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Biomedical subjects

M M Redfield

Publications and source records attributed to M M Redfield.

At least 19 recordsLinked to original sources
PubMed2001

Heart failure with preserved systolic function. A different natural history?

Three well-controlled epidemiology studies in the U.S. have reported that 40% of incident congestive heart failure (CHF) cases and 50% to 60% of prevalent CHF cases occur in the setting of preserved systolic function. This condition has been termed "diastolic heart failure" (DHF). Despite minor differences in the types of populations examined, these community-based studies have established DHF as a major health problem in the U.S., particularly among the elderly. Although extensive data are available concerning the natural history of CHF associated with reduced systolic dysfunction (systolic heart failure; SHF), the natural history of DHF is not well-characterized. Indeed, it remains unclear whether patients with DHF share the grim prognosis described for patients with SHF. In this review we examine the available studies comparing survival observed in patients with DHF to that observed in patients with SHF. Although there are insufficient data at present to make definitive conclusions, careful examination of the available studies raises the possibility that the natural history of patients with DHF may not be different from that observed in patients with CHF and reduced systolic function.

Age Distribution↗
PubMed2001

Load versus humoral activation in the genesis of early hypertensive heart disease.

BACKGROUND: The role of load versus angiotensin II (Ang II) and endothelin-1 (ET) in the pathogenesis of hypertensive heart disease is controversial. We sought to determine whether alterations in cardiac structure and function due to hypertension (HTN) were dependent on Ang II or ET activation. Methods and Results-- Bilateral renal wrapping to produce HTN (n=12) or sham surgery (n=6) was performed in adult dogs. Weekly blood pressure, plasma renin activity, Ang II, ET, and catecholamines were measured. Systolic (end-systolic elastance, Ees) and diastolic (tau) function were assessed in sham and HTN dogs at 5 (HTN-5wk) or 12 (HTN-12wk) weeks. Ang II and ET were assayed in the left ventricle (LV) and kidney. Mean arterial pressure was higher in renal wrap dogs at week 1 (*P<0.05 versus controls: 139+/-4* versus 123+/-4 mm Hg), week 5 (174+/-7* versus 124+/-4 mm Hg), and week 12 (181+/-12* versus 124+/-4 mm Hg). LV mass index was increased in HTN-5wk (22%*) and HTN-12wk (39%*). LV fibrosis was increased in HTN-12wk. Ees was preserved in HTN-5wk and HTN-12wk. tau was increased in HTN-5wk (50+/-3* ms) and HTN-12wk (62+/-10* ms) dogs compared with sham (41+/-2 ms). Plasma Ang II, ET, catecholamines, and plasma renin activity were unchanged during the progressive HTN. Ang II and ET in LV and kidney were not different from controls. CONCLUSIONS: Systemic HTN induces LV hypertrophy, myocardial fibrosis, and isolated diastolic dysfunction in the absence of local or systemic activation of Ang II or ET. These findings suggest that load is the prevailing stimulus for the structural and functional changes associated with early hypertensive heart disease.

Angiotensin II↗
PubMed2001

Regulation of cardiac adrenomedullin in heart failure.

Adrenomedullin (ADM), a potent natriuretic and vasorelaxing peptide with inotropic properties, is elevated in plasma in human and experimental congestive heart failure (CHF). Recent studies suggest that angiotensin II stimulates ADM production and secretion from cardiac myocytes and fibroblasts. In the present study, we investigated cardiac ADM in experimental CHF, and tested the hypothesis that angiotensin converting enzyme (ACE) inhibition modulates cardiac ADM in CHF. Cardiac tissue ADM immunoreactivity and gene expression were assessed by radioimmunoassay, immunohistochemistry, in situ hybridization and Northern blot analysis in normal and CHF dogs in the presence and absence of ACE inhibition. Experimental CHF was produced by progressive rapid ventricular pacing and characterized by increased ventricular ADM concentrations as well as increased ventricular ADM gene expression. ACE inhibition abolished the increases in ventricular ADM concentrations and ventricular ADM gene expression in CHF. Ventricular ADM gene expression was localized to ventricular myocytes and correlated with left ventricular mass index, suggesting that ventricular ADM is a marker for ventricular hypertrophy. In contrast, atrial ADM concentrations and gene expression did not change in CHF with or without ACE inhibition. Increased plasma ADM concentrations in CHF were also abolished with ACE inhibition. The present study demonstrates that circulating and ventricular ADM are activated in pacing-induced experimental CHF and that ACE inhibition reverses ventricular ADM activation in CHF. This study also indicates that cardiac ADM gene expression is differently regulated between atrium and ventricle in CHF.

