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1.
Eur J Vasc Endovasc Surg ; 46(3): 338-46, 2013 Sep.
Article in English | MEDLINE | ID: mdl-23835110

ABSTRACT

OBJECTIVES: To determine whether increases in central aortic pulse pressure (PPc), but decreases in carotid-femoral pulse wave velocity (PWV) predict the presence of advanced peripheral arterial disease (PAD). METHODS: Applanation tonometry and vascular ultrasound were employed to assess carotid-femoral PWV, PPc, and carotid intima media thickness (IMT) in 136 patients of African ancestry with chronic critical lower limb ischaemia (CLI) and in 1,030 randomly selected healthy adults of African ancestry, 194 of whom were age- and sex matched (controls). RESULTS: With adjustments for confounders, compared with age- and sex-matched controls, participants with CLI had an increased carotid IMT (p = .0001) and PPc (p < .0001), but a markedly reduced PWV (m/second) (CLI = 5.7 ± 3.7, controls = 8.6 ± 3.4, p < .0001). PWV was correlated with PPc in controls (r = .52, p < .0001), but not in CLI (r = -.06). A PPc/PWV mismatch index showed increased values in participants with CLI over the full adult age range assessed. With carotid IMT, PPc, or aortic augmentation index in the same regression model, an increase in the PPc/PWV mismatch index was independently associated with CLI (p < .0001) and a PPc/PWV value upper 95% confidence interval in the community sample predicted CLI (odds ratio = 32 [6-169], p < .0001). PPc/PWV predicted CLI with a similar level of performance and accuracy and a greater specificity (98%) than that of IMT (82%). CONCLUSION: In CLI, while PPc increases, carotid-femoral PWV is markedly reduced. A PPc/PWV mismatch may be a new risk marker for advanced PAD.


Subject(s)
Arterial Pressure/physiology , Peripheral Arterial Disease/diagnosis , Peripheral Arterial Disease/physiopathology , Pulse Wave Analysis , Adult , Carotid Intima-Media Thickness , Case-Control Studies , Female , Humans , Male , Middle Aged , Peripheral Arterial Disease/diagnostic imaging , Predictive Value of Tests , Regression Analysis , Risk Factors , South Africa , Surveys and Questionnaires
2.
Clin Exp Rheumatol ; 29(3): 506-12, 2011.
Article in English | MEDLINE | ID: mdl-21640040

ABSTRACT

OBJECTIVES: The burden of depressive symptoms and how demographic and disease characteristics relate to depressive symptoms in patients with rheumatoid arthritis (RA) that belong to developing populations, are currently unknown and were therefore assessed in a case-control study in public healthcare patients in South Africa, a lower-middle income country. Public healthcare attendance is a surrogate of belonging to the developing population in South Africa. METHODS: Demographic and RA features were recorded in 441 public and 202 private healthcare patients. The outcome characteristic was the Arthritis Impact Measure Scales (AIMS) depression score. Relationships of patient characteristics and public healthcare attendance with depressive symptoms were determined in multivariable regression models. RESULTS: The mean ± SD AIMS depression score was 3.6±2.1 and 2.3±1.7 in public and private healthcare patients, respectively (p<0.0001 before and after adjustment for covariates). Physical disability was associated with depressive symptoms in both healthcare sectors. Other characteristics that were related to depressive symptoms comprised younger age, male sex and pain in public healthcare patients and fatigue and non-use of disease modifying agents in private healthcare patients. In all patients, public healthcare attendance (standardised ß [95% CI]=0.22 [0.12, 0.32], p<0.0001) and physical disability (standardised ß [95% CI]=0.25 [0.16, 0.34], p<0.0001) were most strongly associated with depressive symptoms. CONCLUSIONS: The burden of depressive symptoms is markedly enhanced in our developing population with RA, independent of age, sex, ethnic origin and disease characteristics. In this setting, the role of social factors should be assessed and, despite restricted resources, depressive symptoms should be routinely addressed.


Subject(s)
Arthritis, Rheumatoid/complications , Arthritis, Rheumatoid/psychology , Cost of Illness , Depression/epidemiology , Health Services , Adult , Aged , Arthritis, Rheumatoid/ethnology , Case-Control Studies , Cross-Sectional Studies , Depression/ethnology , Female , Humans , Incidence , Male , Middle Aged , Regression Analysis , Risk Factors , South Africa/epidemiology
3.
Cardiovasc J Afr ; 22(5): 261-7, 2011.
Article in English | MEDLINE | ID: mdl-21161117

