Negative Inotropic Drugs Research Articles

YAP dysregulation triggers hypertrophy by CCN2 secretion and TGFβ uptake in human pluripotent stem cell-derived cardiomyocytes.

Hypertrophy Cardiomyopathy (HCM) is the most prevalent hereditary cardiovascular disease - affecting >1:500 individuals. Advanced forms of HCM clinically present with hypercontractility, hypertrophy and fibrosis. Several single-point mutations in b-myosin heavy chain (MYH7) have been associated with HCM and increased contractility at the organ level. Different MYH7 mutations have resulted in increased, decreased, or unchanged force production at the molecular level. Yet, how these molecular kinetics link to cell and tissue pathogenesis remains unclear. The Hippo Pathway, specifically its effector molecule YAP, has been demonstrated to be reactivated in pathological hypertrophic growth. We hypothesized that changes in force production (intrinsically or extrinsically) directly alter the homeostatic mechano-signaling of the Hippo pathway through changes in stresses on the nucleus. Using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), we asked whether homeostatic mechanical signaling through the canonical growth regulator, YAP, is altered 1) by changes in the biomechanics of HCM mutant cardiomyocytes and 2) by alterations in the mechanical environment. We use genetically edited hiPSC-CM with point mutations in MYH7 associated with HCM, and their matched controls, combined with micropatterned traction force microscopy substrates to confirm the hypercontractile phenotype in MYH7 mutants. We next modulate contractility in healthy and disease hiPSC-CMs by treatment with positive and negative inotropic drugs and demonstrate a correlative relationship between contractility and YAP activity. We further demonstrate the activation of YAP in both HCM mutants and healthy hiPSC-CMs treated with contractility modulators is through enhanced nuclear deformation. We conclude that the overactivation of YAP, possibly initiated and driven by hypercontractility, correlates with excessive CCN2 secretion (connective tissue growth factor), enhancing cardiac fibroblast/myofibroblast transition and production of known hypertrophic signaling molecule TGFβ. Our study suggests YAP being an indirect player in the initiation of hypertrophic growth and fibrosis in HCM. Our results provide new insights into HCM progression and bring forth a testbed for therapeutic options in treating HCM.

Impact of heart rate, aortic compliance and stroke volume on the aortic regurgitation fraction studied in an ex vivo pig model

IntroductionDrug therapy to reduce the regurgitation fraction (RF) of high-grade aortic regurgitation (AR) by increasing heart rate (HR) is generally recommended. However, chronic HR reduction in HFREF patients can significantly...

Quartz Crystal Microbalance Technology Coupled with Impedance for the Dynamic Monitoring of the Cardiomyocyte Beating Function and Drug Screening

The main sensing techniques used to study myocardial pulsation are electrical impedance sensing (EIS) and by quartz crystal microbalance (QCM). While electrical impedance technology is the gold standard for the study of myocardial pulsation, the clinical application of drugs is being followed up in real time additionally, thus, QCM technology needs to be further developed as a very important class of quality sensor technology. Moreover, the application of EIS, in combination with the QCM, for monitoring myocardial pulsation, has been rarely reported. In this paper, a series of cell growth and adhesion conditions were optimized using rat primary cardiomyocytes, and QCM was used in combination with EIS to monitor the adhesion and the myocardial pulsation ability of the cells in real time. Furthermore, cardiomyocytes that adhered to the QCM and EIS were treated with isoprenaline (ISO), a positive inotropic drug, and verapamil (VRP), a negative inotropic drug. Next, the cell index (CI)-time (T) plots, beating amplitude (BA) and beating rate (BR) of the cardiomyocytes were calculated and changes in these parameters, before and after, dosing were evaluated. The results showed that the QCM technique results were not only consistent with the results obtained with EIS, but also that the QCM technique had a certain degree of sensitivity for the calculation of cardiomyocyte beating. Thus, our findings validate the reliability and validity of the QCM technique for measuring cardiomyocyte beating and drug testing. We hope that further studies would evaluate the application of the QCM technology for clinical use.

Actuation-Augmented Biohybrid Robot by Hyaluronic Acid-Modified Au Nanoparticles in Muscle Bundles to Evaluate Drug Effects.

