Severe low-gradient aortic stenosis: impact of inadequate left ventricular responses to high afterload on diagnosis and therapeutic decision-making.

The fact that nearly 50% of patients with an aortic valve (AV) area < 1.0 cm2, consistent with severe aortic stenosis (AS), can have mean trans-AV pressure gradients < 40 mmHg, consistent with non-severe AS, indicates that "low-gradient" (LG) severe AS, which is often associated with poor prognosis, deserves particular consideration. Inadequate left ventricular (LV) adaptation to severe AV stenosis resulting from preexistent intrinsic myocardial damages and/or maladaptive LV responses to increased afterload are typical features of severe LG-AS. The diagnosis and management of patients with severe LG-AS are particularly challenging because the discrepancy between the AV area and the trans-AV pressure gradient raises doubts concerning the actual severity of AS and therefore also about the necessity of AV replacement (AVR). LG-AS diagnosis requires integrative multimodality evaluation of both the AV and the LV and therapeutic decision-making necessitates careful individual benefit-risk estimation. Although patients with severe LG-AS associated with low trans-AV flow (i.e., stroke volume ≤ 35 ml/m2) have worse outcomes after AVR than those with high-gradient severe AS, even those with reduced LV ejection fraction (LVEF) can have a significant survival benefit particularly by transcatheter AVR. Dobutamine stress echocardiography facilitates distinction between true-severe and pseudo-severe low-flow LG-AS with reduced LVEF. The review aimed to provide an updated theoretical and practical basis for those engaged in this demanding and still current topic due to the new aspects which have emerged in conjunction with both the evolving scientific knowledge about the various LV responses to the increased afterload and the increasing use of the less invasive transcatheter AVR.

Toxicity-induced Cardiomyopathy in a Patient with Femoral Sarcoma: Heart Transplantation After Support with Ventricular Assist Device as Bridge to Transplantability.

This case report exemplifies how a ventricular assist device successfully supported a 15 year old tumor patient with anthracycline-induced cardiomyopathy for 419 days until she was confirmed free from tumor recurrence to undergo heart transplantation, presently with an 18 year follow up without any malignancy.

Heart failure in the young: Insights into myocardial recovery with ventricular assist device support.

BACKGROUND: Data on ventricular unloading-promoted myocardial recovery and post-weaning outcome in children is scarce. We analyzed the weaning outcome in children with heart failure (HF) supported with ventricular assist device (VAD). METHODS: A multi-institutional data on VAD implanted in 193 children and adolescents with HF between April 1990 and November 2015 was reviewed. Among them, 25 children (mean age 3.4±3.0, range, 0.058-16.3 years, 15 females) were weaned from VAD. Etiology of HF were myocarditis (n=11), dilated cardiomyopathy (DCMP) (n=7), ischemic HF (n=3), arrhythmogenic CMP (n=1), post-correction of congenital heart disease (CHD) (n=1) and acute graft failure (n=1). Mean duration of HF before VAD implantation was 59.4±3 days. RESULTS: Age, duration of HF, DCMP, cardiac arrest and duration of VAD are essential clinical characteristics to delineate who may have the potential to myocardial recovery. Echocardiographic parameters pre-implantation, during the final off-pump trial and during the post-explantation follow-ups revealed that LVEF, LVEDD and relative wall thickness (RWT) showed significant differences (P<0.001) among patients stratified by outcome to assess recovery. Presently, 21 (84.0%) of the weaned patients are alive with their native hearts 1.3-19.1 years after VAD explantation. An additional weaned patient had HF recurrence 3 months post-weaning and was transplanted. CONCLUSIONS: Post-weaning myocardial recovery and cardiac stability of children with HF from several etiologies supported with a VAD appears sustainable and durable. Young patients with short HF duration are more likely to recover. Absence of cardiac arrest, cardiac size, geometry and function may prospectively identify patients who may be likely to have myocardial recovery.

Resumé of the challenges and burden of living with transplanted hearts for >31 years.