ABSTRACT

INTRODUCTION: Blood pressure (BPR) control in people of African descent is poor, largely because of a lack of treatment. Although the requirements for immediate initiation of antihypertensive drug therapy are defined by global cardiovascular risk, the global cardiovascular risk profiles of untreated hypertensives at a community level are uncertain. AIM: To identify the distribution of global cardiovascular risk profiles of untreated hypertensives in an urban, developing community of African descent in South Africa. METHODS: As part of the African Programme on Genes in Hypertension, we assessed nurse-derived clinic BP (the mean of five standardised BP values obtained according to guidelines), current antihypertensive therapy, and total cardiovascular risk in 1 029 participants older than 16 years of age from randomly selected nuclear families from the South West Township of Gauteng (SOWETO). RESULTS: Approximately 46% of participants had systolic/ diastolic BP values ≥ 140/90 mmHg and ∼23% of participants were hypertensives not receiving antihypertensive medication. Approximately 12% of untreated hypertensives had a high added risk and ∼18% a very high added risk (6.7% of the total sample). In untreated hypertensives, in contrast to the absence of severe hypertension and diabetes mellitus in those with lower risk profiles, a high cardiovascular risk profile in this group was characterised by severe hypertension in ∼52% and diabetes mellitus in ∼33%. Based on a high added risk carrying at least a 20% chance and a very high added risk at least a 30% chance of a cardiovascular event in 10 years, this translates into 1 740 events per 100 000 of the population within 10 years, events that could be prevented through antihypertensive drug therapy. CONCLUSION: In an urban, developing community of African ancestry, a significant proportion (6.7%) of people may have untreated hypertension and a global cardiovascular risk profile that suggests a need for antihypertensive drug therapy. Cardiovascular risk in this group is driven largely by the presence of severe hypertension or diabetes mellitus.


Subject(s)
Black People/statistics & numerical data , Blood Pressure , Cardiovascular Diseases/ethnology , Developed Countries/statistics & numerical data , Hypertension/ethnology , Urban Health/statistics & numerical data , Adult , Aged , Antihypertensive Agents/therapeutic use , Blood Pressure/drug effects , Cardiovascular Diseases/physiopathology , Cardiovascular Diseases/prevention & control , Cohort Studies , Diabetes Mellitus/ethnology , Female , Humans , Hypertension/drug therapy , Hypertension/physiopathology , Male , Middle Aged , Regression Analysis , Risk Assessment , Risk Factors , Severity of Illness Index , South Africa/epidemiology , Surveys and Questionnaires , Time Factors , Treatment Outcome , Young Adult
4.
Clin Exp Rheumatol ; 28(2): 230-7, 2010.
Article in English | MEDLINE | ID: mdl-20483045

ABSTRACT

OBJECTIVES: To assess whether public healthcare attendance associates with altered atherosclerotic cardiovascular disease risk in established rheumatoid arthritis (RA). METHODS: We determined disparities in major conventional (hypertension, dyslipidemia, smoking and diabetes), other conventional (underweight, obesity, metabolic syndrome, chronic kidney disease, alcohol use, tension, depression and body height) and non-conventional (current and cumulative inflammation markers) cardiovascular risk factors between 424 consecutive public and 202 private healthcare patients in mixed regression models. RESULTS: Eighty-one percent of public healthcare patients were black (67%) or caucasian (14%) and 83% of private healthcare cases were caucasian. Seventy percent of the patients had > or = 1 major conventional risk factor. After adjustment for age, gender, ethnic origin and statin use when appropriate, public healthcare attendance associated with the prevalence of hypertension (odds ratio (OR) [95%CI]=1.72 [1.03, 2.85]), having > or = 1 major conventional risk factor (OR [95%CI]=1.83 [1.09, 3.07]) and an increased mean (SD) number of such risk factors (p=0.03), metabolic syndrome frequency (OR [95%CI]=1.90 [1.07, 3.40]), alcohol use (OR [95%CI]=0.07 [0.03, 0.18]), shorter stature (p<0.0001), higher tension (p=0.02) and depression score (p<0.0001) and higher inflammatory markers including the disease activity score in 28 joints (p=0.005), C-reactive protein concentration (p=0.0006), Health Assessment Questionnaire disability index (p<0.0001), and number of deformed joints (p<0.0001). In sensitivity analyses performed in caucasian Africans, public healthcare attendance associated with increased frequencies of each major conventional risk factor (OR=2.06 to 3.69) and higher other conventional and non-conventional mediated cardiovascular risk. CONCLUSIONS: Public healthcare patients with established RA experience markedly enhanced conventional and non-conventional cardiovascular risk burdens.


Subject(s)
Arthritis, Rheumatoid/epidemiology , Atherosclerosis/epidemiology , National Health Programs/statistics & numerical data , Private Sector/statistics & numerical data , Public Sector/statistics & numerical data , Adult , Aged , Black People/statistics & numerical data , Female , Humans , Hypertension/epidemiology , Male , Middle Aged , Prevalence , Regression Analysis , Risk Factors , South Africa/epidemiology , Vulnerable Populations/statistics & numerical data , White People/statistics & numerical data
7.
Clin Exp Rheumatol ; 26(4): 596-603, 2008.
Article in English | MEDLINE | ID: mdl-18799090

