Daniel D. Borgeson

Differential atrial and ventricular expression of myocardial BNP during evolution of heart failure

Although brain natriuretic peptide (BNP) of myocardial origin is important in cardiovascular and renal function and as a marker of cardiac dysfunction, the expression of BNP in atrial and ventricular myocardium remains controversial both under normal conditions and in heart failure. We therefore determined left atrial and left ventricular (LV) gene expression and tissue concentration as well as circulating BNP during the evolution of rapid ventricular pacing-induced congestive heart failure (CHF) in the dog. Early LV dysfunction after 10 days of pacing was characterized by impaired LV function but maintained arterial pressure, and overt CHF after 38 days of pacing was characterized by further impaired LV function and decreased systemic arterial pressure. Under normal conditions, cardiac BNP mRNA and cardiac tissue BNP were of atrial origin. In early LV dysfunction, BNP mRNA and tissue BNP were markedly increased in the left atrium in association with an increase in circulating BNP but remained below or at the limit of detection in the LV. In overt CHF, BNP mRNA was further increased in the left atrium and first increased in the LV, together with an increase in LV tissue BNP and a further increase in circulating BNP. In the progression of CHF, early LV dysfunction is characterized by a selective increase in atrial BNP expression in association with increased circulating BNP. Overt CHF is characterized by an additional recruitment of ventricular BNP expression and a further increase in circulating BNP. These studies provide important new insight into the local and temporal regulation of cardiac BNP gene expression during the progression of heart failure and underscore the predominant endocrine role of atrial myocardium under normal conditions and in early LV dysfunction.Although brain natriuretic peptide (BNP) of myocardial origin is important in cardiovascular and renal function and as a marker of cardiac dysfunction, the expression of BNP in atrial and ventricular myocardium remains controversial both under normal conditions and in heart failure. We therefore determined left atrial and left ventricular (LV) gene expression and tissue concentration as well as circulating BNP during the evolution of rapid ventricular pacing-induced congestive heart failure (CHF) in the dog. Early LV dysfunction after 10 days of pacing was characterized by impaired LV function but maintained arterial pressure, and overt CHF after 38 days of pacing was characterized by further impaired LV function and decreased systemic arterial pressure. Under normal conditions, cardiac BNP mRNA and cardiac tissue BNP were of atrial origin. In early LV dysfunction, BNP mRNA and tissue BNP were markedly increased in the left atrium in association with an increase in circulating BNP but remained below or at the limit of detection in the LV. In overt CHF, BNP mRNA was further increased in the left atrium and first increased in the LV, together with an increase in LV tissue BNP and a further increase in circulating BNP. In the progression of CHF, early LV dysfunction is characterized by a selective increase in atrial BNP expression in association with increased circulating BNP. Overt CHF is characterized by an additional recruitment of ventricular BNP expression and a further increase in circulating BNP. These studies provide important new insight into the local and temporal regulation of cardiac BNP gene expression during the progression of heart failure and underscore the predominant endocrine role of atrial myocardium under normal conditions and in early LV dysfunction.

Frequency of Doppler measurable pulmonary artery pressures

The current literature suggests that right-sided heart pressures can be obtained noninvasively in approximately 60% of patients. We hypothesized that with a focused echocardiographic Doppler examination, measurable tricuspid or pulmonary valve regurgitation suitable for measuring pressures could be obtained in a higher percentage of patients. The study group consisted of 200 consecutive patients undergoing echocardiographic and Doppler hemodynamic evaluation. All patients were first examined by an ultrasonographer instructed to attempt to record tricuspid and pulmonary regurgitant velocities. After this examination, a designated cardiologist performed a focused examination with the intent of improving the signal quality and increasing the number of measurable signals for evaluation. Tricuspid regurgitation of measurable quality was recorded in 147 (73.5%) of 200 patients by the ultrasonographer; this result was improved to 172 patients (86%) by the designated cardiologist. Pulmonary regurgitation was obtainable in 147 (95%) of 154 patients and was of measurable quality in 137 (89%). When results of tricuspid and pulmonary regurgitation were combined, a quantifiable signal was obtained in 194 (97%) of 200 consecutive unselected patients. This study demonstrates that a well-trained ultrasonographer or echocardiologist can obtain right-sided pressures in at least 95% of all unselected cardiovascular patients.

