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Biomedical subjects

Daniel Burkhoff

Publications and source records attributed to Daniel Burkhoff.

At least 37 records · Page 2Linked to original sources

Mechanical device-based methods of managing and treating heart failure.

Despite advances in pharmacological treatments aimed at neurohormonal blockade for heart failure in the setting of left ventricular pump dysfunction, there is still a growing number of patients with advanced symptoms who suffer significant morbidity and mortality. Mechanical stresses and chronic neurohormonal activation conspire to propagate maladaptive ventricular remodeling responsible for the insidious nature of this disease. Recent studies suggest that further pharmacological neurohormonal blockade may not be safe or effective, which has driven development of devices for this patient population. Furthermore, such devices may target fundamental pathophysiological abnormalities that are largely hemodynamic and mechanical in nature that are not addressed by available pharmacological agents. The profound reverse remodeling routinely associated with left ventricular assist device use, reviewed in detail, further validates device-based approaches and should inspire research to find ways to make this recovery more complete and permanent. Accordingly, this review focuses on the multitude of mechanical device-based approaches currently being investigated to manage and treat this population. From devices for monitoring patient status to anticipate congestive heart failure exacerbations and preemptively adjust therapy to devices to support preterminal patients with end-stage disease, it is recognized that these device-based approaches will assume an increasingly important role in treating the growing number of patients with advanced heart failure.

Heart Failure↗

Mechanical unloading during left ventricular assist device support increases left ventricular collagen cross-linking and myocardial stiffness.

BACKGROUND: Left ventricular assist devices (LVADs) induce reverse remodeling of the failing heart except for the extracellular matrix, which exhibits additional pathophysiological changes, although their mechanisms and functional consequences are unknown. METHODS AND RESULTS: Hearts were obtained at transplant from patients with idiopathic dilated cardiomyopathy (DCM) not requiring LVAD support (n=30), patients requiring LVAD support (n=16; LVAD duration, 145+/-33 days), and 5 nonfailing hearts. Left (LV) and right ventricular (RV) ex vivo pressure-volume relationships were measured, and chamber and myocardial stiffness constants were determined. Myocardial tissue content of total and cross-linked collagen, collagen types I and III, MMP-1, MMP-9, TIMP-1, and angiotensin (Ang) I and II were measured. LV size, mass, and myocyte diameter decreased after LVAD compared with DCM without LVAD (P<0.05). Total and cross-linked collagen and ratio of type I to III collagen increased in DCM compared with nonfailing hearts and increased further after LVAD (P<0.05 versus DCM and nonfailing). Concomitantly, chamber and myocardial stiffness increased with LVAD. The ratio of MMP-1 to TIMP-1 increased in DCM and almost normalized after LVAD, favoring decreased collagen degradation. Tissue Ang I and II also increased during LVAD. There was no significant change in the RV of LVAD-supported heart compared with DCM. CONCLUSIONS: LVAD support increases LV collagen cross-linking and the ratio of collagen type I to III, which is associated with increased myocardial stiffness. Decreased tissue MMP-1-to-TIMP-1 ratio (decreased degradation) and increased Ang levels (stimulants of synthesis) are likely mechanisms for these changes. Lack of significant effects on the RV suggest that hemodynamic unloading of the LV (not provided to the RV) might be the primary factor that regulates these extracellular matrix changes.

Adult↗

Left ventricular assist device support normalizes left and right ventricular beta-adrenergic pathway properties.