ABSTRACT

OBJECTIVE: To assess whether obesity and systemic inflammation are potential determinants of circulating adiponectin concentrations and whether low adiponectin levels cluster with metabolic syndrome features that are previously documented cardiovascular risk factors in rheumatoid arthritis (RA). METHODS: We investigated 33 RA patients who were treated with the TNF-alpha antagonist infliximab, immediately prior to an infliximab infusion. Adiponectin levels were also determined immediately after administration of an infliximab dose. RESULTS: Adiponectin concentrations correlated with age (R=0.465, p=0.008) and were higher in women (mean [95% confidence interval]=21,595 [15,366 to 30,349] ng/ml) than in men (9,310 [5,653 to 15,335] ng/ml)(p=0.008). C-reactive protein (CRP) levels correlated with circulating adiponectin concentrations (partial (p) R=-0.370, p=0.04), independent of age and gender. By contrast, the body mass index (BMI) did not correlate with adiponectin levels (pR=-0.039, p=0.8). Adiponectin concentrations correlated with triglycerides/HDL cholesterol ratios (pR=-0.396, p=0.03), total cholesterol/HDL cholesterol ratios (pR=-0.444, p=0.01) and high fasting plasma glucose levels (pR=-0.366, p=0.04), independent of CRP levels and the BMI. Adiponectin levels did not change (p=0.3) upon infliximab administration. CONCLUSION: In this cohort, high-grade inflammation was independently and negatively correlated with circulating adiponectin concentrations whereas low adiponectin levels clustered with metabolic syndrome features that reportedly contribute to atherogenesis in RA. Circulating adiponectin may be involved in cardiovascular disease in RA. The impact of inflammation on circulating adiponectin concentrations is not likely to be TNF-alpha mediated in RA.


Subject(s)
Adiponectin/blood , Arthritis, Rheumatoid/blood , Metabolic Syndrome/blood , Antibodies, Monoclonal/therapeutic use , Antirheumatic Agents/therapeutic use , Arthritis, Rheumatoid/complications , Arthritis, Rheumatoid/drug therapy , Body Mass Index , C-Reactive Protein/analysis , Cholesterol/blood , Cohort Studies , Female , Humans , Inflammation/blood , Infliximab , Male , Metabolic Syndrome/complications , Middle Aged , Obesity/blood , Triglycerides/blood
8.
Cardiovasc J Afr ; 19(4): 188-93, 2008.
Article in English | MEDLINE | ID: mdl-18776959

ABSTRACT

BACKGROUND: Although the beta1-adrenoreceptor (AR) Gly389Arg and alpha2c-AR Del322-325 gene variants are associated with the response to beta-AR-blocker therapy, whether this effect is associated with the risk for heart failure, or the severity or progression of heart failure is uncertain. AIMS: To assess the relationship between Gly389Arg and Del322-325 variants and the presence, severity and progression of idiopathic dilated cardiomyopathy (IDC) in 403 black South African patients. METHODS: Genotypes were identified using a restriction fragment length polymorphism-based technique and automated sequencing. Left ventricular ejection fraction (LVEF) and dimensions were determined at baseline and in 132 patients after six months of standard medical therapy excluding beta-AR-blockers (not indicated as standard care at the time of completing this study). RESULTS: All patients and controls genotyped for the alpha2c-AR variant were homozygous for the Del322-325 (risk) allele. The Gly389Arg polymorphism was not associated with IDC (control n = 429) (Arg389 allele homozygosity: odds ratio = 1.03, confidence limits = 0.78-1.35), nor did it predict LVEF and cavity dimensions either before or after therapy. CONCLUSION: In patients homozygous for the risk allele of the alpha2c-AR variant, the beta1-AR variant neither increased the risk for IDC nor predicted its severity or progression in patients not receiving beta-AR-blockers.


Subject(s)
Black People/genetics , Cardiomyopathy, Dilated/genetics , Polymorphism, Genetic , Receptors, Adrenergic, alpha-2/genetics , Receptors, Adrenergic, beta-1/genetics , Cardiomyopathy, Dilated/drug therapy , Cardiomyopathy, Dilated/ethnology , Cardiomyopathy, Dilated/pathology , Cardiomyopathy, Dilated/physiopathology , Cardiovascular Agents/therapeutic use , Case-Control Studies , Disease Progression , Drug Therapy, Combination , Female , Gene Frequency , Genetic Predisposition to Disease , Homozygote , Humans , Male , Middle Aged , Prospective Studies , Risk Factors , Severity of Illness Index , South Africa , Stroke Volume/drug effects , Stroke Volume/genetics , Treatment Outcome , Ventricular Function, Left/drug effects , Ventricular Function, Left/genetics
9.
Pharmacogenomics J ; 7(5): 339-45, 2007 Oct.
Article in English | MEDLINE | ID: mdl-17117186

