Severe End-stage Heart Failure Research Articles

Total artificial heart: past, present, and future

Every year, approximately 5 out of 1000 patients receive a diagnosis of advanced heart failure, with a prevalence of 1-2% in the adult population. This figure is likely underestimated, considering undiagnosed cases. Despite significant progress in medical therapy for heart failure, mortality rates persist around 20% within the first year, reaching 50-60% at 5 years from the initial diagnosis. For patients with severe end-stage heart failure, the 1-year mortality rate can reach up to 70%. Heart transplantation remains the preferred treatment for terminal stages of the disease; however, the significant challenge lies in the mismatch between available donors and recipients. Given this dilemma, both short-term solutions including extracorporeal membrane oxygenation and long-term options such as left ventricular assist devices have gained prominence. These mechanical circulatory support systems become crucial for patients in critical conditions, temporarily ineligible for heart transplantation, such as those with severe irreversible pulmonary hypertension or acute organ failure. Despite these advancements, a growing number of patients on the waiting list develops severe biventricular dysfunction, precluding the use of a left ventricular assist device as a bridge to transplant. In such cases, a total artificial heart emerges as a viable therapeutic option.

Numerical Study on the Effect of Miniaturized Impeller Diameter on Mechanical Performance in a Left Ventricular Assist Device

Heart failure continues to be a major global health problem causing significant health issues and deaths. Left Ventricular Assist Device (LVAD) was developed as an alternative to heart transplant to support the patients with severe end stage heart failure. Despite the current advancement of LVAD, constant improvements are always being made in making it smaller LVADs tailored for patients with smaller physiology while still maintaining the flow ventricular pump capability to the body. This study evaluated the effect of using a smaller sized LVAD using Computation Fluid Dynamics (CFD) and compared with the initial pump size at their respective designed rotating speed. Two model variants were studied, the initial design with 44.8mm diameter impeller (2000 rpm rotating speed) and the smaller 37.0 mm diameter impeller (2500 rpm rotating speed). These designs were compared by their key criteria mechanical performances particularly the produced pressure difference along a range of flowrate and the efficiency curve. At the required flowrate of 5 L/min, the smaller sized 37.0 mm impeller was able to deliver the flowrate at a slightly higher pressure difference of 114.60 mmHg as compared to the 44.8 mm impeller at 106.01 mmHg. In overall, both model variant produced similar pressure-flowrate curve with the 37.0 mm impeller performing marginally better at higher flowrates. Efficiency was able to be maintained at 49-60 percent despite being a smaller impeller at a faster rotating speed. Miniaturizing the LVAD has been numerically demonstrated to be feasible to produce the needed flow output at the required pressure difference without affect efficiency significantly .

Reverse Remodeling With Left Ventricular Assist Devices.

This review provides a comprehensive overview of the past 25+ years of research into the development of left ventricular assist device (LVAD) to improve clinical outcomes in patients with severe end-stage heart failure and basic insights gained into the biology of heart failure gleaned from studies of hearts and myocardium of patients undergoing LVAD support. Clinical aspects of contemporary LVAD therapy, including evolving device technology, overall mortality, and complications, are reviewed. We explain the hemodynamic effects of LVAD support and how these lead to ventricular unloading. This includes a detailed review of the structural, cellular, and molecular aspects of LVAD-associated reverse remodeling. Synergisms between LVAD support and medical therapies for heart failure related to reverse remodeling, remission, and recovery are discussed within the context of both clinical outcomes and fundamental effects on myocardial biology. The incidence, clinical implications and factors most likely to be associated with improved ventricular function and remission of the heart failure are reviewed. Finally, we discuss recognized impediments to achieving myocardial recovery in the vast majority of LVAD-supported hearts and their implications for future research aimed at improving the overall rates of recovery.