Angiotensin II in the Evolution of Experimental Heart Failure

Although angiotensin II (Ang II) has been implicated in the pathophysiology of congestive heart failure, its temporal and regional changes during the development and progression of the disease are poorly defined. Our objective was to assess circulating, renal, cardiac, and vascular Ang II in a canine model of rapid ventricular pacing-induced heart failure that evolves from early left ventricular dysfunction to overt congestive heart failure. Ang II was measured by radioimmunoassay with low cross-reactivity to other angiotensins. Control, early left ventricular dysfunction, and overt congestive heart failure dogs were studied. Early left ventricular dysfunction was characterized by impaired cardiac function, cardiac enlargement, preserved renal perfusion pressure, maintained urinary sodium excretion, and normal plasma renin activity. Overt congestive heart failure was characterized by further impaired cardiac function and cardiac enlargement, reduced renal perfusion pressure, urinary sodium retention, and increased plasma renin activity and plasma Ang II. In early left ventricular dysfunction dogs, renal cortical, renal medullary, ventricular, and aortic Ang II were unchanged, and atrial Ang II was decreased. In overt congestive heart failure dogs, Ang II was increased in the kidney and heart compared with normal dogs and in all tissues compared with early left ventricular dysfunction dogs. The greatest increase in tissue Ang II occurred in the renal medulla. We conclude that early increases in local renal, myocardial, and vascular Ang II do not occur in this model of early left ventricular dysfunction and may even be suppressed. In contrast, increased myocardial and particularly renal Ang II in association with increased circulating Ang II are hallmarks of overt experimental congestive heart failure. These studies provide new insights into the temporal and regional alterations in Ang II during the progression of experimental congestive heart failure.

Echocardiographic Variables After Left Ventricular Assist Device Implantation Associated With Adverse Outcome

Background— Operative mortality after left ventricular assist device (LVAD) implantation is heavily influenced by patient selection and the technical difficulty of surgery. However, how we treat our patients and LVAD setting may affect the patient outcome beyond this period. We postulated that the presence of echocardiographic variables 1 month after surgery suggesting appropriate degree of LV unloading and an adequate forward flow would be important in determining clinical outcomes after the initial successful LVAD implantation. Methods and Results— We retrospectively analyzed various variables in echocardiographic examinations performed 30 days after LVAD implant in 76 consecutive patients receiving continuous flow device for their association with a compound end point (90-day mortality, readmission for heart failure, or New York Heart Association class III or higher at the end of the 90-day period). The echocardiographic associations examined included estimated LVAD flow, with and without native LV contribution, interventricular septal position, the status of aortic valve opening, an estimated left atrial pressure (ELAP), the mitral flow E-wave deceleration time, and the ratio of deceleration time to E-wave velocity (mitral deceleration index [MDI]). Four patients died during the 30- to 90-day period, 6 patients were readmitted for heart failure, and 25 patients were considered to have New York Heart Association class III or higher at the end of the 90-day period. Variables associated with adverse outcome included increased ELAP (odds ratio, 1.30 [1.16–1.48]; P<0.0001), MDI <2 ms/[cm/s] (odds ratio, 4.4 implantation [1.22–18]; P=0.02) and decreased tricuspid lateral annulus velocity (odds ratio, 0.70 implantation [0.48–0.95]; P=0.02). A leftward deviation of interventricular septum was associated with a worse outcome (odds ratio, 3.03 implantation [1.21–13.3]; P=0.01). Conclusions— Mortality and heart failure after LVAD surgery appear to be predominantly determined by echocardiographic evidence of inefficient unloading of the left ventricle and persistence of right ventricular dysfunction. Increased estimated LA pressure and short MDI are associated with worse mid term outcome. Leftward deviation of the septum is associated with worse outcome as well.Background —Operative mortality following LVAD implantation is heavily influenced by patient selection and the technical difficulty of surgery. However, how we manage our patients and LVAD setting may affect the patient outcome beyond this period. We postulated that the presence of echocardiographic variables one month after surgery suggesting appropriate degree of LV unloading and an adequate forward flow would be important in determining clinical outcomes following the initial successful LVAD implantation. Methods and Results —We retrospectively analyzed various variables in echocardiographic examinations performed 30 days after LVAD implant in 76 consecutive patients receiving continuous flow device (Heart Mate II) for their association with a compound endpoint (90 day mortality, re-admission for heart failure, or NYHA≥III at the end of the 90 day period). The echocardiographic associations examined included estimated LVAD flow, with and without native LV contribution, inter-ventricular septal position, the status of aortic valve opening, an estimated left atrial pressure (ELAP), the mitral flow E wave deceleration time and the ratio of deceleration time to E wave velocity (mitral deceleration index [MDI]). Four patients died during the 30-90 day period, six patients were re-admitted for heart failure, and 25 patients were considered to have NYHA≥III at the end of the 90 day period. Variables associated with adverse outcome included increased ELAP (Odds Ratio (OR) 1.30(1.16-1.48); p<0.0001), MDI<2 ms/ [cm/s] (OR 4.4(1.22-18); P=0.02) and decreased tricuspid lateral annulus velocity (OR 0.70(0.48-0.95); P=0.02). A leftward deviation of inter-ventricular septum was associated with a worse outcome (OR 3.03(1.21-13.3); P=0.01). Conclusions —Mortality and heart failure after LVAD surgery seem to be predominantly determined by echocardiographic evidence of inefficient unloading of left ventricle and persistence of RV dysfunction. Increased estimated LA pressure and short MDI are associated with worse mid term outcome. Leftward deviation of the septum is associated with worse outcome as well.