OBJECTIVES: We hypothesized that some aspects of left ventricular assist device (LVAD) reverse remodeling could be independent of hemodynamic factors and would primarily depend upon normalization of neurohormonal milieu. BACKGROUND: The relative contributions of LVAD-induced hemodynamic unloading (provided to the left ventricle [LV]) and normalized neurohormonal milieu (provided to LV and right ventricle [RV]) to reverse remodeling are not understood. METHODS: Structural and functional characteristics were measured from hearts of 65 medically managed transplant patients (MED), 30 patients supported with an LVAD, and 5 nonfailing donor hearts not suitable for transplantation. RESULTS: Compared with MED patients, diastolic pulmonary pressures trended lower (p < 0.01) and cardiac output higher (p < 0.001) in LVAD patients; V(30) (ex vivo ventricular volume yielding 30 mm Hg, an index of ventricular size) in LVAD patients was decreased in the LV (p < 0.05) but did not change significantly in RV. The LVAD support improved force generation in response to beta-adrenergic stimulation in isolated LV (increase in developed force from 6.3 +/- 0.6 to 18.5 +/- 4.4 mN/m(2), p < 0.01) and RV (increase in developed force, from 10.9 +/- 2.0 to 20.5 +/- 3.1 mN/m(2), p < 0.05) trabeculae. The LVAD patients had higher myocardial beta-adrenergic receptor density in LV (p < 0.01) and RV (p < 0.01). Protein kinase A (PKA) hyperphosphorylation of the ryanodine receptor 2 (RyR2)/calcium release channel was significantly reduced by LVAD in both RV and LV (p < 0.01). CONCLUSIONS: Improved beta-adrenergic responsiveness, normalization of the RyR2 PKA phosphorylation, and increased beta-adrenergic receptor density in LV and RV after LVAD support suggest a primary role of neurohormonal environment in determining reverse remodeling of the beta-adrenergic pathway.

Adult↗

Catheter-based ventricle-coronary vein bypass.

The goal of this study was to investigate the feasibility of a catheter-based ventricle-to-coronary vein bypass (VPASS) in order to achieve retrograde myocardial perfusion by a conduit (VSTENT) from the left ventricle (LV) to the anterior interventricular vein (AIV). Percutaneous coronary venous arterialization has been proposed as a potential treatment strategy for otherwise untreatable coronary artery disease. In an acute setting, the VSTENT implant was deployed percutaneously using the VPASS procedure in five swine. Coronary venous flow and pressure patterns were measured before and after VSTENT implant deployment with and without AIV and left anterior descending artery (LAD) occlusion. In a separate chronic pilot study, the VPASS procedure was completed on two animals that had a mid-LAD occlusion or LAD stenosis. At day 30 post-VPASS procedure, left ventriculography and magnetic resonance imaging (MRI) were performed to assess the patency and myocardial viability of the VSTENT implants. Pre-VSTENT implantation, the mid-AIV systolic wedge pressure was significantly lower than LV systolic pressure during AIV blockage (46 +/- 19 vs. 90 +/- 16 mm Hg; P < 0.01). The VSTENT implant deployment was performed without complication and achieved equalization of the AIV and LV systolic pressures and creation of retrograde flow in the distal AIV (maximal flow velocity: 37 +/- 7 cm/sec). At day 30 post-VPASS procedure, left ventriculography showed VSTENT implant patency. MRI perfusion images demonstrated myocardial viability even with an LAD occlusion. Coronary retrograde perfusion using the VPASS procedure is feasible and may represent a potential technique for end-stage myocardial ischemia.

Animals↗

Cardioprotection before revascularization in ischemic myocardial injury and the potential role of hemoglobin-based oxygen carriers.

Despite the availability of interventional catheterization for patients with acute coronary syndromes, there is an unavoidable delay until the occluded coronary artery(s) can be revascularized, during which time persistent ischemia may lead to irreversible myocardial damage despite subsequently high patency rates. Accordingly, there has been an intense effort to develop early interventions that will preserve the viability of ischemic myocardium before revascularization. A number of novel strategies have been studied, including hemoglobin-based oxygen carriers. These compounds transport oxygen in the plasma to help maintain more normal oxygen delivery to the myocardium supplied by a thrombosed vessel, and they also release oxygen to tissue more efficiently than intraerythrocytic hemoglobin.