Abstract 221: A Non-invasive Technique for Fast Assessment of Optimal LVAD Outflow Graft Implant Sites

We develop a novel noninvasive technique, named InVascular, for fast hemodynamic assessment of optimal LVAD (left ventricle assist device) outflow-graft (OG) implant suites. LVADs has been a proven and effective therapy for patients with severe end-stage heart failure. Due to the improved pump technology and better patient management, minimally invasive LVAD implantation has emerged as a paradigm shift for clinical surgical techniques. Appropriate OG insertion to either ascending aorta (a), descending thoracic aorta (b), or axillary artery (c) (Fig. 1) is critical in an LVAD surgery. We have recently invented a novel technique that integrates advanced computational modeling based on patient’s CT and ECHO images (Fig. 1d), with cutting-edge GPU (Graphic Processing Units) parallel computing technology to noninvasively quantify 4-D (time+space) flow (Fig. 1e) and pressure in the segment. Comparisons of flow and pressure among 3 OG locations (Fig. 1f) can guide an appropriate OG location for an LVAD implantation. Our results from one study case show that the OG location has important effects on flow in the ascending and descending aorta: OG locations (a) and (b) generate similar flow in the ascending aorta whereas in descending aorta OG location (a) results in larger flow than (b), which is consistent with results in public data. Meanwhile, we found that location (c) produces the smallest flow among the 3 locations in both ascending and descending aorta. Invascular can complete such assessment for an optimal OG site within 30 minutes after a patient’s imaging data are available, which is promising for clinical use in future.

Fine-tuning management of the Heart Assist 5 left ventricular assist device with two- and three-dimensional echocardiography.

SummaryIntroduction:Left ventricular assist device (LVAD) implantation is a viable therapy for patients with severe end-stage heart failure, providing effective haemodynamic support and improved quality of life. The Heart Assist 5 (Micromed Cardiovascular Inc, Houston, TX) continuous-flow LVAD has been on the market in Europe since May 2009.Methods:We evaluated nine Heart Assist 5 LVAD patients with two- and three-dimensional transthoracic echocardiographic (TTE) and transoesophageal echocardiographic (TEE) parameters between December 2011 and December 2013. The pre-operative TTE LVAD evaluations included left ventricular (LV) function and structure, quantification of right ventricular (RV) function and tricuspid regurgitation (TR), assessment of aortic and mitral regurgitation, and presence of patent foramen ovale and intra-cardiac clots. Peri-operative TEE determined the inflow cannula and septum position, and assessed the de-airing process while weaning from cardiopulmonary bypass. Post-operative serial follow-up TTE showed the surgical results of LVAD implantation, determined the overall structure and function of the LV, RV and TR, and observed the inflow and outflow cannula position.Results:Nine patients who had undergone Heart Assist 5 LVAD implantation and had been followed up for more than 30 days were included in this study. Eight patients had ischaemic cardiomyopathy and one had adriamycin-induced cardiomyopathy. Pre-implantation data: the mean age of the patients was 52 ± 13 (34–64) years, mean body surface area (BSA) was 1.8 ± 0.2 (1.6–2.0) m2, mean cardiac index (CI) was 2.04 ± 0.4 (1.5–2.6) l/min/m2, mean cardiac output (CO) was 3.7 ± 0.7 (2.6–4.2) l/min, mean ejection fraction (EF) was 23 ± 5 (18–28)%, and right ventricular fractional area contraction (RVFAC) was 43 ± 9 (35–55)%. One patient had aortic valve replacement (AVR) during the LVAD implantation, and excess current alarms and increased power were suspected to be caused by a possible thrombus. Close follow up with TTE studies were carried out to clear the LV of thrombus formation, and the inflow cannula position was checked to maintain the septum in the midline, so preventing the suction cascade. Four patients were followed up for more than two years, and two were followed up for more than a year. Three patients died due to multi-organ failure. Follow-up speed-change TTE studies of six patients showed that the mean speed was 9 800 ± 600 (9 500–10 400) rpm, and mean CO was 4.7 ± 0.3 (4.3– 5.0) l/min during the three-month post-implant period.Conclusion:We believe that TTE can play a major role in managing LVAD patients to achieve optimal settings for each patient. A large series is mandatory for assessment of echocardiographic studies on Heart Assist 5 LVAD.

LVAD destination therapy: applying what we know about psychiatric evaluation and management from cardiac failure and transplant

Left ventricular assist devices (LVADs) have evolved into long-term use as destination therapy for those with severe end-stage heart failure due to other medical risks. Success with LVAD depends on adherence to a complicated mechanical regimen, and acceptance of a life that is far from normal. Patients with LVADs share characteristics with other end-stage cardiac failure patients and those waiting for or receiving heart transplants. Understanding the more thoroughly studied issues of psychiatric disorders, adherence, and behavioral correlates of success in heart failure and transplantation may identify feasible strategies for optimizing care of LVAD patients and suggest directions for future research. Depression and distress complicate post-transplant care. Psychiatric morbidity is associated with poor outcomes, including graft rejection, non-adherence, hospitalizations, infection, and death. With a high risk of embolic neurological events, patients' ability for self-care may be compromised. Psychiatric symptoms are underdiagnosed and undertreated, which may impact overall survival and quality of life.