Biohybrid robots, which comprise soft materials with biological components, have the potential to sense, respond, and adapt to changing environmental loads dynamically. Instead of humans and other living things, biohybrid robots can be used in various fields such as drug screening and toxicity assessment. In the actuation part, however, since a muscle cell-based biohybrid robot is limited in that the driving force is weak, it is difficult to evaluate drug and toxicological effects by distinguishing changes in the biohybrid robot's motion. To overcome this limitation, we introduced hyaluronic acid-modified gold nanoparticles (HA-AuNPs) into a muscle bundle-based biohybrid robot that moves forward in response to electrical stimulation. To enhance the actuation of muscle bundles, HA-AuNPs were embedded into the muscle bundles. The motion of the fabricated biohybrid robot was improved due to the enhanced differentiation and the improved electrical conductivity of muscle bundles by HA-AuNPs. In addition, the fabricated biohybrid robot exhibited huge changes in motion with respect to the addition of positive and negative inotropic drugs. The proposed biohybrid robot has the potential for neuromuscular disease drug screening by incorporating nervous tissues such as motor neuron organoids and brain organoids.

Is surgical myectomy challenged by emergence of novel drug therapy with mavacamten?

For 60 years, surgical myectomy has been the definitive treatment for symptomatic obstructive hypertrophic cardiomyopathy (HCM). Myectomy provides the opportunity to reverse heart failure symptoms in the vast majority of patient with low risk when performed in experienced centers and associated with extended longevity. More recently, a novel class of negative inotropic drug therapy with mavacamten has emerged offering expanded treatment options for obstructive HCM. In the recently completed phase III clinical trial, the EXPLORER-HCM about one-third of patients on mavacamten achieved the primary end-point of subjective symptomatic improvement and increased functional capacity assessed by peak VO2. Of note, outflow gradients persistent in 43% of patients on mavacamten and 50% with symptoms consistent with NYHA class II or greater. A subset of patients also experienced significant reversible systolic dysfunction. Therefore, it is timely to place into perspective the potential role of mavacamten in context of the established low risk: high benefit of surgical myectomy for treatment of heart failure.

Cardiotoxicity assessment using 3D vascularized cardiac tissue consisting of human iPSC-derived cardiomyocytes and fibroblasts

Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are used for cardiac safety assessment but have limitations for the evaluation of drug-induced contractility. Three-dimensional (3D) cardiac tissues are similar to native tissue and valuable for the assessment of contractility. However, a longer time and specialized equipment are required to generate 3D tissues. We previously developed a simple method to generate 3D tissue in a short period by coating the cell surfaces with extracellular matrix proteins. We hypothesized that this 3D cardiac tissue could be used for simultaneous evaluation of drug-induced repolarization and contractility. In the present work, we examined the effects of several compounds with different mechanisms of action by cell motion imaging. Consequently, human ether-a-go-go-related gene (HERG) channel blockers with high arrhythmogenic risk caused prolongation of contraction-relaxation duration and arrhythmia-like waveforms. Positive inotropic drugs, which increase intracellular Ca2+ levels or myocardial Ca2+ sensitivity, caused an increase in maximum contraction speed (MCS) or average deformation distance (ADD) (ouabain, 138% for MCS at 300 nM; pimobendane, 132% for ADD at 3 μM). For negative inotropic drugs, verapamil reduced both MCS and ADD (61% at 100 nM). Thus, this 3D cardiac tissue detected the expected effects of various cardiovascular drugs, suggesting its usefulness for cardiotoxicity evaluation.