Increased prevalence of diastolic dysfunction in rheumatoid arthritis

Objective To compare the prevalence of left ventricular (LV) diastolic dysfunction in subjects with and without rheumatoid arthritis (RA), among those with no history of heart failure (HF), and to determine risk factors for diastolic dysfunction in RA. Methods A cross-sectional, community-based study comparing cohorts of adults with and without RA and without a history of HF was carried out. Standard two-dimensional/Doppler echocardiography was performed in all participants. Diastolic dysfunction was defined as impaired relaxation (with or without increased filling pressures) or advanced reduction in compliance or reversible or fixed restrictive filling. Results The study included 244 subjects with RA and 1448 non-RA subjects. Mean age was 60.5 years in the RA cohort (71% female) and 64.9 years (50% female) in the non-RA cohort. The vast majority (>98%) of both cohorts had preserved ejection fraction (EF≥50%). Diastolic dysfunction was more common in subjects with RA at 31% compared with 26% (age and sex adjusted) in non-RA subjects (OR=1.6; 95% CI 1.2 to 2.4). Patients with RA had significantly lower LV mass, higher pulmonary arterial pressure and higher left atrial volume index than non-RA subjects. RA duration and interleukin 6 (IL-6) level were independently associated with diastolic dysfunction in RA even after adjustment for cardiovascular risk factors. Conclusion Subjects with RA have a higher prevalence of diastolic dysfunction than those without RA. RA duration and IL-6 are independently associated with diastolic dysfunction, suggesting the impact of chronic autoimmune inflammation on myocardial function in RA. Clinical implications of these findings require further investigation.

Adrenomedullin in experimental congestive heart failure: cardiorenal activation

Adrenomedullin (ADM) is a new member of a family of vasodilating and natriuretic peptides that plays an important role in cardiorenal regulation. This study was designed to establish the plasma, urinary, cardiac, and renal tissue concentrations and immunohistochemical localizations of ADM in normal dogs and dogs with experimental congestive heart failure (CHF) produced by rapid ventricular pacing. Plasma ADM concentration was 5.6 +/- 0.4 pg/ml in normal dogs and significantly increased to 14.5 +/- 2.5 pg/ml in CHF dogs (P < 0.05). Ventricular and renal tissue ADM were significantly increased in CHF dogs compared with normals. Immunohistochemical examination revealed positive ADM immunostaining within the myocytes, and ventricular ADM immunoreactivity was significantly more intense in CHF dogs than in normals. ADM immunoreactivity was also observed in the glomerulus, distal tubules, and medullary collecting duct cells in the kidney, and the intensities of ADM immunoreactivity in these sites were increased in CHF dogs compared with normals. In addition, ventricular ADM was a powerful marker for left ventricular mass, and circulating ADM correlated positively with left ventricular end-diastolic pressure and inversely with cardiac output and ejection fraction. Despite an increase in renal tissue ADM, urinary ADM did not increase in CHF dogs. The current study demonstrates that plasma concentration of ADM is increased in experimental CHF and that ventricular and renal ADM is activated in the progression of CHF. Tissue and circulating ADM also are markers for the alterations in myocardial structure and function. This study supports a potential role for ADM in the neurohumoral activation in experimental CHF.Adrenomedullin (ADM) is a new member of a family of vasodilating and natriuretic peptides that plays an important role in cardiorenal regulation. This study was designed to establish the plasma, urinary, cardiac, and renal tissue concentrations and immunohistochemical localizations of ADM in normal dogs and dogs with experimental congestive heart failure (CHF) produced by rapid ventricular pacing. Plasma ADM concentration was 5.6 ± 0.4 pg/ml in normal dogs and significantly increased to 14.5 ± 2.5 pg/ml in CHF dogs ( P < 0.05). Ventricular and renal tissue ADM were significantly increased in CHF dogs compared with normals. Immunohistochemical examination revealed positive ADM immunostaining within the myocytes, and ventricular ADM immunoreactivity was significantly more intense in CHF dogs than in normals. ADM immunoreactivity was also observed in the glomerulus, distal tubules, and medullary collecting duct cells in the kidney, and the intensities of ADM immunoreactivity in these sites were increased in CHF dogs compared with normals. In addition, ventricular ADM was a powerful marker for left ventricular mass, and circulating ADM correlated positively with left ventricular end-diastolic pressure and inversely with cardiac output and ejection fraction. Despite an increase in renal tissue ADM, urinary ADM did not increase in CHF dogs. The current study demonstrates that plasma concentration of ADM is increased in experimental CHF and that ventricular and renal ADM is activated in the progression of CHF. Tissue and circulating ADM also are markers for the alterations in myocardial structure and function. This study supports a potential role for ADM in the neurohumoral activation in experimental CHF.