Heart transplantation has extended the lives of many patients with end-stage heart failure. Although beset with the arduous aftermaths of immunosuppression, those who survived live meaningful lives similar to that of the general population. In this series, heart transplantation has led to a considerable extension of life span of >31-34 years. Development of cardiac allograft vasculopathy is a major concern in the long-term follow-up of transplant patients. Immunosuppressive drugs have a major impact on the development and progression of cardiac allograft vasculopathy and the main cause of cardiac allograft loss after the first post-transplantation year. Post-transplant neoplasia remains a challenging long-term problem for patients after orthotopic heart transplantation. Post-transplant lymphoproliferative disease appears to be largely the result of the effectiveness of current agents used for long-term immunosuppression, and the neoplasms typically harbor the Epstein Barr virus genome, which is presumed to play a major role in neoplastic transformation. Post-transplantation, new diseases may occur or there may be worsening of pre-existing diseases. By the end of the 5th year, all suffered from hypertension. Renal insufficiency developed within 5 years after transplantation, and 10% have a creatinine value of >2.5 mg/dL. Hyperlipidemia, mostly hypercholesterolemia occurs especially in patients on tacrolimus or everolimus. Quality of life is not impaired despite somatic problems. In this period >31 years post-post-orthotopic heart transplantation, they even reported a surprising increase in their emotional well-being. The 10 patients are active and satisfied with their daily lives. They regard their own life as meaningful, have good families and active social relations. Nonetheless, it is burdened by chronic allograft vasculopathy and immunosuppression sequelae, the main limiting factors for survival, which needed to be constantly addressed throughout their lifetime. This brief report provides an insight into the challenges and burden patients living >31 years with transplanted hearts are confronted with.

Evolution of heart transplantation since Barnard's first.

Barnard's first human heart transplantation in 1967 has paved the channel to numerous extensive researches and clinical experiences, mostly from the Stanford group, on orchestrating criteria for donor and recipient selection, immunosuppression, distant heart procurement, re-transplantation, and further global performance of the procedure until it became the gold standard therapy for end-stage heart failure, even in the face of an utterly limited organ availability. Much has happened since Barnard's first. There has been a rapid rise to 4,000-5,000 transplants per year. Previously, the number of transplants depended on the capacity of the units. Later on, it depended largely on the availability of donor organs. The widening of indications and reduction of contraindications to heart transplantations to include elderly patients >70 years, systemic diseases such as amyloidosis, has emerged. Indeed, heart transplantation has come a long way, and is considered a fruitful and stimulating episode in modern medicine. It is rather deplorable to watch that in the beginning of 1990s, the yearly number of heart transplantations began to decline-not because the operation had proved unsuccessful, but because donor hearts became scarce. It is rather poignant that although science and technology as well as increased experience accumulated over a long time have paved the way to make such an operation possible, its applicability is limited by lack of public awareness or its unwillingness to agree to organ donation. The average transplant survival is now over 10 years. Its prevalence and success, however, belies the fact that over 52 years ago, no one had ever attempted the procedure in man and that the procedure seemed destined for ignominy and failure just a year after the first transplant. Had it not been for the work of a few scientists and physicians, each who stepped on the broad shoulders of those who had come previously, the history of heart transplantation would be nothing more than a few legends and myths in dusty tomes.

Conventional cardiac surgery in patients with end-stage coronary artery disease: yesterday and today.

Surgical therapy of combined coronary artery disease (CAD) and heart failure, also referred to as end-stage CAD, has evolved throughout the years and patients are currently being offered traditional coronary artery bypass grafting (CABG), with or without surgical ventricle restoration (SVR), interventions for ischemic mitral valve regurgitation, heart transplantation or implantation of mechanical cardiovascular support systems. Among surgical methods, operative myocardial revascularization (with or without ventricle restoration) is still playing an important role, aiming at restoration of proper myocardial perfusion, especially if heart muscle viability is present. Facing the donor shortage, CABG may constitute a valuable alternative to transplantation in selected patients. In individuals considered not suitable for surgical revascularization, implantation of mechanical circulatory support (MCS) not only appears as a salvage procedure, but also allows for reevaluation of future therapy directions. This article aims at providing an overview of evolving and current surgical practices in patients with end-stage CAD.

The role of ventricular assist device in children.

The first and successful implantation of a ventricular assist device in 1990 has allowed an 8-year-old child with an end-stage heart failure to undergo a heart transplantation. This milestone paved the way to consider support with ventricular assist in the armamentarium of heart failure management in infants, children and adolescents. Several systems have evolved and faded owing to unacceptable complications. Indications and contraindications to implantation have been established. Anticoagulation management is still on its way to impeccability. Despite the challenges, issues and concerns revolving around ventricular assist devices, the system definitely supports pediatric patients with end-stage heart failure until heart transplantation and could allow recovery of the myocardium.

Organ-saving surgical alternatives to treatment of heart failure.