Impact of negative inotropic drugs on accuracy of diastolic stress echocardiography for evaluation of left ventricular filling pressure

The ratio of early diastolic trans-mitral flow velocity to tissue-Doppler mitral annular early diastolic velocity (E/e′), and left ventricular end-diastolic pressure(LVEDP) have been shown to be correlated at rest, provided that patients are not on positive inotropic drugs. Data concerning the latter correlation during exercise stress are conflicting. Therefore, we investigated if use of negative inotropic drugs (NID), impacts the accuracy of E/e′ as a surrogate for LVEDP during low-level exercise. An exercise(50 watts) during cardiac invasive hemodynamic monitoring and an exercise echocardiography were performed prospectively within 24 hours in 54 patients (81%male, 62 ± 9years) with preserved LV Ejection-Fraction. Before exercise, the patients had scattered LVEDP (13.8 ± 5.8 mmHg) and septal E/e′ (8.7 ± 2.7). Half of them were on NID, mainly betablockers(n = 26). The correlation between septal-E/e′ and LVEDP was low for examinations performed at rest (r = 0.35,p = 0.01) with no significant impact of NID. For measurements performed at 50 Watts, NID had a significant impact on the association between septal-E/e′50 watts and LVEDP50 watts (β = −0.28,p = 0.03). Correlation between septal-E/e′50 watts and LVEDP50 watts persisted in patients on NID (r = 0.61,p = 0.001) while it disappeared in the group of patients with no NID (r = 0.15,p = 0.47). NID use is an important confounding factor to take into consideration when assessing exercise LVFP using stress E/e′ in patients with preserved LVEF.

Pacing for hypertrophic obstructive cardiomyopathy: an update and future directions.

In hypertrophic cardiomyopathy (HCM) patients with symptoms caused by left ventricular outflow tract obstruction (LVOTO), treatment options include negative inotropic drugs, myectomy, septal alcohol ablation and AV sequential pacing with or without an implantable cardioverter defibrillator (ICD). Pacing is rarely used in spite of its relative simplicity and promising results. In this review the current evidence of AV sequential pacing from observational, randomised studies and long and very long-term follow-up studies is given and put in the context of present guidelines recommendations. These studies indicate that AV sequential pacing improves symptoms and quality of life through decreases in LVOTO, systolic anterior movement and mitral regurgitation. Effects on morbidity and mortality are lacking. We describe the mechanisms of action, the prerequisites for successful pacing and provide practical advice on how to optimise therapy. Moreover, the role of the ICD for primary and secondary prevention is discussed with reference to the ESC HCM guidelines. In summary, AV sequential pacing for HOCM is underused in clinical practise despite evidence from two randomised controlled studies. This concept is currently the focus of two randomised studies: a planned randomised controlled study that will compare AV sequential pacing to TASH and an ongoing study that compares CRT to AAI pacing in HOCM patients. In this review we highlight the current evidence and the new interest for this therapy.

Extracorporeal life support for refractory ventricular tachycardia.

Extracorporeal life support (ECLS) is a very effective bridging therapy in patients with refractory ventricular tachycardia (VT) associated with cardiogenic shock. A moribund patient in extremis, is not amenable to optimization by standard ACC/AHA guidelines. New approaches and novel salvage techniques are necessary to improve outcomes in patients with refractory clinical settings such as malignant ventricular arrhythmias, cardiac arrest, cardiogenic shock and/or pulmonary failure until further management options are explored. Data base searches were done using key words such as ECLS, VT, cardiac arrest, VT ablation, venoarterial extra-corporeal membrane oxygenation (VA-ECMO). The use of ECLS has been described in a few case reports to facilitate VT ablation for incessant VT refractory to medical therapy. For patients with, out-of- hospital ventricular fibrillation (VF) and VT, Minnesota Resuscitation Consortium has implemented emergent advanced perfusion and reperfusion strategy, followed by coronary angiography and primary coronary intervention to improve outcome. The major indications for ECLS are cardiogenic shock related to acute myocardial infarction, myocarditis, post embolic acute cor pulmonale, drug intoxication and post cardiac arrest syndrome with the threat of multi-organ failure. ECLS permits the use of negative inotropic antiarrhythmic drug therapy, facilitates the weaning of catecholamine administration, thereby ending the vicious cycle of catecholamine driven electric storm. ECLS provides hemodynamic support during ablation procedure, while mapping and induction of VT is undertaken. ECLS provides early access to cardiac catheterization laboratory in patients with cardiac arrest due to shockable rhythm. The current evidence from literature, supports the use of ECLS to ensure adequate vital organ perfusion in patients with refractory VT. ECLS is a safe, feasible and effective therapeutic option when conventional therapies are insufficient to support cardiopulmonary function. A highly driven multidisciplinary team approach is essential to accomplish this task.