ABSTRACT

In heart failure, the Arg16Gly and Gln27Glu polymorphisms of the beta2-adrenoreceptor (beta2-AR) gene are associated with exercise-capacity, clinical outcomes and response to beta-AR blocker therapy. Whether beta2-AR gene variants mediate these effects in-part through an impact on cardiac structural remodeling and pump function independent of the effects of beta-blockers is uncertain. We evaluated whether the Arg16Gly and Gln27Glu variants of the beta2-AR gene predict left ventricular ejection fraction (LVEF) and LV end diastolic diameter (LVEDD) in patients with idiopathic dilated cardiomyopathy (IDC) before and 6 months after receiving standard medical therapy other than beta-AR blockers. In all, 394 patients with IDC and 393 age and gender-matched controls were genotyped for the beta2-AR gene variants using restriction-fragment length polymorphism-based techniques. LVEF and dimensions were determined in 132 patients (of whom 71 were newly diagnosed) both at baseline and after 6 months. Genotype of neither variant was associated with the presence of IDC. Moreover, beta2-AR genotype did not determine LVEF or LV dimensions prior to initiating therapy. After 6 months of therapy, LVEF increased by 7.1+/-1.0 absolute units (P<0.0001) and LVEDD decreased by 0.27+/-0.06 cm (P<0.02). Adjusting for baseline values as well as gender, age, and type of angiotensin-converting enzyme inhibitor therapy received, genotype was associated with neither final LVEF and LVEDD, nor change in LVEF and LVEDD. In conclusion, these data suggest that in heart failure, the functional Arg16Gly and Gln27Glu variants of the beta2-AR gene have no independent effect on adverse structural remodeling and pump function.


Subject(s)
Cardiomyopathy, Dilated/genetics , Cardiovascular Agents/therapeutic use , Polymorphism, Restriction Fragment Length , Receptors, Adrenergic, beta-2/genetics , Ventricular Function, Left/genetics , Ventricular Remodeling/genetics , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Cardiomyopathy, Dilated/drug therapy , Cardiomyopathy, Dilated/pathology , Cardiomyopathy, Dilated/physiopathology , Cardiotonic Agents/therapeutic use , Cardiovascular Agents/pharmacology , Case-Control Studies , Digoxin/therapeutic use , Diuretics/therapeutic use , Drug Therapy, Combination , Female , Furosemide/therapeutic use , Gene Frequency , Genetic Predisposition to Disease , Haplotypes , Heart Ventricles/pathology , Humans , Male , Middle Aged , Prospective Studies , Risk Factors , Stroke Volume/drug effects , Stroke Volume/genetics , Systole , Time Factors , Treatment Outcome , Ventricular Function, Left/drug effects , Ventricular Remodeling/drug effects
12.
Hypertension ; 38(4): 846-51, 2001 Oct.
Article in English | MEDLINE | ID: mdl-11641297

ABSTRACT

Whether left ventricular (LV) hypertrophy is important in the development of LV failure associated with advanced myocardial damage and detrimental chamber and interstitial remodeling in hypertension has not been established. We examined the effect of an antihypertensive agent without the ability to regress LV hypertrophy on the development of LV changes in spontaneously hypertensive rats (SHR). Hydralazine given to SHR from 5.2 to 26 months of age returned systolic blood pressure to Wistar Kyoto (WKY) control values but failed to prevent the increase in LV mass noted in SHR (at 26 months of age: WKY, 0.99+/-0.02 g; untreated SHR, 1.40+/-0.02 g; treated SHR, 1.36+/-0.02 g; P<0.001 in SHR versus WKY). In comparison to both 16-month-old SHR and age-matched WKY, 26-month-old untreated SHR developed signs consistent with heart failure, LV dilatation (an increased LV internal radius), an eccentric LV geometry, advanced myocyte necrosis, an increase in myocardial collagen solubility (an index of decreases in myocardial collagen cross-linking), and marked increases in myocardial total, type III, and non-cross-linked myocardial collagen concentrations. Despite the inability of hydralazine to regress LV hypertrophy, treated SHR did not develop signs of heart failure, myocyte necrosis, decreases in myocardial collagen cross-linking, or increases in myocardial total, type III, and non-cross-linked collagen at 26 months of age. Moreover, treatment attenuated the development of LV dilatation and an eccentric LV geometry. In conclusion, antihypertensive therapy that does not attenuate LV hypertrophy but achieves normal blood pressure in SHR, is able to hinder the development of heart failure associated with advanced myocardial damage and detrimental chamber and interstitial remodeling.


Subject(s)
Heart Failure/prevention & control , Hypertension/drug therapy , Hypertrophy, Left Ventricular/pathology , Animals , Antihypertensive Agents/therapeutic use , Blood Pressure/drug effects , Body Weight/drug effects , Collagen/drug effects , Collagen/metabolism , Heart Failure/pathology , Heart Ventricles/drug effects , Heart Ventricles/metabolism , Heart Ventricles/pathology , Hydralazine/therapeutic use , Hypertension/physiopathology , Hypertrophy, Left Ventricular/physiopathology , Myocardium/metabolism , Myocardium/pathology , Organ Size/drug effects , Rats , Rats, Inbred SHR , Rats, Inbred WKY , Time Factors
13.
Cardiovasc J S Afr ; 12(2): 75-80, 2001.
Article in English | MEDLINE | ID: mdl-11447495