Treatment of refractory heart failure with a percutaneous circulatory support device

End-stage heart failure refractory to medical therapy is a clinical challenge. Heart transplantation is considered the best strategy, but it remains burdened with substantial limitations due to the scanty availability of facilities with a transplant programme, donor shortage, and unpredictable waiting lists. Alternatively, assist devices may allow an improvement of the haemodynamic conditions, modifying the history of end-stage heart failure and introducing new management strategies. The goal of a minimally invasive short-term circulatory support device in the treatment of end-stage heart failure patients awaiting heart transplant is to restore the haemodynamic conditions and to improve end-organ dysfunction, with a low incidence of major adverse cardiac events. This report describes the first implantation in Italy of a new percutaneous circulatory support device, the Cancion cardiac recovery system, in a patient with severe end-stage heart failure listed for transplantation.

Moderate severity heart failure does not involve a downregulation of myocardial fatty acid oxidation.

Recent human and animal studies have demonstrated that in severe end-stage heart failure (HF), the cardiac muscle switches to a more fetal metabolic phenotype, characterized by downregulation of free fatty acid (FFA) oxidation and an enhancement of glucose oxidation. The goal of this study was to examine myocardial substrate metabolism in a model of moderate coronary microembolization-induced HF. We hypothesized that during well-compensated HF, FFA oxidation would predominate as opposed to a more fetal metabolic phenotype of greater glucose oxidation. Cardiac substrate uptake and oxidation were measured in normal dogs (n = 8) and in dogs with microembolization-induced HF (n = 18, ejection fraction = 28%) by infusing three isotopic tracers ([9,10-(3)H]oleate, [U-(14)C]glucose, and [1-(13)C]lactate) in anesthetized open-chest animals. There were no differences in myocardial substrate metabolism between the two groups. The total activity of pyruvate dehydrogenase, the key enzyme regulating myocardial pyruvate oxidation (and hence glucose and lactate oxidation) was not affected by HF. We did not observe any difference in the activity of carnitine palmitoyl transferase I (CPT-I) and its sensitivity to inhibition by malonyl-CoA between groups; however, malonyl-CoA content was decreased by 22% with HF, suggesting less in vivo inhibition of CPT-I activity. The differences in malonyl-CoA content cannot be explained by changes in the Michaelis-Menten constant and maximal velocity for malonyl-CoA decarboxylase because neither were affected by HF. These results support the concept that there is no decrease in fatty acid oxidation during compensated HF and that the downregulation of fatty acid oxidation enzymes and the switch to carbohydrate oxidation observed in end-stage HF is only a late-stage phenomenon.

Inflammatory parameters as predictors of clinical course in patients with end-stage heart failure

Background: The optimal timing for heart transplantation (HTx) or implantation of a ventricular assist device (VAD) in patients with end-stage heart failure is a key issue. Methods: In 76 patients with severe heart failure requiring inotropic support and subsequent HTx or VAD implantation blood was sampled daily. TNF-alpha, E-selectin, IL-6 and 10, neopterin, high sensitive CrP and procalcitonin (PCT) were measured at the end of the study. Clinical and hemodinamic parameters were also evaluated daily. The patients were divided into groups with regard to the following endpoints: Group I – deterioration into cardiogenic shock after an initially stable clinical course (n 26); Group II – stable clinical course allowed urgent HTx or VAD implantation (n 41); Group III – weaning from inotropic support (n 9). The data are presented as median values. Results: On admission there were no differences in clinical and hemodynamical parameters between the groups. Higher E-selectin (107.6 vs. 55 ng/ml, p 0.0001) and IL-6 levels were found in group I compared to group II (34.1 vs. 18.1 pg/ml, p 0.015). E-selectin remained significantly higher three days, two days and one day before profound cardiogenic shock occurred (150 vs. 52.7, p 0.0001; 128.8 vs. 46.3, p 0.0001; 96.4 vs. 50.5 ng/ml, p 0.001), while IL-6, 10 and PCT showed significant elevation only 1 day before (31.5 vs. 16.9 pg/ml, p 0.015; 5.1 vs. 4.9 pg/ml, p 0.002; 0.38 vs. 0.19 pg/ml, p 0.026 resp.). There were no differences for TNF-alpha, neopterin and high sensitive CrP between groups. Conclusion: While routine parameters did not predict the clinical course, selected inflammatory markers, especialy E-selectin, showed significant differences between groups on admission and before clinical deterioration. Daily measurement of these markers may be used to determine optimal time-point for HTx or VAD implantation in patients with severe end-stage heart failure.