Adrenomedullin↗
PubMed2001

Radiographic measurements of cardiac size as predictors of outcome in patients with dilated cardiomyopathy.

BACKGROUND: Cardiac dilatation is a predictor of poor outcome in patients with dilated cardiomyopathy. Whereas cardiac chamber dimensions or volumes can be assessed by various noninvasive and invasive techniques, simple chest radiography also may provide a valuable assessment of cardiac size. METHODS AND RESULTS: To determine the relative power of radiographic heart measurements for predicting outcome in dilated cardiomyopathy, we retrospectively studied 88 adult patients with chest radiographs obtained within 35 days of echocardiography. Standard radiographic variables were measured for each patient, and the cardiothoracic (CT) ratio, frontal cardiac area, and volume were calculated. During a mean 4.1-year follow-up, 62 of the 88 (71%) patients died. CT ratio was the best predictor of mortality among the radiographic cardiac measurements. By multivariate analysis, a model including echocardiographic ejection fraction, New York Heart Association (NYHA) functional class, and history of heart failure was highly predictive of survival. When added to this model, CT ratio also was independently associated with mortality, but not radiographic cardiac area or volume. When radiographic variables were each added to CT ratio, they did not add incremental predictive value to the model that included CT ratio alone. Echocardiographic measurement of left ventricular (LV) size, especially when indexed for body size, was independently predictive of outcome, but it did not supersede the predictive power of CT ratio. CONCLUSION: The simply derived radiographic CT ratio is a useful predictor of outcome in patients with dilated cardiomyopathy and compares favorably with other clinical and selected echocardiographic variables.

Adolescent↗
PubMed2001

Differential effects of natriuretic peptides and NO on LV function in heart failure and normal dogs.

beta-Adrenergic hyporesponsiveness in congestive heart failure (CHF) is mediated, in part, by nitric oxide (NO). NO and brain natriuretic peptide (BNP) share cGMP as a second messenger. Left ventricular (LV) function and inotropic response to intravenous dobutamine (Dob) were assessed during sequential intracoronary infusion of saline, HS-142-1 (a BNP receptor antagonist), and HS-142-1 + N(G)-monomethyl-L-arginine (L-NMMA) in anesthetized dogs with CHF due to rapid pacing and in normal dogs during intracoronary infusion of saline, exogenous BNP, and sodium nitroprusside (SNP). In CHF dogs, intracoronary HS-142-1 did not alter the inotropic response to Dob [percent change in first derivative of LV pressure (% Delta dP/dt) 47 +/- 4% saline vs. 54 +/- 7% HS-142-1, P = not significant]. Addition of intracoronary L-NMMA to HS-142-1 enhanced the response to Dob (% Delta dP/dt 73 +/- 8% L-NMMA + HS-142-1, P < 0.05 vs. H142-1). In normal dogs, intracoronary SNP blunted the inotropic response to Dob (% Delta dP/dt 93 +/- 6% saline vs. 71 +/- 5% SNP, P < 0.05), whereas intracoronary BNP had no effect. In CHF dogs, the time constant of LV pressure decay during isovolumic relaxation increased with intracoronary HS-142-1 (48 +/- 4 ms saline vs. 58 +/- 5 ms HS-142-1, P < 0.05) and further increased with intracoronary L-NMMA (56 +/- 6 ms HS-142-1 vs. 66 +/- 7 ms L-NMMA + HS-142-1, P < 0.05). Endogenous BNP and NO preserve diastolic function in CHF, whereas NO but not BNP inhibits beta-adrenergic responsiveness.

Adrenergic beta-Agonists↗
PubMed2001

Effects of avertin versus xylazine-ketamine anesthesia on cardiac function in normal mice.