Adult↗

Intramyocardial left ventricle-to-coronary artery stent: a novel approach for the treatment of coronary artery disease.

BACKGROUND: The direct intramyocardial left ventricle-to-coronary artery stent may provide an optional minimally invasive technique for coronary artery bypass graft surgery. We seek to test whether blood flow and regional myocardial function improve with this stent in totally ischemic myocardium. METHODS: The stent device was implanted in 8 anesthetized dogs using an open chest approach, arteriotomy of the proximal left anterior descending coronary artery, and connection of the vessel to the left ventricular chamber. Regional coronary blood flow and myocardial function were monitored under three conditions: normal coronary flow (baseline), coronary ligation, and stent flow. RESULTS: Left anterior descending coronary ligation markedly reduced coronary artery blood flow and regional myocardial function. With flow solely from the stent, the blood flow pattern changed to one with high peak forward flow during systole compared with baseline (94.8 +/- 48.9 versus 56.8 +/- 21.1 mL/min; p < 0.05) and one with significant negative backflow during diastole compared with baseline (-37.4 +/- 23.1 versus 11.3 +/- 17.2 mL/min; p < 0.05). However, the resultant mean forward flow increased to approximately 50% of baseline compared with less than 5% of baseline after coronary ligation. Regional myocardial function diminished entirely after coronary ligation, but recovered to approximately 60% of baseline with the stent. Normal systemic hemodynamics and global ventricular contractile function were maintained with the stent. CONCLUSIONS: The left ventricle-to-coronary artery stent is a simple and readily deployable device that allows the perfusion of epicardial vessels directly from the left ventricle and can provide significant blood flow to improve the performance of ischemic myocardium. It may provide an effective, alternative means of treating coronary artery disease when standard coronary artery bypass graft surgery is not suitable.

Animals↗

Left heart failure with a normal ejection fraction: identification of different pathophysiologic mechanisms.

BACKGROUND: Although heart failure with a normal ejection fraction (HFNEF) is a clinically heterogeneous syndrome, a single pathophysiologic mechanism, diastolic dysfunction, is often ascribed to explain this condition. In view of the clinical heterogeneity of these patients, we hypothesized that subgroups of HFNEF patients may have different underlying pathophysiologic mechanisms. METHODS AND RESULTS: Freehand 3-dimensional echocardiography was used to measure left ventricular end-systolic and end-diastolic volumes in 99 asymptomatic normal controls and 2 groups with chronic heart failure: 35 patients with normal ejection fraction with longstanding hypertension (hypertensive HFNEF) and 11 patients with hypertrophic cardiomyopathy without a history of hypertension (nonhypertensive HFNEF). These data, combined with cuff sphygmomanometry and Doppler estimates of LV end-diastolic pressure (EDP) yielded estimated pressure-volume loops and slope (E es,sb ) of the end-systolic pressure-volume relationship, a load independent index of chamber contractility. Nonhypertensive HFNEF patients required high EDPs (21 +/- 2 versus 15 +/- 3 mm Hg in normals, P < .0001) to achieve normal EDVs (98 +/- 25 versus 95 +/- 21 mL in normals, P = NS). Although systolic function (E es,sb ) did not differ from normal, systolic blood pressure was lower than normal in these patients (114 +/- 10 versus 124 +/- 14 mm Hg in normals, P < .05). Hypertensive HFNEF patients also had increased EDP (20 +/- 2 mm Hg), but this was observed at higher than normal EDVs (118 +/- 29 mL, P < .05). Among patients with hypertensive HFNEF, 2 subgroups emerged, 1 with a high E es,sb (4.23 +/- 0.54 versus 2.1 +/- 0.7 mm Hg/mL) and 1 with normal E es,sb (2.31 +/- 0.51 mm Hg/mL). The former group was composed of elderly women with small body size (body surface area 1.7 +/- 0.2 versus 1.9 +/- 0.2 m 2 , P = .02) who had concentrically remodeled ventricles and low stroke volumes. The latter group was more diverse in age, body size, and included patients of both genders with increases in ventricular volumes, stroke volume, and mass consistent with a volume overload state. CONCLUSION: Although HFNEF is commonly thought of as being the result of a single hemodynamic mechanism, these data indicate that subgroups exist with distinctly different underlying pathophysiologies.