Echocardiographic Variables Post LVAD Associated with Adverse Outcome

Background— Operative mortality after left ventricular assist device (LVAD) implantation is heavily influenced by patient selection and the technical difficulty of surgery. However, how we treat our patients and LVAD setting may affect the patient outcome beyond this period. We postulated that the presence of echocardiographic variables 1 month after surgery suggesting appropriate degree of LV unloading and an adequate forward flow would be important in determining clinical outcomes after the initial successful LVAD implantation. Methods and Results— We retrospectively analyzed various variables in echocardiographic examinations performed 30 days after LVAD implant in 76 consecutive patients receiving continuous flow device for their association with a compound end point (90-day mortality, readmission for heart failure, or New York Heart Association class III or higher at the end of the 90-day period). The echocardiographic associations examined included estimated LVAD flow, with and without native LV contribution, interventricular septal position, the status of aortic valve opening, an estimated left atrial pressure (ELAP), the mitral flow E-wave deceleration time, and the ratio of deceleration time to E-wave velocity (mitral deceleration index [MDI]). Four patients died during the 30- to 90-day period, 6 patients were readmitted for heart failure, and 25 patients were considered to have New York Heart Association class III or higher at the end of the 90-day period. Variables associated with adverse outcome included increased ELAP (odds ratio, 1.30 [1.16–1.48]; P<0.0001), MDI <2 ms/[cm/s] (odds ratio, 4.4 implantation [1.22–18]; P=0.02) and decreased tricuspid lateral annulus velocity (odds ratio, 0.70 implantation [0.48–0.95]; P=0.02). A leftward deviation of interventricular septum was associated with a worse outcome (odds ratio, 3.03 implantation [1.21–13.3]; P=0.01). Conclusions— Mortality and heart failure after LVAD surgery appear to be predominantly determined by echocardiographic evidence of inefficient unloading of the left ventricle and persistence of right ventricular dysfunction. Increased estimated LA pressure and short MDI are associated with worse mid term outcome. Leftward deviation of the septum is associated with worse outcome as well.Background —Operative mortality following LVAD implantation is heavily influenced by patient selection and the technical difficulty of surgery. However, how we manage our patients and LVAD setting may affect the patient outcome beyond this period. We postulated that the presence of echocardiographic variables one month after surgery suggesting appropriate degree of LV unloading and an adequate forward flow would be important in determining clinical outcomes following the initial successful LVAD implantation. Methods and Results —We retrospectively analyzed various variables in echocardiographic examinations performed 30 days after LVAD implant in 76 consecutive patients receiving continuous flow device (Heart Mate II) for their association with a compound endpoint (90 day mortality, re-admission for heart failure, or NYHA≥III at the end of the 90 day period). The echocardiographic associations examined included estimated LVAD flow, with and without native LV contribution, inter-ventricular septal position, the status of aortic valve opening, an estimated left atrial pressure (ELAP), the mitral flow E wave deceleration time and the ratio of deceleration time to E wave velocity (mitral deceleration index [MDI]). Four patients died during the 30-90 day period, six patients were re-admitted for heart failure, and 25 patients were considered to have NYHA≥III at the end of the 90 day period. Variables associated with adverse outcome included increased ELAP (Odds Ratio (OR) 1.30(1.16-1.48); p<0.0001), MDI<2 ms/ [cm/s] (OR 4.4(1.22-18); P=0.02) and decreased tricuspid lateral annulus velocity (OR 0.70(0.48-0.95); P=0.02). A leftward deviation of inter-ventricular septum was associated with a worse outcome (OR 3.03(1.21-13.3); P=0.01). Conclusions —Mortality and heart failure after LVAD surgery seem to be predominantly determined by echocardiographic evidence of inefficient unloading of left ventricle and persistence of RV dysfunction. Increased estimated LA pressure and short MDI are associated with worse mid term outcome. Leftward deviation of the septum is associated with worse outcome as well.