Anesthetic regimens commonly administered during studies that assess cardiac structure and function in mice are xylazine-ketamine (XK) and avertin (AV). While it is known that XK anesthesia produces more bradycardia in the mouse, the effects of XK and AV on cardiac function have not been compared. We anesthetized normal adult male Swiss Webster mice with XK or AV. Transthoracic echocardiography and closed-chest cardiac catheterization were performed to assess heart rate (HR), left ventricular (LV) dimensions at end diastole and end systole (LVDd and LVDs, respectively), fractional shortening (FS), LV end-diastolic pressure (LVEDP), the time constant of isovolumic relaxation (tau), and the first derivatives of LV pressure rise and fall (dP/dt(max) and dP/dt(min), respectively). During echocardiography, HR was lower in XK than AV mice (250 +/- 14 beats/min in XK vs. 453 +/- 24 beats/min in AV, P < 0.05). Preload was increased in XK mice (LVDd: 4.1 +/- 0.08 mm in XK vs. 3.8 +/- 0.09 mm in AV, P < 0.05). FS, a load-dependent index of systolic function, was increased in XK mice (45 +/- 1.2% in XK vs. 40 +/- 0.8% in AV, P < 0.05). At LV catheterization, the difference in HR with AV (453 +/- 24 beats/min) and XK (342 +/- 30 beats/min, P < 0.05) anesthesia was more variable, and no significant differences in systolic or diastolic function were seen in the group as a whole. However, in XK mice with HR <300 beats/min, LVEDP was increased (28 +/- 5 vs. 6.2 +/- 2 mmHg in mice with HR >300 beats/min, P < 0.05), whereas systolic (LV dP/dt(max): 4,402 +/- 798 vs. 8,250 +/- 415 mmHg/s in mice with HR >300 beats/min, P < 0.05) and diastolic (tau: 23 +/- 2 vs. 14 +/- 1 ms in mice with HR >300 beats/min, P < 0.05) function were impaired. Compared with AV, XK produces profound bradycardia with effects on loading conditions and ventricular function. The disparate findings at echocardiography and LV catheterization underscore the importance of comprehensive assessment of LV function in the mouse.

Adrenergic alpha-Agonists↗
PubMed2001

Diastolic dysfunction: insights into pathophysiology and pharmacotherapy.

This review focuses on diastolic dysfunction with special emphasis on isolated diastolic dysfunction where impairment in diastolic function occurs in the absence of concomitant reduction in systolic function. The phenomena which influence diastolic function, the clinical spectrum of diastolic dysfunction, the physiological perturbations which may serve as therapeutic targets for pharmacological therapy and recent therapeutic trials are reviewed. Recommendations regarding the therapeutic approach to the patient with diastolic dysfunction are summarised.

Animals↗
PubMed2001

Approach to patients with heart failure and normal ejection fraction.

Approximately 50% of patients with a firm clinical diagnosis of heart failure (HF) have a normal ejection fraction. Some patients have valvular disease, but most have underlying diastolic dysfunction that leads to pulmonary and systemic congestion and signs and symptoms of HF. Although diastolic HF is clinically and radiographically indistinguishable from HF with depressed left systolic ventricular function, knowledge of which patients are at risk of diastolic HF, the common clinical profiles, and the common echocardiographic findings enhances the clinician's ability to diagnose diastolic HF with confidence. The prognostic implications of a diagnosis of diastolic HF and the therapeutic approach to such patients are reviewed.

Diagnosis, Differential↗
PubMed2001

Circulating natriuretic peptide concentrations in patients with end-stage renal disease: role of brain natriuretic peptide as a biomarker for ventricular remodeling.

OBJECTIVES: To determine levels of natriuretic peptides (NPs) in patients with end-stage renal disease (ESRD) and to examine the relationship of these cardiovascular peptides to left ventricular hypertrophy (LVH) and to cardiac mortality. PATIENTS AND METHODS: One hundred twelve dialysis patients without clinical evidence of congestive heart failure underwent plasma measurement of NP concentrations and echocardiographic investigation for left ventricular mass index (LVMI). RESULTS: Plasma atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) concentrations correlated positively with LVMI and inversely with left ventricular ejection fraction, whereas C-type NP and Dendroaspis NP levels did not correlate with LVMI. In dialysis patients with LVH (LVMI >125 g/m2), plasma ANP and BNP concentrations were increased compared with those in dialysis patients without LVH (both P<001). In a subset of 15 dialysis patients without LVH or other concomitant diseases, plasma BNP concentrations were not significantly increased compared with those in 35 controls (mean +/- SD, 20.1+/-13.4 vs 13.5+/-9.6 pg/mL; P=.06), demonstrating that the BNP concentration was not increased by renal dysfunction alone. Furthermore, the BNP level was significantly higher in the 16 patients who died from cardiovascular causes compared with survivors (mean +/- SD, 129+/-13 vs 57+/-7 pg/mL; P<.003) and was significantly associated with greater risk of cardiovascular death in Cox regression analysis (P<.001), as was the ANP level (P=.002). CONCLUSIONS: Elevation of the plasma BNP concentration is more specifically related to LVH compared with the other NP levels in patients with ESRD independent of congestive heart failure. Thus, BNP serves as an important plasma biomarker for ventricular hypertrophy in dialysis patients with ESRD.

