Marvin W. Kronenberg

Effect of transendocardial delivery of autologous bone marrow mononuclear cells on functional capacity, left ventricular function, and perfusion in chronic heart failure: the FOCUS-CCTRN trial.

CONTEXT Previous studies using autologous bone marrow mononuclear cells (BMCs) in patients with ischemic cardiomyopathy have demonstrated safety and suggested efficacy. OBJECTIVE To determine if administration of BMCs through transendocardial injections improves myocardial perfusion, reduces left ventricular end-systolic volume (LVESV), or enhances maximal oxygen consumption in patients with coronary artery disease or LV dysfunction, and limiting heart failure or angina. DESIGN, SETTING, AND PATIENTS A phase 2 randomized double-blind, placebo-controlled trial of symptomatic patients (New York Heart Association classification II-III or Canadian Cardiovascular Society classification II-IV) with a left ventricular ejection fraction of 45% or less, a perfusion defect by single-photon emission tomography (SPECT), and coronary artery disease not amenable to revascularization who were receiving maximal medical therapy at 5 National Heart, Lung, and Blood Institute-sponsored Cardiovascular Cell Therapy Research Network (CCTRN) sites between April 29, 2009, and April 18, 2011. INTERVENTION Bone marrow aspiration (isolation of BMCs using a standardized automated system performed locally) and transendocardial injection of 100 million BMCs or placebo (ratio of 2 for BMC group to 1 for placebo group). MAIN OUTCOME MEASURES Co-primary end points assessed at 6 months: changes in LVESV assessed by echocardiography, maximal oxygen consumption, and reversibility on SPECT. Phenotypic and functional analyses of the cell product were performed by the CCTRN biorepository core laboratory. RESULTS Of 153 patients who provided consent, a total of 92 (82 men; average age: 63 years) were randomized (n = 61 in BMC group and n = 31 in placebo group). Changes in LVESV index (-0.9 mL/m(2) [95% CI, -6.1 to 4.3]; P = .73), maximal oxygen consumption (1.0 [95% CI, -0.42 to 2.34]; P = .17), and reversible defect (-1.2 [95% CI, -12.50 to 10.12]; P = .84) were not statistically significant. There were no differences found in any of the secondary outcomes, including percent myocardial defect, total defect size, fixed defect size, regional wall motion, and clinical improvement. CONCLUSION Among patients with chronic ischemic heart failure, transendocardial injection of autologous BMCs compared with placebo did not improve LVESV, maximal oxygen consumption, or reversibility on SPECT. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00824005.

Pilot study of a Web-based compliance monitoring device for patients with congestive heart failure

BACKGROUND Web-based home care monitoring systems can assess medication compliance, health status, quality of life, and physiologic parameters. They may help overcome some of the limitations associated with current congestive heart failure management models. OBJECTIVES This pilot study compared the effects of a self-care and medication compliance device, linked to a Web-based monitoring system, to the effects of usual care alone on compliance with recommended self-care behaviors; medication taking; quality of life; distance walked during a 6-minute walk test; and New York Heart Association Functional Class. We also assessed patient experiences living with the compliance device. METHODS We enrolled 18 patients with Functional Class II-III congestive heart failure in an urban VA Medical Center. The patients were randomized into 2 groups. Group A received usual care plus the compliance device. Group B (controls) received usual care only. Data were collected using the compliance device, the Heart Failure Self-Care Behavior Scale, pill counts, 6-minute walk test, and the Minnesota Living with Heart Failure Questionnaire at baseline and at 3 months follow-up. RESULTS At baseline and at 3 months, there were no differences between the compliance device group and the usual care group in self-care behaviors, pill counts, 6-minute walk-test distance, or Functional Class. However, quality of life improved significantly from baseline to 3-month follow-up (ANOVA, P =.006). This difference was due to an improvement in quality of life for the monitor group (P =.002) but not the usual care only group (P =.113). Patients in the compliance device group had a 94% medication compliance rate, 81% compliance with daily blood pressure monitoring, and 85% compliance with daily weight monitoring as compared to 51% for blood pressure monitoring and 79% for weight monitoring in the usual care group (P = NS). CONCLUSION These are promising pilot results that, if replicated in a larger sample, may significantly improve care and outcomes for patients with heart failure.