044 - Impact of negative inotropic drugs on echocardiographic evaluation of left ventricular filling pressure in patients with normal left ventricular ejection fraction during exercise stress test

044 - Impact of negative inotropic drugs on echocardiographic evaluation of left ventricular filling pressure in patients with normal left ventricular ejection fraction during exercise stress test

Cardiac Non-myocyte Cells Show Enhanced Pharmacological Function Suggestive of Contractile Maturity in Stem Cell Derived Cardiomyocyte Microtissues.

The immature phenotype of stem cell derived cardiomyocytes is a significant barrier to their use in translational medicine and pre-clinical in vitro drug toxicity and pharmacological analysis. Here we have assessed the contribution of non-myocyte cells on the contractile function of co-cultured human embryonic stem cell derived cardiomyocytes (hESC-CMs) in spheroid microtissue format. Microtissues were formed using a scaffold free 96-well cell suspension method from hESC-CM cultured alone (CM microtissues) or in combination with human primary cardiac microvascular endothelial cells and cardiac fibroblasts (CMEF microtissues). Contractility was characterized with fluorescence and video-based edge detection. CMEF microtissues displayed greater Ca2+ transient amplitudes, enhanced spontaneous contraction rate and remarkably enhanced contractile function in response to both positive and negative inotropic drugs, suggesting a more mature contractile phenotype than CM microtissues. In addition, for several drugs the enhanced contractile response was not apparent when endothelial cell or fibroblasts from a non-cardiac tissue were used as the ancillary cells. Further evidence of maturity for CMEF microtissues was shown with increased expression of genes that encode proteins critical in cardiac Ca2+ handling (S100A1), sarcomere assembly (telethonin/TCAP) and β-adrenergic receptor signalling. Our data shows that compared with single cell-type cardiomyocyte in vitro models, CMEF microtissues are superior at predicting the inotropic effects of drugs, demonstrating the critical contribution of cardiac non-myocyte cells in mediating functional cardiotoxicity.

Intra-Aortic Balloon Pump Support in the Isolated Beating Porcine Heart in Nonischemic and Ischemic Pump Failure.

The blood pressure changes induced by the intra-aortic balloon pump (IABP) are expected to create clinical improvement in terms of coronary perfusion and myocardial oxygen consumption. However, the measured effects reported in literature are inconsistent. The aim of this study was to investigate the influence of ischemia on IABP efficacy in healthy hearts and in shock. Twelve slaughterhouse porcine hearts (hearts 1-12) were connected to an external circulatory system, while physiologic cardiac performance was restored. Different clinical scenarios, ranging from healthy to cardiogenic shock, were simulated by step-wise administration of negative inotropic drugs. In hearts 7-12, severe global myocardial ischemia superimposed upon the decreased contractile states was created. IABP support was applied in all hearts under all conditions. Without ischemia, the IABP induced a mild increase in coronary blood flow and cardiac output. These effects were strongly augmented in the presence of persisting ischemia, where coronary blood flow increased by 49 ± 24% (P < 0.01) and cardiac output by 17 ± 6% (P < 0.01) in case of severe pump failure. As expected, myocardial oxygen consumption increased in case of ischemia (21 ± 17%; P < 0.01), while it slightly decreased without (-3 ± 6%; P < 0.01). In case of progressive pump failure due to persistent myocardial ischemia, the IABP increased hyperemic coronary blood flow and cardiac output significantly, and reversed the progressive hemodynamic deterioration within minutes. This suggests that IABP therapy in acute myocardial infarction is most effective in patients with viable myocardium, suffering from persistent myocardial ischemia, despite adequate epicardial reperfusion.