Over time, various surgical treatment strategies have evolved to manage advanced heart failure (HF). Scientific and technological breakthroughs through the last 50 years have put forward various surgical alternatives to patients with advanced HF encompassing surgical ventricular restoration to surgical gene therapy and stem cell replacement of the diseased ventricles. Organ-saving surgical options which used to be promising included dynamic cardiomyoplasty, partial resection of ventricle and cardiac wrapping with Acorn CorCap cardiac support device. These procedures were eventually abandoned due to negative outcomes and without proven disadvantages. Another organ-saving surgical option currently being considered but still make little sense is cardiac regeneration by stem cell therapy, i.e., cardiomyocyte restoration and replacement. Presently, the organ-saving surgical alternatives to treat end-stage HF are revascularization for ischemic cardiomyopathy, mitral valve surgery (repair or replacement) for ischemic mitral incompetence (IMI), left ventricular (LV) aneurysmectomy (surgical ventricular restoration) and mitral valve repair for IMI. These aforementioned procedures have become quite established approaches and with increasing experience are continuously being modified to improve outcome. Various mechanical circulatory support systems have emerged over time to improve functional status of patients with advanced HF, either as a bridge to heart transplantation or as a bridge to myocardial recovery. Likewise offered in those with contraindications to transplantation. Ventricular assist devices (VAD) can keep patients alive until an eventual transplantation. This article reviews the variety of the myriad of alternative organ-saving surgical alternatives that have been available or are currently available provided to patients with end-stage HF, their advantages and deficiencies, as well as prospects in HF therapy.

Heart transplantation: the Berlin experience and perspectives.

In patients with end-stage heart failure, heart transplants are now an ingrained practice, as they provide satisfying long-term results with good predictability and quality of life. The successful outcome has evolved from the development of effective immunosuppression, recognition of allograft rejection through diagnostic modalities and improvement in donor organ perfusion. Unfortunately, transplant availability is constrained by the shortage of donor organs and is therefore considered a casuistic therapy. The outcome is defined by unwanted effects of immunosuppressants, increased tumor occurrence and chronic transplant angiopathies. In the long term, patients fear primarily the occurrence of renal insufficiency and secondly osteoporosis with its skeletal complications and corresponding pain. Nevertheless, the overall quality of life is not very limited; on the contrary, patients demonstrate a surprisingly meaningful lives 10-20 years after the transplant. Their physical presentation is similar to those with varying co-morbidities. Most of the 20-year surviving patients are physically active and happy with their daily lives. Medical ambition has seen heart transplantation become reality and develop into an influential force regarding heart surgery, immunology, pharmacology, organ logistics and medical ethics. Its development has also molded our definitions of death and has driven public and health care approval of medical advances. It has provided a strong solidarity among politicians, sociologists, physicians and citizens. Problems regarding ethics continue to endure, and will forecast heart transplants as a defining, but temporary era in human medicine. The donor organ shortage has stimulated the use of resuscitated donor hearts and encouraged exploration and advancement of mechanical circulatory support systems and xenotransplantation as alternatives in the management of end-stage heart failure.

Weaning from ventricular assist device support after recovery from left ventricular failure with or without secondary right ventricular failure.

Although complete myocardial recovery after ventricular assist device (VAD) implantation is rather seldom, systematic search for recovery is worthwhile because for recovered patients weaning from VADs is feasible and can provide survival benefits with long-term freedom from heart failure (HF) recurrence, even if a chronic cardiomyopathy was the primary cause for the drug-refractory HF necessitating left ventricular (LVAD) or biventricular support (as bridge-to-transplantation or definitive therapy) and even if recovery remains incomplete. LVAD patients explanted for myoacardial recovery compared to those transplanted from LVAD support showed similar survival rates and a significant proportion of explanted patients can achieve cardiac and physical functional capacities that are within the normal range of healthy controls. In apparently sufficiently recovered patients, a major challenge remains still the pre-explant prediction of the weaning success which is meanwhile reliably possible for experienced clinicians. In weaning candidates, the combined use of certain echocardiography and right heart catheterization parameters recorded before VAD explantation can predict post-weaning cardiac stability with good accuracy. However, in the absence of standardization or binding recommendations, the protocols for assessment of native cardiac improvement and also the weaning criteria differ widely among centers. Currently there are still only few larger studies on myocardial recovery assessment after VAD implantation. Therefore, the weaning practice relies mostly on small case series, local practice patterns, and case reports, and the existing knowledge, as well as the partially differing recommendations which are based mainly on expert opinions, need to be periodically systematised. Addressing these shortcomings, our review aims to summarize the evidence and expert opinion on the evaluation of cardiac recovery during mechanical ventricular support by paying special attention to the reliability of the methods and parameters used for assessment of myocardial recovery and the challenges met in both evaluation of recovery and weaning decision making.