Contemporary Medical, Surgical, and Device Therapies for End-stage Heart Failure.

Despite recent advances in medical therapy, mortality remains high following the diagnosis of heart failure (HF). Cardiac transplantation is still the standard surgical treatment option for highly selected patients with severe end-stage HF; however, it is only available to a small percentage of patients. The small number of available donor hearts is an inherent limitation on the ability of cardiac transplantation to greatly impact the management of advanced HF. The increased incidence and prevalence of HF in an ever aging and medically complex population has paved the way for alternative surgical and device treatment strategies. Some of these treatment options include ventricular reduction/remodeling surgery, mitral valve repair, mechanical ventricular assist device implantation, implantable cardioverter-defibrillators, and cardiac resynchronization therapy. Several recent trials have demonstrated the effectiveness of these therapies with regard to improvement in primary cardiac end points, HF symptoms, and survival. Surgical and device techniques are usually combined with optimal medical management of HF. The total cost and actual cost-effectiveness of employing these new therapeutic modalities in a growing population of HF patients remains to be determined.

Natriuretic peptides as predictors of clinical course in patients with end-stage heart failure

The optimal time-point for HTx or implantation of a VAD in patients with end-stage heart failure is a key issue. In 73 patients with heart failure requiring inotropic support blood was sampled daily and big endothelin-1 (big ET) and natriuretic peptides were measured at the end of the study. Clinical parameters were also evaluated daily. The patients were divided into groups with regard to the following endpoints: Group I immediate VAD placement due to profound cardiogenic shock on admission (n 9); Group II deterioration into cardiogenic shock after an initially stable clinical course (n 21); Group III stable clinical course allowed urgent HTx or VAD implantation (n 35); Group IV weaning from inotropic support (n 8). The parameters were evaluated as potential predictors for clinical course. On admission there were no significant predictors for the clinical course except lower ANP level in group IV compared to group II (p 0-005). Among the parameters evaluated, only BNP and big ET showed significant differences between groups II and III during follow up. BNP was elevated in group II compared to the group III three days, two days and one day before profound cardiogenic shock occurred (p 0.04; p 0.05; p 0.019 resp.). Big ET was elevated in group II only 1 day before profound cardiogenic shock occurred (p 0.02). ProBNP remained unchanged during treatment in groups II and III, but decreased significantly in group IV (p 0.9, p 0.6 and p 0.025 resp.). While clinical parameters on admission did not predict the clinical course, lower ANP was found in patients weaned from inotropic support. A decrease of proBNP was also found in these patients. Elevated BNP indicated cardiogenic shock up to 3 days before its occurrence. Daily measurement of natriuretic peptides may be used for determination of optimal time-point for VAD implantation in patients with severe end-stage heart failure.

End-stage Heart Failure: Surgical Therapy and Implantable Devices.

Despite recent advances in medical therapy, mortality remains high following the diagnosis of heart failure (HF). Cardiac transplantation is still the standard surgical treatment option for highly selected patients with severe end-stage HF; however, it is available only to a small percentage of patients. The small number of available donor hearts is an inherent limitation on the ability of cardiac transplantation to greatly impact the management of advanced HF. The increased incidence and prevalence of HF in an ever aging and medically complex population has paved the way for alternative surgical and device treatment strategies. Some of these treatment options include ventricular reduction and remodeling surgery, mitral valve repair, mechanical ventricular assist device implantation, implantable cardioverter defibrillators, and cardiac resynchronization therapy. Several recent trials have demonstrated effectiveness of these therapies with regard to improvement in physiologic end points, HF symptoms, and survival. Surgical and device techniques are usually combined with optimal medical management of HF. The total cost and actual cost-effectiveness of employing these new therapeutic modalities in a growing population of HF patients remain to be determined.