Chronic Oral Endothelin Type A Receptor Antagonism in Experimental Heart Failure

Endothelin-1 (ET-1) is a cardiovascular peptide that binds to two distinct receptors, ET(A) and ET(B), resulting in systemic and regional vasoconstriction, alteration in sodium excretion, mitogenesis, and release of other vasoactive peptides such as atrial natriuretic peptide (ANP). A role for ET-1 has been proposed in congestive heart failure (CHF) based on the increase in circulating ET-1 in this cardiovascular disease state. The present study determined the cardiorenal and endocrine responses to chronic selective oral ETA antagonism in experimental CHF. Two groups of conscious dogs underwent 21 days of pacing-induced CHF. These groups included a control untreated group (n = 6) and a group that received an orally active ET(A) receptor antagonist (A-127722, Abbott Pharmaceuticals, 5 mg/kg PO bid, n = 6). Each group was studied at baseline before the onset of CHF and after 14 and 21 days of CHF. Compared with the CHF control group, the ET(A) receptor antagonism group at 14 days of CHF showed lower mean arterial pressure and systemic vascular resistance. Similarly, ET(A) receptor antagonism markedly attenuated the increase in circulating ANP despite similar atrial pressures. At 21 days of CHF, ET(A) receptor antagonism lowered pulmonary artery pressure, pulmonary vascular resistance, and systemic vascular resistance in association with a higher cardiac output. Plasma ANP remained suppressed. Despite the lower mean arterial pressure and circulating ANP in the ET(A) receptor antagonist group, the absolute decrease in sodium excretion from baseline was less compared with the untreated CHF control group. The present investigation supports the conclusion that endogenous ET-1 participates in the systemic and pulmonary vasoconstriction, the elevation of ANP, and the sodium retention that characterize this model of experimental CHF, suggesting a potential therapeutic role for ET(A) receptor antagonism in CHF.

Brief report: rheumatoid arthritis is associated with left ventricular concentric remodeling: results of a population-based cross-sectional study.

OBJECTIVE To study left ventricular (LV) geometry in patients with rheumatoid arthritis (RA) and no history of heart failure compared with that in subjects with neither RA nor a history of heart failure, and to determine the impact of RA on LV remodeling. METHODS A cross-sectional, community-based study was conducted among adult (age ≥50 years) patients with RA and age- and sex-matched subjects with neither RA nor a history of heart failure. All participants underwent standard 2-dimensional Doppler echocardiography. LV geometry was classified into the following 4 categories based on relative wall thickness and sex-specific cutoffs for the LV mass index: concentric remodeling, concentric hypertrophy, eccentric hypertrophy, or normal geometry. RESULTS Among 200 patients with RA and 600 age- and sex-matched subjects without RA, the mean age was 65 years, and 74% of the individuals in both cohorts were female. Compared with subjects without RA, patients with RA were significantly more likely to have abnormal LV geometry (odds ratio [OR] 1.44, 95% confidence interval [95% CI] 1.03-2.00), even after adjusting for cardiovascular risk factors and comorbidities. Among subjects with abnormal LV geometry, the odds of concentric LV remodeling were significantly increased in patients with RA (OR 4.73, 95% CI 2.85-7.83). In linear regression analyses, the LV mass index appeared to be lower in patients with RA who were currently receiving corticosteroids (β ± SE -0.082 ± 0.027, P = 0.002), even after adjusting for cardiovascular risk factors and comorbidities. CONCLUSION RA was strongly associated with abnormal LV remodeling (particularly concentric LV remodeling) among RA patients without heart failure. This association remained significant after adjustment for cardiovascular risk factors and comorbidities. RA disease-related factors may promote changes in LV geometry. The biologic mechanisms underlying LV remodeling warrant further investigation.

Use of B-Type Natriuretic Peptide as a Screening Tool for Left Ventricular Diastolic Dysfunction in Rheumatoid Arthritis Patients Without Clinical Cardiovascular Disease

Patients with rheumatoid arthritis (RA) are at an increased risk for heart failure and left ventricular diastolic dysfunction (LVDD). B‐type natriuretic peptide (BNP) may be useful to screen for LVDD in the general population. We compared the effectiveness of BNP as a screening tool for LVDD in RA and non‐RA subjects without cardiovascular disease (CVD).