Mechanical circulatory support systems: evolution, the systems and outlook.

The joint efforts in the fields of surgery, medicine and biomedical engineering, sponsored by both the government and the industry, have led to the development of mechanical support devices that can provide reliable circulatory support, which can temporarily support a patient's circulation until either the heart recovers or until a new heart can be transplanted or permanently replace a failed heart. Their development has been driven by the shortage of donor organs. Various systems have eventually evolved for short or long-term support of patients suffering from cardiogenic and/or advanced heart failure (HF). Over time, several have been withdrawn from the market due to high rate of thromboembolism and pump-related complications, but many others remained with modern principles of circulatory support proved to be durable and reliable. Hopefully, the ever-evolving technology will yield several devices aimed at their miniaturization, with an energy supply without risk of infection, a system which is simple to implant and to exchange, minimalization of thrombus formation by optimal interior pump design, new antithrombotic medications and a system with demand-based pump activity. It is important to remember that such devices are only implanted to keep a patient alive or in an immediate life-threatening stage. In such circumstances, attribution of aforementioned difficulties to pump limitations or to advanced disease states remains difficult. In the coming years, ventricular assist devices (VADs) could be the most common surgical preference for treating severe HF.

Non-invasive cardiac allograft rejection surveillance: reliability and clinical value for prevention of heart failure.

Allograft rejection-related acute and chronic heart failure (HF) is a major cause of death in heart transplant recipients. Given the deleterious impact of late recognized acute rejection (AR) or non-recognized asymptomatic antibody-mediated rejection on short- and long-term allograft function improvement of AR surveillance and optimization of action strategies for confirmed AR can prevent AR-related allograft failure and delay the development of cardiac allograft vasculopathy, which is the major cause for HF after the first posttransplant year. Routine non-invasive monitoring of cardiac function can improve both detection and functional severity grading of AR. It can also be helpful in guiding the anti-AR therapy and timing of routine surveillance endomyocardial biopsies (EMBs). The combined use of EMBs with non-invasive technologies and methods, which allow detection of subclinical alterations in myocardial function (e.g., tissue Doppler imaging and speckle-tracking echocardiography), reveal alloimmune activation (e.g., screening of complement-activating donor-specific antibodies and circulating donor-derived cell-free DNA) and help in predicting the imminent risk of immune-mediated injury (e.g., gene expression profiling, screening of non-HLA antibodies, and circulating donor-derived cell-free DNA), can ensure the best possible surveillance and management of AR. This article gives an overview of the current knowledge about the reliability and clinical value of non-invasive cardiac allograft AR surveillance. Particular attention is focused on the potential usefulness of non-invasive tools and techniques for detection and functional grading of early and late ARs in asymptomatic patients. Overall, the review aimed to provide a theoretical and practical basis for those engaged in this particularly demanding up-to-date topic.

Ventricular systolic dysfunction with and without altered myocardial contractility: Clinical value of echocardiography for diagnosis and therapeutic decision-making.

The inability of one of the two or both ventricles to contract normally and expel sufficient blood to meet the functional demands of the body results from a complex interplay between intrinsic abnormalities and extracardiac factors that limit ventricular pump function and is a major cause for heart failure (HF). Even if impaired myocardial contractile function was the primary cause for ventricular dysfunction, with the progression of systolic dysfunction, additionally developed diastolic dysfunction can also contribute to the severity of HF. Although at the first sight, the diagnosis of systolic HF appears quite easy because it is usually defined by reduction of the ejection fraction (EF), in reality this issue is far more complex because ventricular pumping performance depends not only on myocardial contractility, but also largely on loading conditions (preload and afterload), being also influenced by valvular function, ventricular interdependence, pericardial constraint, synchrony of ventricular contrac-tion and heart rhythm. Conventional echocardiography (ECHO) combined with new imaging techniques such as tissue Doppler and tissue tracking can detect early subclinical alteration of ventricular systolic function. However, no single ECHO parameter reveals alone the whole picture of systolic dysfunction. Multiparametric ECHO evaluation and the use of integrative approaches using ECHO-parameter combinations which include also the ventricular loading conditions appeared particularly useful especially for differentiation between primary (myocardial damage-induced) and secondary (hemodynamic overload-induced) systolic dysfunction. This review summarizes the available evidence on the usefulness and limitations of comprehensive evaluation of LV and RV systolic function by using all the currently available ECHO techniques.