ABSTRACT

AIM: We evaluated whether any one variant of genes that encode for substances that could modulate renin-angiotensin-aldosterone (RAA) system activity can account for a substantial proportion of the variability of plasma RAA system profiles in black South African hypertensives (HTs). METHODS: Plasma renin activity (PRA) and aldosterone concentrations (ALD) were determined in 59 black subjects with mild-to-moderate HT off therapy on an ad libitum diet. Patients were genotyped for the angiotensin-converting enzyme (ACE) gene insertion/deletion, angiotensinogen (AGT) gene M235T, A-20C and G-6A, aldosterone synthase (CYP11B2) gene C-344T, G protein beta3-subunit (GNB3) gene C825T, G(s) protein gene C131T, atrial natriuretic peptide (ANP) gene exon 3 stop condon and intron 2, alpha-adducin gene Gly460Trp, and epithelial Na(+) channel (eNa(+) (c)) gene T594M polymorphisms. RESULTS: Risk genotype frequencies for the G(s) (7%), ANP intron 2 (0%), and eNa(+)(c)(7%) variants were too low for each to account for a substantial portion of the variability of plasma RAA profiles in the group studied. Moreover, assuming either recessive or dominant inheritance models, neither ACE, AGT, GNB3, CYP11B2, ANP exon 3 nor alpha-adducin polymorphisms were significantly associated with the variance of PRA, ALD or ALD/PRA. CONCLUSIONS: These results do not support a substantial individual role for the gene candidates studied in contributing to plasma RAA system profiles in black South African HTs. However, a potential small role for some loci may exist, and epistasis or genotype-phenotype interactions as well as alternative inheritance models and variants still need to be evaluated.


Subject(s)
Black People/genetics , Hypertension/genetics , Hypertension/physiopathology , Renin-Angiotensin System/genetics , Renin-Angiotensin System/physiology , Aldosterone/blood , Aldosterone/genetics , Female , Genotype , Humans , Hypertension/blood , Male , Middle Aged , Renin/blood , Renin/genetics , South Africa/ethnology
14.
Hypertension ; 37(3): 862-8, 2001 Mar.
Article in English | MEDLINE | ID: mdl-11244009

ABSTRACT

In the present study, we sought to evaluate whether the antiadrenergic action of adenosine in the heart is altered in pressure overload hypertrophy produced in rats by suprarenal aortic banding. Epicardial and coronary effluent adenosine and inosine concentrations and release were significantly elevated in compensated pressure overload hypertrophy but not in hearts with left ventricular failure. In pressure overload hearts, the contractile response to beta-adrenergic stimulation was less inhibited by incremental concentrations of either adenosine or the selective A(1) receptor agonist chloro-N:(6)-cyclopentyl adenosine than in controls. Furthermore, the extent of desensitization to the antiadrenergic actions of adenosine in pressure overload hypertrophy appeared to be proportional to the extent of chamber dilation and dysfunction. A 60-minute infusion of adenosine produced a sustained antiadrenergic effect that lasted up to 45 minutes after the infusion was terminated in both controls and hearts with compensated hypertrophy. This effect was not observed in the decompensated left ventricular failure group. Subsequent infusion with adenosine of the A(2A) receptor antagonist 8-(3-chlorostyryl)-caffeine to counteract the proadrenergic effect of A(2A) receptor stimulation did not alter the decreased sensitivity to the antiadrenergic actions of adenosine in hypertrophied hearts. Finally, isolated myocytes from hypertrophied hearts demonstrated a decreased ability to suppress isoproterenol-elicited increases in [Ca(2+)](i) transients in the presence of adenosine and the A(2A) receptor antagonist compared with myocytes from control hearts. Myocardial adenosine concentrations increase during the compensated phase of pressure overload hypertrophy but then decrease when there is evidence of decompensation. The antiadrenergic actions of adenosine transduced via the myocardial A(1) receptor are diminished in pressure overload hypertrophied hearts. These factors may render these hearts more vulnerable to the detrimental effects of chronically increased sympathetic activity.


Subject(s)
Adenosine/analogs & derivatives , Adenosine/pharmacology , Adrenergic Antagonists/pharmacology , Cardiomegaly/physiopathology , Adenosine/metabolism , Adrenergic beta-Agonists/pharmacology , Animals , Blood Pressure , Body Weight , Caffeine/analogs & derivatives , Caffeine/pharmacology , Calcium/metabolism , Cardiomegaly/etiology , Cells, Cultured , Coronary Circulation/drug effects , Disease Models, Animal , Echocardiography , In Vitro Techniques , Inosine/metabolism , Isoproterenol , Male , Myocardial Contraction/drug effects , Myocardium/metabolism , Organ Size , Perfusion , Purinergic P1 Receptor Agonists , Purinergic P1 Receptor Antagonists , Rats , Rats, Sprague-Dawley
15.
Circulation ; 103(1): 155-60, 2001 Jan 02.
Article in English | MEDLINE | ID: mdl-11136701