Adolescent↗
PubMed2000

Subcutaneous administration of brain natriuretic peptide in experimental heart failure.

OBJECTIVES: The objective of this investigation was to define for the first time the cardiorenal and humoral actions of repeated short-term administration of subcutaneous (SQ) brain natriuretic peptide (BNP) administration during the evolution of experimental heart failure. BACKGROUND: The rationale of this study was based on BNP as a vasodilating, natriuretic, renin-inhibiting and lusitropic peptide of cardiac origin. METHODS: First, we defined the cardiorenal and humoral responses to acute low and high dose (5 microg/kg or 25 microg/kg) of SQBNP in experimental heart failure to establish the acute efficacy of an SQ delivery. Second, we characterized the response to 10 days of repeated short-term administration of BNP during the evolution of experimental heart failure produced by rapid ventricular pacing. RESULTS: Plasma BNP and 3',5'-cyclic guanosine monophosphate rapidly increased and peaked at 30 min after acute SQBNP administration with increases in urinary sodium excretion, urine flow and renal blood flow in association with reductions in cardiac filling pressures. After 10 days of repeated short-term administration of SQBNP, cardiac output was increased and systemic vascular resistance and pulmonary capillary wedge pressure were decreased, as compared with untreated dogs with heart failure. CONCLUSIONS: This study demonstrated for the first time that repeated short-term administration of SQ BNP administration for 10 days during the evolution of left ventricular dysfunction in a canine model results in an improvement in cardiovascular hemodynamics. This investigation supports a potential novel strategy for the chronic administration of BNP in the therapeutics of heart failure.

Animals↗
PubMed2000

Clinical utility of Doppler echocardiography and tissue Doppler imaging in the estimation of left ventricular filling pressures: A comparative simultaneous Doppler-catheterization study.

BACKGROUND: Noninvasive assessment of diastolic filling by Doppler echocardiography provides important information about left ventricular (LV) status in selected subsets of patients. This study was designed to assess whether mitral annular velocities as assessed by tissue Doppler imaging are associated with invasive measures of diastolic LV performance and whether additional information is gained over traditional Doppler variables. METHODS AND RESULTS: One hundred consecutive patients referred for cardiac catheterization underwent simultaneous Doppler interrogation. Invasive measurements of LV pressures were obtained with micromanometer-tipped catheters, and the mean LV diastolic pressure (M-LVDP) was used as a surrogate for mean left atrial pressure. Doppler signals from the mitral inflow, pulmonary venous inflow, and TDI of the mitral annulus were obtained. Isolated parameters of transmitral flow correlated with M-LVDP only when ejection fraction <50%. The ratio of mitral velocity to early diastolic velocity of the mitral annulus (E/E') showed a better correlation with M-LVDP than did other Doppler variables for all levels of systolic function. E/E' <8 accurately predicted normal M-LVDP, and E/E' >15 identified increased M-LVDP. Wide variability was present in those with E/E' of 8 to 15. A subset of those patients with E/E' 8 to 15 could be further defined by use of other Doppler data. CONCLUSIONS: The combination of tissue Doppler imaging of the mitral annulus and mitral inflow velocity curves provides better estimates of LV filling pressures than other methods (pulmonary vein, preload reduction). However, accurate prediction of filling pressures for an individual patient requires a stepwise approach incorporating all available data.

Aged↗
PubMed2000

Mechanical unloading versus neurohumoral stimulation on myocardial structure and endocrine function In vivo.