Medical, Surgical and Interventional Management of Hypertrophic Cardiomyopathy With Obstruction

Patients with hypertrophic cardiomyopathy (HCM) are classified as having hypertrophic obstructive cardiomyopathy (HOCM) if a left ventricular outflow tract (LVOT) gradient is present at rest or during provocation, as with Valsalva maneuver or exercise. Management of HCM in general and HOCM in particular encompasses (1) activity restriction with avoidance of volume depletion, (2) prevention of sudden cardiac death, (3) control of symptoms, and (4) screening of relatives. Those patients at high risk of sudden cardiac death (SCD) should be offered an implantable cardioverter-defibrillator (ICD). Pharmacologic treatment of symptoms in patients with HOCM consists of negative inotropic drugs, namely beta blockers, and disopyramide; a nondihydropyridine calcium channel blocker (CCB), usually verapamil, may be used in patients with noncardiac side-effects of beta blockers. Patients who have a dual-chamber pacemaker (PM) or ICD should undergo a trial of pacing with short atrioventricular (AV) delay. For patients with intolerable symptoms despite optimal conservative therapy, septal reduction therapy (SRT) should be considered and should be performed by experienced operators in institutions with multidisciplinary HCM programs. Younger patients with extreme hypertrophy are usually offered septal myectomy, while older patients, and those with important comorbidities are usually directed to alcohol septal ablation (ASA). For patients for whom either therapy is appropriate, there should be a balanced discussion with the patients of the benefits and risks of the 2 procedures.

Relevance of the volume-axis intercept,V0, compared with the slope of end-systolic pressure-volume relationship in response to large variations in inotropy and afterload in rats

The end-systolic pressure-volume relationship (ESPVR) is proposed and used as a reliable index of left ventricular (LV) contractility despite the fact that its afterload independence has been challenged. Furthermore, the physiological relevance of its volume-axis intercept, V(0), remains unclear. Systemic haemodynamics and pressure-volume loops obtained by inferior vena cava occlusion were recorded in 21 rats anaesthetized by isoflurane inhalation and instrumented with a conductance pressure-volume catheter in response to incremental I.V. doses of adrenaline, dobutamine, phenylephrine, metoprolol, papaverine and isoflurane inhalation. In conditions with large variations (± 100%) of both inotropy and afterload, infusion of negative inotropic drugs was associated with a dose-dependent rightward shift of ESPVR accompanied by a decrease in its slope (end-systolic elastance, E(es)), whereas positive inotropic agents produced an isolated decrease in V(0). With the predominant vasoactive drugs, there was a dose-dependent change in E(es) without major horizontal shifts, demonstrating that this slope mainly represents LV afterload rather than inotropy. When contractility was altered, V(0) was negatively correlated to the preload-adjusted contractility index, PAdP/dt(max), demonstrating that a reduced V(0) provides a good reflection of increased LV contractility. From these results, we computed a logarithmically adjusted E(es)/V(0) ratio, which resulted in reasonably strong concordance with PAdP/dt(max), including all the investigated drugs and dosages [n = 288; bias, 0.8 ± 16.2% (SD)]. Concordance with E(es) (bias, 7.2 ± 58.7%) or V(0) (bias, -0.6 ± 33.4%), used alone or with other commonly used contractility indices, was far less significant. In contrast to E(es), V(0) provides a relatively good LV contractility index because it is much less sensitive to afterload.

Recommendations for the transfusion of red blood cells.

The transfusion of red cell concentrates (RCC) is indicated in order to achieve a fast increase in the supply of oxygen to the tissues, when the concentration of haemoglobin (Hb) is low and/or the oxygen carrying capacity is reduced, in the presence of inadequate physiological mechanisms of compensation (table I)1–14. Table I Mechanisms of adaptation to anaemia Tissue oxygenation depends on various factors - the concentration of Hb; - the saturation of Hb, which, in turn, depends on the O2 tension and the affinity of the Hb for O2; - the O2 requirement, that is, the volume of oxygen needed by the tissues to carry out their aerobic function. Clinical factors that affect the physiological mechanisms of adaptation to anaemia5–8,15–19 - a reduced increase in cardiac output: hypovolaemia, coronary artery disease, disorders of heart valves, congestive heart disease, negative inotropic drugs; - decreased capacity to increase the extraction of O2: acute respiratory distress syndrome (ARDS), sepsis, systemic inflammatory response syndrome (SIRS), traumatic ischaemia-reperfusion damage syndrome; - altered gas exchange: chronic obstructive pulmonary disease (COPD), ARDS; - increased consumption of O2: fever, pain, stress, sepsis, SIRS, hyperventilation syndromes. When there is an indication to correct anaemia, but the situation is not urgent, strategies other than transfusion are preferred, such as the use of haematopoietic drugs (iron, vitamin B12, folic acid, recombinant erythropoietin)5–8,20. In order to reduce perioperative bleeding, it is important to suspend treatment with platelet anti-aggregants, adapt/neutralise anticoagulant therapy and use drugs such as antifibrinolytics and desmopressin9,20–23. Autotransfusion, carried out according to the criteria set out in the appropriate pre-operative request schemes (maximum surgical blood order schedule -MSBOS), and surgical and anaesthetic techniques to limit blood loss are useful strategies for decreasing the use of homologous blood (Grade of recommendation: 1C+)5,6,13,14,20–24.