ABSTRACT

BACKGROUND: The transition from compensated left ventricular hypertrophy (LVH) to heart failure is associated with alterations in the myocardial interstitium. We hypothesized that LV dilatation is associated with modifications in collagen cross-linking. METHODS AND RESULTS: We studied 2 rat models of LV dilatation: (1) pressure-overload hypertrophy with heart failure (POH-F) induced by suprarenal abdominal aortic banding and (2) LVH induced by 7 months of isoproterenol (ISO, 0.04 mg x kg(-1) x d(-1)) administration. In POH-F rats and in rats receiving ISO, LV dilatation and a reduced systolic chamber performance were noted. Myocardial hydroxyproline concentrations ([HPRO]) were increased in the POH-F rats, whereas in rats receiving ISO, [HPRO] was decreased. In POH-F rats, the ratio of myocardial collagen type I to type III was increased, but in rats receiving ISO, myocardial collagen I/III was unchanged. In contrast to the diverse changes in myocardial collagen concentrations and phenotypes observed in the 2 models of LV dilatation, the ratio of myocardial insoluble to soluble (relationship between cross-linked and non-cross-linked) collagen was decreased in both the POH-F and ISO groups. Moreover, administration of captopril (0.22 mmol x kg(-1) x d(-1)), which inhibited the ISO-induced reduction in myocardial insoluble/soluble collagen but not the reduction in [HPRO], prevented the ISO-induced alterations in LV dimensions and performance. CONCLUSIONS: Because decreases in the ratio of myocardial insoluble to soluble collagen parallel LV dilatation in rats, reductions in myocardial collagen cross-linking may be an important mechanism contributing to LV dilatation in heart disease.


Subject(s)
Collagen/metabolism , Hypertrophy, Left Ventricular/metabolism , Myocardium/metabolism , Systole/drug effects , Ventricular Dysfunction, Left/drug therapy , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Animals , Aorta, Abdominal/physiopathology , Aorta, Abdominal/surgery , Body Weight/drug effects , Captopril/therapeutic use , Collagen/chemistry , Constriction, Pathologic , Disease Models, Animal , Echocardiography , Hydroxyproline/metabolism , Hypertrophy, Left Ventricular/chemically induced , Hypertrophy, Left Ventricular/diagnostic imaging , Hypertrophy, Left Ventricular/drug therapy , Hypertrophy, Left Ventricular/pathology , In Vitro Techniques , Isoproterenol , Male , Myocardium/pathology , Organ Size/drug effects , Perfusion , Rats , Rats, Sprague-Dawley , Regression Analysis , Ventricular Remodeling/drug effects
16.
Eur J Appl Physiol ; 81(4): 310-6, 2000 Mar.
Article in English | MEDLINE | ID: mdl-10664090

ABSTRACT

Androgenic steroids administered in doses at pharmacological levels to sedentary animals have been shown to result in a reduced beta-adrenoceptor-mediated increase in systolic cardiac performance when assessed in vivo. Whether the attenuated adrenergic response occurs as a consequence of alterations in either cardiac loads, heart rate, modifications in left ventricular (LV) geometry, or a decrease in myocardial contractile performance has not been determined. In this study the effect of chronic administration (over 3 months) of an androgenic steroid (nandrolone decanoate, 5 mg. kg(-1) biweekly) on the response of load-insensitive indices of myocardial contractile function [the slope of the LV systolic stress-strain relationship (LV-E(n)(max), where E(n)(max) is systolic myocardial elastance)] to an adrenergic-inotropic stimulus was examined ex vivo in paced rat hearts. Systolic cardiac performance was assessed at 300 beats. min(-1) in isolated constant flow perfused heart preparations both before and during 10(-8.5) mol. l(-1) isoproterenol (ISO) infusion (approximate concentration of ISO eliciting 50% maximal inotropic response to ISO). Steroid administration resulted in left-shifted LV systolic and diastolic pressure-volume (P-V ) relationships. The leftshifted P-V relationships were attributed, in part, to increased slopes of these relationships. However, the steroid-mediated increment in the slope of the systolic P-V relationship (systolic chamber elastance, E(max)) was not associated with a similar change in LV E(n)(max) [control 19.2 (SEM 2.1) g. cm(-2), steroid 18.3 (SEM 2.4) g. cm(-2)] as determined in the absence of ISO. Isoproterenol infusion resulted in an increase in both E(max) and E(n)(max) in the control rats, without altering systolic performance in the steroid treated rats. Consequently, in the presence of ISO, the steroid treated rats exhibited a similar E(max), but a reduction in E(n)(max) compared to the control rats [control 25.6 (SEM 1.9) g. cm(-2), steroid 18.5 (SEM 1.5) g. cm(-2); P < 0.05]. In conclusion, these results would suggest that chronic high dose androgenic steroid administration produces a decrease in myocardial contractile reserve to beta-adrenoceptor stimulation.