BACKGROUND-Mechanical load and humoral stimuli such as endothelin (ET) and angiotensin II (Ang II) are potent modulators of cardiac structure and endocrine function, specifically gene expression and production and release of atrial natriuretic peptide (ANP). We define the contribution of mechanical load compared with neurohumoral stimulation in vivo with specific focus on myocardial and circulating ANP during chronic myocardial unloading produced by thoracic inferior vena caval constriction (TIVCC). METHODS AND RESULTS-TIVCC was produced by banding the IVC for 10 days in 7 dogs, whereas in the 6 control dogs, the band was not constricted. TIVCC was characterized by a decrease in cardiac output, right atrial pressure, and left ventricular (LV) end-diastolic diameter and marked activation of ET and Ang II in plasma and atrial and ventricular myocardium. Despite neurohumoral stimulation, LV mass index and myocyte diameters in unloaded hearts decreased, reflecting myocyte atrophy. The total number of myocytes in the LV remained unchanged. Atrial stores of ANP increased, but plasma ANP did not change, in association with a trend toward ANP gene expression to decrease in unloaded hearts. CONCLUSIONS-Chronic mechanical unloading of the heart results in myocardial atrophy and lack of activation of ANP synthesis despite marked neurohumoral stimulation by the growth promoters ET and Ang II.

Angiotensin II↗
PubMed2000

Diastolic heart failure in the community.

Although it is now widely recognized that isolated diastolic dysfunction can lead to the classic signs and symptoms of congestive heart failure (CHF), this disease process is poorly understood and remains of great interest and concern to cardiovascular disease specialists, as well as to primary care physicians. Recent epidemiologic data have suggested that diastolic heart failure is predominantly a disease of the elderly, the fastest growing segment of our population. Diagnosis is often difficult in this subgroup of patients due to the presence of confounding comorbidities. However, early identification in community-based practices and timely intervention is important due to the significant disability and death that results from this progressive disease process. The poor prognosis of CHF patients with systolic dysfunction is shared by those with isolated diastolic heart failure and preserved systolic function. Further studies of the prevalence, clinical characteristics, and natural history of patients with diastolic dysfunction are needed. This review focuses on the emerging data regarding the prevalence and natural history of diastolic heart failure in the community.

Diastole↗
PubMed2000

Failing energetics in failing hearts.

The perpetual and vigorous nature of heart muscle work requires efficient myocardial energetics. This depends not only on adequate ATP production, but also on efficient delivery of ATP to muscle ATPases and rapid removal of ADP and other by-products of ATP hydrolysis. Indeed, recent evidence indicates that defects in communication between ATP-producing and ATP-consuming cellular sites are a major factor contributing to energetic deficiency in heart failure. In particular, the failing myocardium is characterized by reduced catalytic activity of creatine kinase, adenylate kinase, carbonic anhydrase, and glycolytic enzymes, which collectively facilitate ATP delivery and promote removal of ADP, Pi, and H+ from cellular ATPases. Although energy transfer through adenylate kinase and glycolytic enzymes has been recognized as an adaptive mechanism supporting compromised muscle energetics, in the failing myocardium the total compensatory potential of these systems is diminished. A gradual accumulation of defects at various steps in myocardial energetic signaling, along with compromised compensatory mechanisms, precipitates failure of the whole cardiac energetic system, ultimately contributing to myocardial dysfunction. These advances in our understanding of the molecular bioenergetics in heart failure provide a new perspective toward improving the energetic balance of the failing myocardium.

Adenosine Triphosphate↗
PubMed2000

Relationship between left ventricular wall stress and ANP gene expression during the evolution of rapid ventricular pacing-induced heart failure in the dog.