Age Factors↗

Sarcomeric genes involved in reverse remodeling of the heart during left ventricular assist device support.

BACKGROUND: Left ventricular assist devices (LVADs) implanted in patients with severe congestive heart failure (CHF) as a bridge to transplantation have been shown to reverse chamber enlargement, regress cellular hypertrophy, and increase contractility. The purpose of this study was to gain a better understanding of the molecular changes associated with increased contractility after LVAD support. METHODS: We took tissue sections from the left ventricular apex of 12 patients with CHF who were undergoing LVAD insertion (pre-LVAD) and from the LV free wall of those same patients before transplantation (post-LVAD). To control for sample-site differences, we obtained samples from the same regions in 7 patients with CHF who were undergoing transplantation without LVAD support and in 4 non- failing donor hearts. Gene expression was then probed on a custom DNA array containing 2,700 cardiac-enriched cDNA clones. RESULTS: Calcium-handling genes were up-regulated by LVAD support, as previously reported. Sarcomeric genes were the other principle class of genes up-regulated by LVAD support, consistent with a possible restoration of sarcomere structure in reverse ventricular remodeling. However, a decrease in the fibrous component of the myocardium, also potentially involved in reverse remodeling, was not evident at the level of gene transcription because fibroblast markers were either unchanged or up-regulated. The remaining regulated genes did not fall into any defined functional class. CONCLUSIONS: Changes in the regulation of sarcomeric, calcium-handling, and fibroblast genes during LVAD support indicate a cardiac molecular adaptation to mechanical unloading. These molecular changes may play a role in the observed increase in contractile function during reverse remodeling.

Adult↗

Biventricular assist device-induced right ventricular reverse structural and functional remodeling.

BACKGROUND: Support with a left ventricular assist device (LVAD) induces LV reverse structural and functional remodeling, evidenced by normalization of passive end-diastolic pressure-volume relationships (EDPVRs) and cardiomyocyte function. These changes are not evident in the right ventricle (RV), which remains dilated during LVAD support. However, studies on whether RV reverse remodeling could be induced by RV or biventricular assist support (BiVAD) have not been published. METHODS: Whole hearts from 16 patients with end-stage congestive heart failure (CHF) at the time of cardiac transplantation without LVAD support, 16 patients with LVAD support, and 3 patients with BiVAD support were used to study RV EDPVRs, with estimation of chamber stiffness. Perfused isolated myocardial trabeculae were used for functional studies. Furthermore, RV free wall samples were used for histology and collagen determination by hydroxyproline. RESULTS: The RV size, calculated from the ex vivo RV EDPVRs, RV mass, and myocyte diameter were significantly smaller in BiVAD-supported hearts than in non-supported or LVAD-supported hearts (p < 0.05) and reached normal levels. Furthermore, cardiomyocyte function demonstrated a normalized response to increased stimulation frequency and after perfusion with isoproterenol following BiVAD support. In addition, myocardial collagen content and chamber stiffness increased tremendously after BiVAD support (p < 0.05 vs CHF and LVAD). CONCLUSION: BiVAD-induced hemodynamic unloading support resulted in significant reverse structural and functional remodeling of the right chamber. The lack of these findings during LVAD support alone provides additional support that diastolic pressure and volume unloading is an important mechanism underlying the process of reverse remodeling.

Adult↗

In vitro ablation of cardiac valves using high-intensity focused ultrasound.