The ventricular septum: the lion of right ventricular function, and its impact on right ventricular restoration☆

To evaluate the structure-function relationships of the right ventricle (RV) and septum and determine if the helical ventricular band model would define fiber orientation for maximal force response. Implications were made for right ventricular function. The right ventricular free wall and biventricular septum were studied by inserting sonomicrometer crystals at different angulations to determine the maximum response of fiber shortening. These reactions were compared to the lateral left ventricular (LV) wall and further tested by use of positive and negative inotropic drug infusions. The maximum contraction of the free wall was achieved by placing crystals in the transverse orientation angulations, whereas oblique orientation allowed the maximal septal response. Fiber orientation angulation was the same for the LV free wall and septum. These angulations correlate with the MRI-related twisting actions of septal motion needed for ejection and suction for rapid filling. These findings have important impact, because they imply that the septum is 'lion of right ventricular function,' since septal twisting is essential when pulmonary vascular resistance is increased. The incidence of postoperative right heart failure due to septal dyssyncrony, with loss of septal twisting action from inadequate myocardial protection, is explored relative to RV free wall and septum function. Furthermore, early studies of right ventricular restoration in patients with RV dysplasia and RV failure after chronic pulmonary insufficiency following repair of Tetralogy of Fallot are described, with predominant attention directed toward rebuilding normal septal architecture and function. This experimental and clinical overview indicates that the septum is 'the lion of right ventricular function,' and implies that the use of this knowledge can become an important guideline for planning novel surgical geometric interventions after RV failure.

Hypertrophic Cardiomyopathy

Hypertrophic Cardiomyopathy

Negative inotropic drugs alter indexes of cytosolic [Ca(2+)]-left ventricular pressure relationships after ischemia.

Negative inotropic agents may differentially modulate indexes of cytosolic [Ca(2+)]-left ventricular (LV) pressure (LVP) relationships when given before and after ischemia. We measured and calculated [Ca(2+)], LVP, velocity ratios [[(d[Ca(2+)]/dt(max))/(dLVP/dt(max)); VR(max)] and [(d[Ca(2+)]/dt(min))/(dLVP/dt(min)); VR(min)]], and area ratio (AR; area [Ca(2+)]/area LVP per beat) before and after global ischemia in guinea pig isolated hearts. Ca(2+) transients were recorded by indo 1-AM fluorescence via a fiberoptic probe placed at the LV free wall. [Ca(2+)]-LVP loops were acquired by plotting LVP as a function of [Ca(2+)] at multiple time points during the cardiac cycle. Hearts were perfused with bimakalim, 2,3-butanedione monoxime (BDM), nifedipine, or lidocaine before and after 30 min of ischemia. Before ischemia, each drug depressed LVP, but only nifedipine decreased both LVP and [Ca(2+)] with a downward and leftward shift of the [Ca(2+)]-LVP loop. After ischemia, each drug depressed LVP and [Ca(2+)] with a downward and leftward shift of the [Ca(2+)]-LVP loop. Each drug except BDM decreased d[Ca(2+)]/dt(max); nifedipine decreased d[Ca(2+)]/dt(min), whereas lidocaine increased it, and bimakalim and BDM had no effect on d[Ca(2+)]/dt(min). Each drug except bimakalim increased VR(max) and VR(min) before ischemia; after ischemia, only BDM and nifedipine increased VR(max) and VR(min). Before and after ischemia, BDM and nifedipine increased AR, whereas lidocaine and bimakalim had no effect. At 30 min of reperfusion, control hearts exhibited marked Ca(2+) overload and depressed LVP. In each drug-pretreated group Ca(2+) overload was reduced on reperfusion, but only the group pretreated with nifedipine exhibited both higher LVP and lower [Ca(2+)]. These results show that negative inotropic drugs are less capable of reducing [Ca(2+)] after ischemia so that there is a relatively larger Ca(2+) expenditure for contraction/relaxation after ischemia than before ischemia. Moreover, the differential effects of pretreatment with negative inotropic drugs on [Ca(2+)]-LVP relationships after ischemia suggest that these drugs, especially nifedipine, can elicit cardiac preconditioning.