Reproducibility of Left Ventricular Mass Measurements by Two-Dimensional and M-Mode Echocardiography

Both two-dimensional and M-mode echocardiography provide accurate estimates of left ventricular mass. However, their reproducibility in serial studies has not been compared, although this issue is critical to evaluation of regression of hypertrophy. To determine which technique provides more reproducible estimates of left ventricular mass, three serial studies were performed prospectively in each of eight normal adults over 5 months. Both two-dimensional and M-mode echocardiograms were obtained at each of these 24 studies. Measurements were performed by two independent observers who did not know patient identity. For the two-dimensional method, left ventricular mass was determined with use of a computer light-pen system and the truncated ellipsoid formula. For the M-mode method, mass was calculated from Penn convention measurements with use of the cube formula. At study 1 the group mean left ventricular mass by two-dimensional echocardiography (115 +/- 20 g) did not differ from that by M-mode study (127 +/- 37 g, p = NS). However, serial estimates of left ventricular mass were more reproducible by two-dimensional echocardiography. The mean difference among the three serial two-dimensional studies in each individual was 4.8 +/- 4 g (4.2 +/- 3%) by the two-dimensional method, but was 18.5 +/- 13 g (14.9 +/- 10%) by the M-mode method (p = 0.01). Interobserver results for left ventricular mass by two-dimensional echocardiography correlated closely (r = 0.95, n = 24, p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Left ventricular dysfunction induced by cold exposure in patients with systemic sclerosis

Raynauds phenomenon and cardiac abnormalities are frequent in patients with systemic sclerosis. Radionuclide ventriculograms were obtained in 16 patients with Raynauds phenomenon and systemic sclerosis or the related CREST syndrome and in 11 normal volunteers in order to evaluate changes in left ventricular function that might be induced by exposure to cold. Left ventricular regional wall motion abnormalities developed in nine of 16 patients during cooling compared with only one of 11 control subjects, despite a comparable rise in mean arterial pressure (p less than 0.02). The abnormalities occurred in seven of 11 patients with systemic sclerosis, one of four with CREST syndrome, and one with Raynauds disease. To test the potential protective effect of nifedipine, radionuclide ventriculograms were then obtained during cooling after sublingual nifedipine (20 mg). Only five of 13 patients had wall motion abnormalities, and the severity of the abnormalities was significantly less than during the first cooling period (p = 0.03). Five of eight patients who had cold-induced wall motion abnormalities during the first cooling period had none after nifedipine, whereas two other patients demonstrated small abnormalities only during the second cooling period after treatment with nifedipine. It is concluded that cold induces segmental myocardial dysfunction in patients with systemic sclerosis and that nifedipine may blunt the severity of this abnormal response.

Dynamic fluctuations in blood and spleen radioactivity: Splenic contraction and relation to clinical radionuclide volume calculations

Alterations in the blood radioactivity affect ventricular volume calculations using count-based radionuclide ventriculography. To study this phenomenon, the effect of time, posture and supine exercise on blood radioactivity, red blood cell count and splenic radioactivity was evaluated. The red blood cell count, and blood, splanchnic and splenic radioactivity remained stable in five patients studied at rest in the supine position. On standing, blood radioactivity increased 10 +/- 3% (standard error of the mean), and abdominal radioactivity decreased 14.5 +/- 6.5% (both p less than 0.05). In 10 patients, splenic radioactivity decreased after supine exercise by 49 +/- 7%, while blood radioactivity increased 10.5 +/- 1.5% and red blood cell count increased 7.5 +/- 1.5% (all p less than 0.001). Splenic radioactivity increased gradually after exercise and decreased after a second exercise period. In the exercising patients, blood radioactivity increased by 14.5% and correlated with an increase in the red blood cell count (r = 0.57, p = 0.01, 19 samples from 10 patients). Reduction in splenic radioactivity also correlated with the increase in red blood cell count (r = -0.51, p = 0.025). The data demonstrate splenic shrinkage in human beings and an inverse relation between changes in splenic and blood radioactivity. These dynamic fluctuations emphasize the need for simultaneous blood sampling for accurate calculation of left ventricular volume and high-light the importance of regional volume shifts during exercise.