The purpose of this study was to evaluate the possibility of using high-intensity focused ultrasound (US), or HIFU, to create lesions in cardiac valves in vitro. Calf mitral valves and aortic valves were examined. Focused US energy was applied with an operating frequency of 4.67 MHz at a nominal acoustic power of 58 W for 0.2, 0.3 and 0.4 s at 4-s intervals. Mitral valve perforation was achieved with 20.8 +/- 3.7 exposures of 0.2 s, 15.4 +/- 2.1 exposures of 0.3 s or 11.2 +/- 2.3 exposures of 0.4 s. Aortic valve perforation was achieved with 13.3 +/- 2.4 exposures of 0.2 s, 10.3 +/- 2.2 exposures of 0.3 s or 8.4 +/- 1.8 exposures of 0.4 s. The mean diameter of the perforated area was 1.09 +/- 0.11 mm. The lesions were slightly discolored and coagulation of tissue around the perforation was observed. HIFU was successful in perforating cardiac valves. With further refinement, HIFU may prove useful for valvulotomy or valvuloplasty.

Animals↗

Assessment of systolic and diastolic ventricular properties via pressure-volume analysis: a guide for clinical, translational, and basic researchers.

Assessment of left ventricular systolic and diastolic pump properties is fundamental to advancing the understanding of cardiovascular pathophysiology and therapeutics, especially for heart failure. The use of end-systolic and end-diastolic pressure-volume relationships derived from measurements of instantaneous left ventricular pressure-volume loops emerged in the 1970s as a comprehensive approach for this purpose. As invasive and noninvasive techniques for measuring ventricular volume improved over the past decades, these relations have become commonly used by basic, translational, and clinical researchers. This review summarizes 1) the basic concepts underlying pressure-volume analysis of ventricular and myocardial systolic and diastolic properties, 2) deviations from ideal conditions typically encountered in real-life applications, 3) how these relationships are appropriately analyzed, including statistical analyses, and 4) the most common problems encountered by investigators and the appropriate remedies. The goal is to provide practical information and simple guidelines for accurate application and interpretation of pressure-volume data as they pertain to characterization of ventricular and myocardial properties in health and disease.

Animals↗

Role of impaired myocardial relaxation in the production of elevated left ventricular filling pressure.

Although present in many patients with heart failure and a normal ejection fraction, the role of isolated impairments in active myocardial relaxation in the genesis of elevated filling pressures is not well characterized. Because of difficulties in determining the effect of prolonged myocardial relaxation in vivo, we used a cardiovascular simulated computer model. The effect of myocardial relaxation, as assessed by tau (exponential time constant of relaxation), on pulmonary vein pressure (PVP) and left ventricular end-diastolic pressure (LVEDP) was investigated over a wide range of tau values (20-100 ms) and heart rate (60-140 beats/min) while keeping end-diastolic volume constant. Cardiac output was recorded over a wide range of tau and heart rate while keeping PVP constant. The effect of systolic intervals was investigated by changing time to end systole at the same heart rate. At a heart rate of 60 beats/min, increases in tau from a baseline to extreme value of 100 ms cause only a minor increase in PVP of 3 mmHg. In contrast, at 120 beats/min, the same increase in tau increases PVP by 23 mmHg. An increase in filling pressures at high heart rates was attributable to incomplete relaxation. The PVP-LVEDP gradient was not constant and increased with increasing tau and heart rate. Prolonged systolic intervals augmented the effects of tau on PVP. Impaired myocardial relaxation is an important determinant of PVP and cardiac output only during rapid heart rate and especially when combined with prolonged systolic intervals. These findings clarify the role of myocardial relaxation in the pathogenesis of elevated filling pressures characteristic of heart failure.

Blood Pressure↗

Diastolic dysfunction: can it be diagnosed by Doppler echocardiography?