Subject(s)
Anabolic Agents/pharmacology , Myocardial Contraction/drug effects , Myocardial Contraction/physiology , Nandrolone/analogs & derivatives , Receptors, Adrenergic, beta/physiology , Animals , Cardiotonic Agents/pharmacology , Diastole/drug effects , Heart/anatomy & histology , Heart/physiology , Isoproterenol/pharmacology , Male , Nandrolone/pharmacology , Nandrolone Decanoate , Organ Size , Physical Conditioning, Animal , Rats , Rats, Sprague-Dawley , Systole/drug effects
17.
J Appl Physiol (1985) ; 88(2): 409-15, 2000 Feb.
Article in English | MEDLINE | ID: mdl-10658005

ABSTRACT

Habitual exercise results in a rightward shift in left ventricular end diastolic (LVED) pressure-volume or internal dimension (P-D) relationships [left ventricular (LV) remodeling]. However, exercise-mediated LV hypertrophy (LVH) produces an increased LV relative wall thickness [ratio (h/r) of wall thickness (h) to internal radius (r)] and hence a decrement in diastolic wall stress despite LV remodeling. In this study, the effect of chronic administration of an androgenic steroid on exercise-induced LV remodeling and h/r was examined in rats. Habitual exercise on voluntary running wheels resulted in LVH and a rightward shift in the LVED P-D relationships. However, LVH was sufficient to increase LVED h/r. Androgenic steroid administration to exercised rats, without influencing the development of exercise-induced LVH, produced a further rightward shift in the LVED P-D relationship associated with an increased diameter intercept. As a consequence, LVED h/r was reduced to control values. The steroid-mediated effects were not associated with alterations in either the quantity or quality of LV collagen. In conclusion, high-dose androgenic steroid administration alters exercise-induced LV remodeling and subsequently reduces the beneficial effect of physiological LVH on LV h/r.


Subject(s)
Anabolic Agents/pharmacology , Physical Conditioning, Animal/physiology , Testosterone Congeners/pharmacology , Ventricular Remodeling/drug effects , Animals , Collagen/drug effects , Collagen/metabolism , Heart/anatomy & histology , Heart Ventricles/anatomy & histology , Heart Ventricles/drug effects , Heart Ventricles/metabolism , Male , Organ Size/drug effects , Rats , Rats, Sprague-Dawley , Stroke Volume/drug effects , Stroke Volume/physiology , Ventricular Function, Left/drug effects , Ventricular Function, Left/physiology , Ventricular Remodeling/physiology
18.
Am J Hypertens ; 12(6): 563-71, 1999 Jun.
Article in English | MEDLINE | ID: mdl-10371365

ABSTRACT

Our objective was to evaluate the safety and antihypertensive efficacy of sampatrilat, a novel dual inhibitor of both angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP), in subjects poorly responsive to ACE inhibitor monotherapy. The ability of sampatrilat (50 to 100 mg daily) (n = 28) to lower blood pressure was compared with that of the ACE inhibitor lisinopril (10 to 20 mg daily) (n = 30) using a double-blind, randomized, parallel group study design over a 56-day treatment period in black hypertensives. Changes in systolic (SBP) and diastolic (DBP) blood pressure were determined using repeated ambulatory blood pressure (ABP) monitoring. Both sampatrilat and lisinopril decreased plasma ACE concentrations after 28 and 56 days. The decrease in plasma ACE concentrations (U/L) was greater after lisinopril (-9.33 +/- 0.52) as compared with sampatrilat (-6.31 +/- 0.70) (P = .0001) therapy. Lisinopril, but not sampatrilat, increased plasma renin activity. Lisinopril produced a transient decrease in mean 24-h ABP (mm Hg) at 28 days (SBP = -9.0 +/- 2.3, DBP = -5.7 +/- 1.3; P < .01), which returned to pretreatment values by 56 days of therapy. Alternatively, sampatrilat produced a sustained decrease in mean ABP over the 56-day treatment period (day 28: SBP = -7.3 +/- 1.8, DBP = -5.2 +/- 1.2; P < .01: day 56: SBP = -7.8 +/- 1.5; DBP = -5.2 +/- 0.95; P < 0.01) with a greater treatment effect on DBP than that of lisinopril at day 56 (P = .05). Treatment-emergent adverse events were noted to be similar between both treatment groups. We conclude that the antihypertensive actions of ACE/NEP inhibitor monotherapy in black subjects offers a novel therapeutic approach to patients otherwise resistant to the sustained antihypertensive actions of ACE inhibitor monotherapy.


Subject(s)
Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Antihypertensive Agents/therapeutic use , Enzyme Inhibitors/therapeutic use , Hypertension/drug therapy , Mesylates/therapeutic use , Neprilysin/antagonists & inhibitors , Tyrosine/analogs & derivatives , Adult , Aged , Angiotensin-Converting Enzyme Inhibitors/adverse effects , Antihypertensive Agents/adverse effects , Black People , Blood Pressure/drug effects , Double-Blind Method , Enzyme Inhibitors/adverse effects , Female , Heart Rate/drug effects , Hormones/blood , Humans , Hypertension/physiopathology , Lisinopril/therapeutic use , Male , Mesylates/adverse effects , Middle Aged , Tyrosine/adverse effects , Tyrosine/therapeutic use
19.
Am J Physiol ; 276(5): H1434-41, 1999 05.
Article in English | MEDLINE | ID: mdl-10330225

