inhibition with ramipril was started orally at week 13 (1 mg/kg/d). At the end of the study rats were sacrificed and plasma aldosterone concentration and plasma renin activity were measured. Aldosterone synthase (CYP11B2) mRNA expression in the adrenals, kidney, heart and adipose tissue was assessed by real-time PCR. Urinary albumin excretion as marker for diabetic nephropathy was measured in metabolic cages and correlated to aldosterone. Plasma aldosterone concentration and aldosterone-glucuronide was significantly elevated in ZDF rats, and significantly reduced by ACE-inhibiton. In contrast, plasma renin activity was significantly reduced in ZDF rats and normalized by ACE-inhibition. The urinary aldosterone correlated significantly to albuminuria. Adrenal CYP11B2 expression was not significantly higher in ZDF rats. CYP11B2 mRNA was not detected in the kidney, heart and adipose tissue. In ZDF rats, urinary and plasma aldosterone levels were elevated despite reduced plasma renin activity. The reversible effect of ACE-inhibition shows that the up-regulation of aldosterone must be dependent of the renin-angiotensin-system in this type II diabetes model. The correlation between aldosterone and diabetic nephropathy suggests a clinical relevance of this observation.

Reproducibility of Carotid Intima-Media Thickness Measurements in Young Adults

To prospectively compare the reproducibility of carotid intima-media thickness (CIMT) measurements obtained from the right and left carotid arteries in young adults by using ultrasonographic (US) images acquired at the maximum dimension, minimum dimension, and electrocardiographically (ECG)-triggered cardiac end diastole. This study was HIPAA compliant and approved by the institutional review board; all participants provided informed consent. Medical history, anthropometric measurements, and blood pressure (BP) values were obtained from 50 men and 50 women aged 18-25 years. Images of the common carotid arteries were acquired from three independent complete cardiac cycles by using a 15L8-MHz US transducer. CIMT was measured on the images of each cycle that depicted the narrowest and widest vessel diameters, and at the R wave of the ECG. Measurements from the right and left carotid arteries were analyzed by using paired t tests; possible sex differences, by using unpaired t tests. Reproducibility was determined by using coefficients of variation and intraclass correlations (ICCs). Pearson correlations and multiple regression analyses were used to compare CIMT, body mass index (BMI), and BP. CIMT values were 7.2% and 7% greater in frames showing the narrowest lumen diameter and in R-wave ECG-triggered frames, respectively, than in those with the widest diameter. CIMT measurements were 2.2%-3.1% greater in the right carotid artery than in the left (P < .001) and were significantly related to BMI (r = 0.40, P < .001) and systolic BP (r = 0.34, P < .001). ICCs were stronger when assessments were obtained in three different cardiac cycles (0.92-0.98), rather than in one (0.79-0.91). In healthy young adults, reproducibility of CIMT measurements is greatest when combining values from both carotid arteries and/or from the maximal and minimal arterial diameters.

Reciprocal interactions between bradykinin and thromboxane A2 during stimulation of ischemically sensitive cardiac spinal afferent

We have demonstrated that the ischemic metabolites thromboxane A2 (TxA2) and bradykinin (BK) contribute to activation of cardiac afferents during ischemia. The present study tested the hypothesis that there are reciprocal interactions between these two metabolites in stimulation of ischemically sensitive cardiac afferents. Nerve activity of single cardiac afferent units was recorded from the left sympathetic chain or rami communicantes (T2 – T5) of anesthetized cats. Twenty two ischemically sensitive afferents (CV= 0.46 – 4.34 m/s, 5 Aδ17 C‐fibers) were identified. In the first protocol, a repeat injection (2.5 μg) of TxA2 into left atrium (LA) 4 min after administration of BK (1 μg, LA) induced a significantly larger cardiac afferents’ response than the first TxA2 response (0.55±0.17 to 1.54±0.41 vs.0.64±0.13 to 2.28±0.36 imp/s, first vs. second injection, n=5). In a control group, repeated TxA2 (2.5 μg, LA) evoked consistent responses in four other ischemically sensitive afferents. Secondly, we observed that administration of TxA2 (2.5 μg) and BK (1 μg, LA) together appeared to cause a response that was approximately additive of the individual responses. Finally, blockade of the TxA2 receptors with BM13177 attenuated the responses of four cardiac afferent to BK (1 μg, LA) by 47%. In contrast, repeated BK (1 μg, LA) induced a consistent discharge activity in three other afferents. These preliminary data suggest that BK and TxA2 reciprocally enhance the responses of ischemically sensitive cardiac afferent endings to the other metabolite (Supported by NIH HL66217).

Cell Type-specific Functions of the Lysosomal Protease Cathepsin L in the Heart

Deficiency of the lysosomal cysteine protease cathepsin L (Ctsl) in mice results in a phenotype affecting multiple tissues, including thymus, epidermis, and hair follicles, and in the heart develops as a progressive dilated cardiomyopathy (DCM). To understand the role of Ctsl in the maintenance of regular heart morphology and function, it is critical to determine whether the DCM in Ctsl-/- mice is primarily because of the lack of Ctsl expression and activity in the cardiomyocytes or is caused by the additional extracardiac pathologies. Cardiomyocyte-specific expression of Ctsl in Ctsl-/- mice, using an alpha-myosin heavy chain promoter-Ctsl transgene, results in improved cardiac contraction, normal mRNA expression of atrionatriuretic peptide, normal heart weight, and regular ultrastructure of cardiomyocytes. Epithelial expression of cathepsin L2 (CTSL2) by a K14 promoter-CTSL2-transgene resulted in rescue of the Ctsl-/- hair loss phenotype. In these mice, cardiac atrionatriuretic peptide expression and end systolic heart dimensions were also significantly attenuated. However, cardiac contraction was not improved, and increased heart weight as well as the typical changes in lysosomal ultrastructure of Ctsl-/- hearts persisted. Myocardial fibrosis was detected in all Ctsl-/- mice irrespective of transgene-mediated cardiac Ctsl expression or extracardiac CTSL2 expression. Expression of collagen 1 was not enhanced in Ctsl-/- hearts, but a reduced collagenolytic activity suggests a role for Ctsl in collagen turnover by cardiac fibroblasts. We conclude that the DCM of Ctsl-/- mice is primarily caused by absence of the protease in cardiomyocytes, whereas the complex gross phenotype of Ctsl-deficient mice, i.e. the fur defect, results in additional stress to the heart.