Heart failure with a normal ejection fraction (HFNEF) predominantly afflicts older, female individuals and is considered to be a consequence of diastolic dysfunction. Doppler echocardiography has become the standard method for identifying and characterizing diastolic function. However, the important distinction between Doppler measures of filling dynamics and true indexes of intrinsic ventricular diastolic chamber properties is not widely appreciated. Herein, we delineate physiologic measures of intrinsic ventricular diastolic function, as determined by pressure volume analysis, and compare and contrast these measures with those derived from Doppler echocardiography. Doppler-derived indexes of ventricular filling do not provide specific information on intrinsic passive diastolic properties, and thus, abnormal filling dynamics do not necessarily equate with intrinsic myocardial diastolic dysfunction. This raises a fundamental question as to whether delayed relaxation and/or stiffened passive properties are the unifying pathophysiologic mechanisms in all patients who present with HFNEF.

Aged↗

Mechanisms of heart failure with well preserved ejection fraction in dogs following limited coronary microembolization.

OBJECTIVE: It has been suggested that in some settings, heart failure (HF) may occur with normal ejection fraction (EF) as a consequence of undetected systolic dysfunction. However, others have argued that this can only occur in the presence of diastolic dysfunction. We therefore sought to determine the contribution of diastolic dysfunction in an animal model of HF with normal EF. METHODS AND RESULTS: Limited myocardial injury was induced in 21 dogs chronically instrumented to measure hemodynamics and LV properties by daily coronary microembolization ( approximately 115 microm beads) until LV end diastolic pressure (LVEDP) was > or =16 mm Hg. Nine dogs developed HF within 16+/-6 days (LVEDP 12+/-2 vs. 21+/-2 mm Hg, p<0.001) with no significant change in dP/dt(max) (2999+/-97 vs. 2846+/-189 mm Hg/s), mean arterial pressure (103+/-4 vs. 100+/-4 mm Hg), EF (57+/-5% vs. 53+/-4%) or E(es) (end-systolic elastance, 3.1+/-0.9 vs. 2.9+/-0.8 mm Hg/ml) but with an approximately 10 ml increase in V(o) (14+/-12 vs. 25+/-16 ml; p<0.01). The EDPVR and time constant of relaxation (tau, 25+/-3 vs. 28+/-3 ms) did not change significantly. These animals were hemodynamically stable out to 3 1/2 months. Neurohormonal activation occurred (elevations of NE, AngII, BNP) and there was intravascular volume expansion by approximately 16% (p<0.05). CONCLUSIONS: A small amount of myocardial injury can lead to neurohormonal activation with intravascular volume expansion and elevation of LVEDP in the absence of reductions in dP/dt(max) or EF and without diastolic dysfunction. Thus, HF with preserved EF does not a priori equate with diastolic heart failure.

Angiotensin II↗

Development and validation of a patient questionnaire to determine New York Heart Association classification.

BACKGROUND: New York Heart Association (NYHA) classification correlates with quality of life and is useful in tracking changes in status in clinical trials. We explored methods to determine NYHA class in multicenter trials where double-blind conditions could not be maintained. METHODS AND RESULTS: A questionnaire was developed containing 7 major questions based on the standard definitions of NYHA classes. The questionnaire was administered to 116 patients with varying degrees of heart failure. When comparing NYHA determined by physicians at the site to NYHA assigned by 3 independent physician graders, there was an approximate 60% concordance. Concordance between independent reviewers was approximately 75%. Results of repeat grading of 30 randomly selected questionnaires indicated that graders provided the same score 90% of the time. Thus, although there were some differences from the site determination of NYHA class, the questionnaire had good inter- and intragrader reproducibility. In a second group of 103 patients enrolled in an ongoing device-intervention trial, we demonstrated that it is feasible to employ the questionnaire in a multicenter trial. Finally, NYHA class was correlated with quality of life and peak exercise oxygen consumption. CONCLUSIONS: A standardized questionnaire provided an approximate 60% concordance in assigning NYHA classification compared to the site assessment with approximately 90% reproducibility. This approach may be useful to determine NYHA classification within the context of clinical trials where blinded conditions are not possible.

Clinical Trials as Topic↗