ABSTRACT

Adenosine A2a receptor (A2aR) stimulation enhances the shortening of ventricular myocytes. Whether the A2aR-mediated increase in myocyte contractility is associated with alterations in the amplitude of intracellular Ca2+ transients was investigated in isolated, contracting rat ventricular myocytes using the Ca2+-sensitive fluorescent dye fura 2-AM. In the presence of intact inhibitory G protein pathways, 10(-4) M 2-p-(2-carboxyethyl)phenethyl-amino-5'-N-ethylcarboxamidoadenosine (CGS-21680), an A2aR agonist, insignificantly increased Ca2+ transients by 8 +/- 5%, whereas myocyte shortening increased by 54 +/- 1%. In contrast, 2 x 10(-7) M isoproterenol, a beta-adrenergic receptor agonist, increased Ca2+ transients by 104 +/- 15% and increased myocyte shortening by 61 +/- 6%. When A2aR were stimulated in myocytes that had the antiadrenergic actions of adenosine (Ado) abolished by either treatment with pertussis toxin (PTx) or the presence of 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), an adenosine A1-receptor antagonist, the maximum increases in Ca2+ transients were similarly nominal (with PTx: 10(-4) M CGS-21680, 14 +/- 6% and 10(-4) M Ado, 15 +/- 4%; without PTx: 10(-5) M Ado + 2 x 10(-7) M DPCPX, 19 +/- 1%). These results indicate that compared with beta-adrenergic stimulation, which markedly increases myocyte Ca2+ transients and shortening, A2aR-mediated increases in myocyte shortening are accompanied by only modest increases in Ca2+ transients. These observations suggest that the A2aR-induced contractile effects are mediated predominantly by Ca2+-independent inotropic mechanisms.


Subject(s)
Calcium/metabolism , Muscle Fibers, Skeletal/physiology , Myocardial Contraction/physiology , Myocardium/cytology , Receptors, Adrenergic, alpha-2/physiology , Adenosine/analogs & derivatives , Adenosine/pharmacology , Adrenergic beta-Agonists/pharmacology , Animals , Antihypertensive Agents/pharmacology , Carotenoids/pharmacology , Isoproterenol/pharmacology , Male , Muscle Fibers, Skeletal/chemistry , Myocardium/chemistry , Oxygenases/pharmacology , Pertussis Toxin , Phenethylamines/pharmacology , Rats , Rats, Sprague-Dawley , Virulence Factors, Bordetella/pharmacology , Xanthines/pharmacology
20.
Am J Cardiol ; 83(5): 740-4, 1999 Mar 01.
Article in English | MEDLINE | ID: mdl-10080429

ABSTRACT

The insertion-deletion (ID) polymorphism of the angiotensin-converting enzyme (ACE) gene is a marker linked to differences in plasma and cardiac ACE activity as well as to an increased mortality in patients with idiopathic heart failure. We examined the possibility that ACE gene ID variants are associated with differences in left ventricular (LV) systolic performance or internal LV dimensions in a high-risk cohort of patients with idiopathic dilated cardiomyopathy (IDC). The ACE genotype was determined in 171 patients selected with IDC in New York Heart Association functional class II to III heart failure and with a LV ejection fraction of < or = 40%. Left ventricular performance and dimensions were assessed using echocardiography (n = 161) and radionuclide ventriculography (n = 169). The frequency of ACE gene ID alleles was not different in the study versus non-age-matched (n = 171; odds ratio 0.94) and age-matched (n = 106, odds ratio 0.88) control groups. Ejection fraction was found to be worse in patients with the DD genotype (echocardiography, DD = 23.5 +/- 0.70, ID + II = 26.8 +/- 0.8, p = 0.009; ventriculography, DD = 21.7 +/- 0.9, ID + II = 25.3 +/- 0.8, p = 0.003). LV end-systolic and end-diastolic diameters were increased in patients with the DD genotype. Multifactor regression analysis showed the ACE genotype to be an independent predictor of both ejection fraction (echocardiography, p <0.02; ventriculography, p <0.03) and end-diastolic diameter (p <0.02). In conclusion, the results of this study indicate that the DD genotype of the ACE gene is independently associated with both a reduced LV systolic performance and an increased LV cavity size in patients with IDC.


Subject(s)
Cardiomyopathy, Dilated/enzymology , Heart Ventricles/pathology , Peptidyl-Dipeptidase A/genetics , Systole/physiology , Ventricular Function, Left/physiology , Aged , Alleles , Cardiac Output, Low/enzymology , Cardiac Output, Low/genetics , Cardiac Output, Low/physiopathology , Cardiomyopathy, Dilated/genetics , Cardiomyopathy, Dilated/physiopathology , Case-Control Studies , Cohort Studies , Diastole , Echocardiography , Female , Forecasting , Gated Blood-Pool Imaging , Gene Deletion , Genetic Markers , Genotype , Humans , Male , Middle Aged , Mutagenesis, Insertional/genetics , Myocardium/enzymology , Odds Ratio , Peptidyl-Dipeptidase A/blood , Peptidyl-Dipeptidase A/metabolism , Polymorphism, Genetic/genetics , Regression Analysis , Risk Factors , Stroke Volume/physiology , Survival Rate
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