Surgical options for the treatment of heart failure

This article will examine the role of specific surgical interventions for congestive heart failure (CHF). The most definitive surgical option for severe end-stage heart failure is cardiac transplantation. In general, patients considered for heart transplant should have severe heart disease despite all other therapies with a high risk of death within I year. Noncardiac conditions that would by themselves shorten life expectancy or increase the risks of rejection, infection, or other fatal complication, should not be present. However, in light of the limited donor pool, complications associated with long-term immunosuppressive therapy, and the ever-increasing number of CHF patients, the role of cardiac transplantation for CHF will continue to be limited. The conduct of and evaluation for cardiac transplantation has been well described previously and therefore will not be evaluated in this review (1); however, there has been recent progress in the genetic modification of animal organs for potential use in transplantation (xenografts) (2). If these developments come to fruition, then cardiac transplantation/organ replacement may become a surgical option for a much greater number of CHF patients. One alternative approach to complete cardiac transplantation is the surgical placement of transformed cells into the diseased myocardium, briefly discussed under “Future Directions.” This article will examine surgical options that are currently being used for CHF patients, surgical modalities that are currently under clinical evaluation, and finally, potential future therapies with respect to surgical options for heart failure.

Expression and regulation of ryanodine receptor/calcium release channels

Intracellular calcium release channels on the endoplasmic or sarcoplasmic reticula (ryanodine receptors, RyR, and inositol 1,4,5-trisphosphate receptors, IP 3R) comprise a unique family of molecules that are structurally and functionally distinct from all other known ion channels. These channels play crucial roles in many cellular signaling pathways including excitation-contraction coupling, oocyte fertilization, hormone secretion, neurotransmitter release, and T lymphocyte activation. Three forms of RyR have been identified: RyR1 expressed predominantly in skeletal muscle, RyR2 in cardiac muscle, and RyR3 in the brain. The tetrameric structures of RyR1 and RyR2 are stabilized by a channel-associated protein, FKBP12. The immunosuppressant drugs FK506 and rapamycin inhibit the prolyl isomerase activity of FKBP12 and could cause cardiac dysfunction by inducing a Ca 2+ leak from the sarcoplasmic reticulum. RyR2 is downregulated and IP 3R is upregulated during severe end-stage heart failure secondary to dilated cardiomyopathies in humans, suggesting that these channels may contribute to abnormalities in Ca 2+ homeostasis.

Treatment of severe heart failure: quantity or quality of life? A trial of enoximone. Enoximone Investigators.

To determine the effects of enoximone on mortality and quality of life in patients with severe end stage heart failure. A randomised, double blind, placebo controlled trial of the addition of enoximone to conventional treatment. Planned minimum follow up of one year. District general hospitals and cardiological referral centres in the United Kingdom. Planned 200 patients with severe, symptomatic heart failure despite treatment with diuretics and where appropriate and tolerated angiotensin converting enzyme inhibitors and digoxin. The study was ended early by the ethics committee after 151 patients had been recruited because of an excess mortality in the enoximone group: 27 deaths compared with 18 in the placebo group (P < 0.05). Quality of life measured with a disease specific questionnaire showed a clinically significant improvement at week 2 with a mean increase score of 0.48 in the enoximone treated patients compared with 0.14 in those receiving placebo (P = 0.0086). With the Nottingham health profile questionnaire the physical mobility score was improved after three months in the enoximone group, median 21.3 compared with 41.8 in the placebo group (P = 0.008). In patients with severe heart failure who remain incapacitated despite conventional treatment enoximone reduced survival but had a beneficial effect on the quality of life. Drugs that improve symptoms in severe end stage heart failure should not be discarded lightly.

Prognostic Value of Heart Rate Variability in Patients Awaiting Cardiac Transplantation

Time and frequency domain parameters of heart rate variability (HRV) were determined in patients with severe endstage heart failure awaiting cardiac transplantation (HTX). These parameters were then correlated with mortality to investigate the performance of HRV in discriminating between groups with high and low risk of death. The standard deviation of five consecutive RR intervals (SDANN) was found to be the parameter with the greatest sensitivity (90%) and specificity (91%). Patients with SDANN values of < 55 msec had a twenty-fold increased risk of death (90% confidence limits: 4-118, P < 0.001). The results furthermore suggest that measurements of HRV are superior to other prognostic markers such as left ventricular ejection fraction, pulmonary artery wedge pressure, cardiac index, and serum sodium levels. We conclude that HRV is a powerful, noninvasive tool to assess the risk of death in candidates for HTX. HRV measurements can therefore be used as a supplement to other markers of risk to determine the optimal therapeutic strategy in patients with severe congestive heart failure.