Enhanced Left Ventricular Contractility in Autonomic Failure: Assessment Using Pressure-Volume Relations

Severe autonomic failure is usually characterized by both supine hypertension and orthostatic hypotension. Inadequate preload reserve, insufficient arterial resistance and abnormal cardiac performance have been postulated to contribute to the hypotension. To clarify these mechanisms, left ventricular performance and contractility were assessed using radionuclide ventriculography and systolic pressure-volume relations when supine and with graded head-up tilt in 11 patients with autonomic failure. Results were compared with those of 12 normal subjects, using phenylephrine infusion for pharmacologic afterload augmentation after autonomic blockade with atropine and propranolol. In a subset of four patients with autonomic failure, systolic pressure-volume relations were similar by both the tilt and phenylephrine methods. In autonomic failure, end-diastolic volume, end-systolic volume and stroke volume decreased with progressive degrees of tilt (p less than or equal to 0.007 for each). The supine radionuclide ejection fraction and cardiac output were similar to those of normal subjects (69% versus 68% and 5.4 versus 4.9 liters/min, respectively, p = NS). However, the slopes of the pressure-volume relations and the supine pressure/volume ratio in autonomic failure were much greater than normal (8.8 versus 2.5, and 6.3 versus 3.6 mm Hg/ml, respectively, p less than or equal to 0.04 for both). The baseline total peripheral resistance was greater than normal (24.9 versus 17.4 mm Hg.min-1/liter, p = 0.01), but the resistance at maximal tilt failed to increase (20.8 +/- 6.1 units). Plasma norepinephrine concentrations were lower than normal. Thus, patients with autonomic failure had hypercontractile left ventricular performance when assessed by pressure-volume relations, and their hearts were well matched to the elevated peripheral resistance.(ABSTRACT TRUNCATED AT 250 WORDS)

Effectiveness of preload reserve as a determinant of clinical status in patients with left ventricular systolic dysfunction

The hemodynamic determinants of clinical status in patients with left ventricular (LV) systolic dysfunction have not been established. In the present study, preload reserve--LV distension during exercise--was related to clinical status, and the effect of acute angiotensin-converting enzyme inhibition was examined in 97 patients with ejection fraction less than or equal to 0.35 enrolled in the trial, Studies of Left Ventricular Dysfunction (SOLVD). Sixty-one asymptomatic patients (group I) were compared with 36 patients with symptomatic heart failure (group II). Radionuclide LV volumes were measured at rest and during maximal cycle exercise. Group II patients had higher resting heart rates, end-diastolic and end-systolic volumes, and lower ejection fractions (all p less than 0.005). During exercise, only patients in group I had increased stroke volume (from 35 +/- 8 to 39 +/- 11 ml/m2 [mean +/- SD; p less than 0.0005]) due to an increase in end-diastolic volume (from 119 +/- 29 to 126 +/- 29 ml/m2 [p less than 0.0005]), contributing to a greater increase in LV minute output (p less than 0.0001, group I vs group II). After administration of intravenous enalapril (1.25 mg), LV end-diastolic volume response to exercise was augmented in group II (rest, 140 +/- 42; exercise, 148 +/- 43 ml/m2; p less than 0.0005) and LV output response increased slightly (p less than 0.05). Thus, in patients with asymptomatic systolic dysfunction, recruitment of preload during exercise is responsible for maintaining a stroke volume contribution to the cardiac output response.(ABSTRACT TRUNCATED AT 250 WORDS)

Intravenous Glial Growth Factor 2 (GGF2) Isoform of Neuregulin-1β Improves Left Ventricular Function, Gene and Protein Expression in Rats after Myocardial Infarction