Congenital heart disease in adults: management of advanced heart failure

The number of adults living with congenital heart disease grows annually. The sequelae of congenital heart disease surgery may involve the electrical conduction system, cardiac valves, prosthetic materials, the myocardium, vascular beds, and the nervous system. These sequelae may lead to heart failure. Adults with congenital heart disease develop heart failure as a consequence of: (1) chronic cyanosis, volume overload, and other hemodynamic abnormalities, (2) low cardiac output with outflow obstruction, or (3) acquired cardiac disease superimposed on pre-existing congenital heart disease. Heart failure is characterized by myocardial remodeling in response to injury. It is associated with maladaptive neurohormonal activation, cytokine release, and vasoconstriction leading to sodium and fluid retention and arrhythmias. Angiotensin converting enzyme inhibitors, β-blockers, and spironolactone address these neurohumoral derangements. Digoxin and diuretics may reduce the frequency of hospitalization. Angiotensin-II receptor blockers, warfarin and amiodarone may benefit selected patients, although a survival benefit has not been established. Implantable cardiac defibrillators and atrio-biventricular pacemakers may prolong life in specific groups of patients. Infusions of nesiritide, dobutamine, or milrinone will improve cardiac output and facilitate diuresis. Dobutamine and milrinone may increase mortality due to neurohumoral activation. Pharmaceutical agents under investigation include tumor necrosis factor receptor antagonists and endothelin receptor blockers. Reversible factors that may precipitate heart failure include: unrecognized fluid retention, tachyarrhythmias, systemic viral infection, endocrine abnormalities, alcohol or substance abuse, negative inotropic drugs, and prostaglandin inhibitors. Intensive patient and family education regarding compliance is critical. This provides patients with a greater sense of control and may reduce the frequency of emergency department visits and hospital admissions. Cardiac transplantation improves survival and quality of life for end-stage heart failure patients. A donor shortage and strict inclusion criteria limit this option. This has led to increased use of mechanical cardiac assist devices as bridges to transplant. Once FDA approved, these devices may become an alternative to transplant for select patients. Cardiologists who treat adults with congenital heart disease must consider the underlying cardiac condition leading to heart failure and tailor therapy. Most of the clinical trials, which guide heart failure therapy do not include a significant number of individuals with congenital heart disease.

Cardiac Performance and Morphology in End-Stage Renal Disease

Patients with end-stage renal disease (ESRD) experience a variety of hemodynamic and metabolic abnormalities that predispose to alterations in cardiac performance and morphology. High cardiac output related to renal anemia, hypertension, volume overload, and the arteriovenous fistula (in patients on hemodialysis) predispose to eccentric left ventricular (LV) hypertrophy. Hypertension, aortic stiffness, and aortic stenosis predispose to concentric LV hypertrophy. Most ESRD patients have a hybrid form of LV hypertrophy. LV hypertrophy is commonly accompanied by LV diastolic dysfunction. LV systolic dysfunction is less common. Newer dialytic techniques, excellent control of hypertension, and correction of renal anemia produce regression of LV hypertrophy. The effect of these interventions on LV systolic and diastolic function is less well established. Alterations in serum calcium, choice of dialysate base, hypoxia, and comorbid conditions may influence the effects of dialysis (particularly hemodialysis) on LV function. A variety of negative inotropic drugs may depress LV function in patients with ESRD.