We have recently described a modified model of progressive rapid ventricular pacing-induced heart failure which evolves over a period of 38 days. To further characterize left ventricular remodeling during the progression of heart failure, we assessed left ventricular geometry, wall stress, and atrial natriuretic peptide (ANP) gene expression and protein content during control conditions, asymptomatic left ventricular dysfunction, and overt congestive heart failure (CHF). Although asymptomatic left ventricular dysfunction was characterized by a significant increase in systolic and diastolic left ventricular dimension (+30% and +6%, respectively, P<0.05 each) and a marked increase in left ventricular systolic wall stress (+68%, P<0.01), left ventricular ANP gene expression was unchanged as compared to control. In contrast, strong left ventricular ANP gene expression (+449%, P<0.05) was observed during overt CHF in the absence of further significant increases in left ventricular systolic wall stress. The onset of strong left ventricular ANP gene expression was associated with increased ANP content (+88%, P<0.05) and left ventricular mass index (+13%, P<0.05). In contrast, left atrial ANP gene expression and left ventricular diastolic wall stress increased progressively during asymptomatic left ventricular dysfunction (+39%, P=n.s. and +131%, P<0.01) and overt CHF (+76% and +336% vs. control, P<0.01 each). Progressive rapid ventricular pacing is associated with the induction of left ventricular ANP gene expression and protein synthesis exclusively during overt CHF. The current studies provide new insight into the temporal pattern of ANP-activation and the disparity between left ventricular systolic wall stress and ANP-activation in a large animal model of progressive CHF.

Animals↗
PubMed2000

The role of coenzyme Q10 in the pathophysiology and therapy of experimental congestive heart failure in the dog.

BACKGROUND: Coenzyme Q10 (CoQ10) is essential for ATP generation and has antioxidant properties. Decreased CoQ10 levels have been reported in human heart failure (CHF), but it remains unclear if this is a conserved feature of CHF. The objective of the study was to determine if tachycardia-induced CHF in the dog is associated with reduced CoQ10 levels. Furthermore, it was hypothesized that CoQ10 supplementation may improve CHF severity by preventing CoQ10 deficiency (if present) or via antioxidant effects. METHODS AND RESULTS: Serum and myocardial levels of CoQ10 were examined in normal dogs (n = 6), dogs with CHF (control, n = 5), and dogs with CHF treated with CoQ10 (CoQ10; 10 mg/kg/day, n = 5). Serum CoQ10 levels did not change with CHF in control dogs, and myocardial levels were similar to those of normal dogs. CoQ10 therapy increased serum but not myocardial levels of CoQ10. In early CHF, CoQ10-treated dogs had lower filling pressures, and, in severe CHF, CoQ10-treated dogs had less hypertrophy as compared with untreated dogs. Other indices of CHF severity were similar in control and CoQ10-treated dogs. CONCLUSION: These data indicate that CoQ10 deficiency is not present in this model of CHF. Although dramatic effects on hemodynamics were not observed, CoQ10 supplementation did appear to attenuate the hypertrophic response associated with CHF. Key words: enzymes, cardiomyopathy, hormones, antioxidant.

Animals↗
PubMed2000

Clinical criteria and biochemical markers for the detection of systolic dysfunction.

BACKGROUND: This study was designed to assess the use of clinical criteria and biochemical testing to detect systolic dysfunction. Our goal is to develop strategies that may enhance the detection and treatment of patients with early ventricular dysfunction while reducing the use of echocardiography. METHODS AND RESULTS: We compared the predictive characteristics of the plasma brain natriuretic peptide (BNP) concentration with that of a 5-point clinical score derived from elements of the history, electrocardiogram, and chest radiograph in outpatients (n = 466) referred for echocardiography because of symptoms of heart failure or risk factors for systolic dysfunction. Systolic dysfunction was defined as an ejection fraction (EF) less than 45% and was present in 10.9% of patients. By receiver operating characteristic analysis, BNP was sensitive and specific for the detection of systolic dysfunction, with an area under the receiver operating characteristic curve for the detection of EF less than 45% of 0.79. The BNP assay was abnormal in 41% of patients and identified a group with a high prevalence of systolic dysfunction (21% with an EF less than 45%), whereas a normal BNP value identified a group with a low prevalence of systolic dysfunction (4% with an EF less than 45%). The clinical score was positive in 43% of the population and identified a group with a high prevalence of systolic dysfunction (24% with an EF less than 45%). A normal score identified a group with a low prevalence of systolic dysfunction (1% with an EF less than 45%). CONCLUSION: This study supports previous studies, which showed that BNP assay predicts systolic dysfunction with acceptable sensitivity and specificity, and it underscores the effectiveness of additional readily available clinical criteria. Both of these strategies should be considered in screening for left ventricular dysfunction in populations at risk while limiting expensive cardiac imaging modalities.

Aged↗