Aims Recombinant Neuregulin (NRG)-1β has multiple beneficial effects on cardiac myocytes in culture, and has potential as a clinical therapy for heart failure (HF). A number of factors may influence the effect of NRG-1β on cardiac function via ErbB receptor coupling and expression. We examined the effect of the NRG-1β isoform, glial growth factor 2 (GGF2), in rats with myocardial infarction (MI) and determined the impact of high-fat diet as well as chronicity of disease on GGF2 induced improvement in left ventricular systolic function. Potential mechanisms for GGF2 effects on the remote myocardium were explored using microarray and proteomic analysis. Methods and Results Rats with MI were randomized to receive vehicle, 0.625 mg/kg, or 3.25 mg/kg GGF2 in the presence and absence of high-fat feeding beginning at day 7 post-MI and continuing for 4 weeks. Residual left ventricular (LV) function was improved in both of the GGF2 treatment groups compared with the vehicle treated MI group at 4 weeks of treatment as assessed by echocardiography. High-fat diet did not prevent the effects of high dose GGF2. In experiments where treatment was delayed until 8 weeks after MI, high but not low dose GGF2 treatment was associated with improved systolic function. mRNA and protein expression analysis of remote left ventricular tissue revealed a number of changes in myocardial gene and protein expression altered by MI that were normalized by GGF2 treatment, many of which are involved in energy production. Conclusions This study demonstrates that in rats with MI induced systolic dysfunction, GGF2 treatment improves cardiac function. There are differences in sensitivity of the myocardium to GGF2 effects when administered early vs. late post-MI that may be important to consider in the development of GGF2 in humans.

Left Ventricular Performance After Coronary Artery Bypass Surgery: Prediction of Functional Benefit

Global left ventricular performance (ejection fraction) and regional function were studied by rest-exercise radionuclide ventriculography in 36 patients before and after (23 +/- 8.5 wk) they had coronary artery bypass surgery for stable angina pectoris. The exercise ejection fraction was less than the resting ejection fraction before surgery (n = 36,p = 0.006), but not after surgery. The degree of postoperative improvement correlated with the degree of preoperative dysfunction (r = 0.55, n = 36, p less than 0.001). Improvement was most likely to occur if exercise-induced dysfunction was present preoperatively (n = 15,p = 0.001), even with old myocardial infarction. Regional dysfunction during preoperative exercise was also likely to improve postoperatively (n = 18, p = 0.001). Protocol design is important in determining the results and their interpretation. Matching postoperative exercise loads to preoperative loads and using regional analysis with two imaging projections improved judgment of the results. Regional dysfunction was commoner than global dysfunction and was less sensitive to workloads than was ejection fraction. This study shows that coronary artery bypass surgery can improve left ventricular performance on exercise if preoperative tests indicate the presence of ischemia-induced dysfunction.

Acute and long-term effects of the angiotensin-converting enzyme inhibitor, enalapril, on adrenergic activity and sensitivity during exercise in patients with left ventricular systolic dysfunction

Patients with heart failure and left ventricular systolic dysfunction exhibit increased adrenergic activity but blunted adrenergic responsiveness. We studied patients enrolled in the Studies of Left Ventricular Dysfunction, examining exercise responses of heart rate (HR) and plasma norepinephrine (PNE). Eighty-seven patients were studied before randomization; 65 of these were examined 1 year after randomization to placebo or enalapril. Compared with prevention trial (asymptomatic) patients, patients in the treatment trial (symptomatic) had higher resting HR and PNE levels and less increase in HR with a greater increase in PNE with exercise. Acute administration of enalapril increased the resting HR in patients in the prevention trial only but had no significant effect on PNE. After 1 year of therapy, patients in the prevention trial exhibited no change. Within the treatment trial, the placebo group displayed both a higher peak PNE and increase in PNE with exercise than did the enalapril group, whose HR response was maintained in spite of a reduction of exercise PNE. We conclude that (1) compared with asymptomatic patients, symptomatic patients with reduced left ventricular ejection fraction manifest greater resting and exercise adrenergic activity, with blunted HR response; and (2) in symptomatic patients, 1 year of enalapril treatment effected an augmented HR response to adrenergic stimulation, supporting an interaction between the renin/angiotensin and adrenergic nervous systems. Normalization of adrenergic tone and response likely contributes to the benefits of long-term angiotensin-converting enzyme inhibitor therapy.