Matthew E. Harinstein

Cardiovascular Risk Assessment of the Liver Transplant Candidate

Liver transplantation (LT) candidates today are increasingly older, have greater medical acuity, and have more cardiovascular comorbidities than ever before. Steadily rising model for end-stage liver disease (MELD) scores at the time of transplant, resulting from high organ demand, reflect the escalating risk profiles of LT candidates. In addition to advanced age and the presence of comorbidities, there are specific cardiovascular responses in cirrhosis that can be detrimental to the LT candidate. Patients with cirrhosis requiring LT usually demonstrate increased cardiac output and a compromised ventricular response to stress, a condition termed cirrhotic cardiomyopathy. These cardiac disturbances are likely mediated by decreased beta-agonist transduction, increased circulating inflammatory mediators with cardiodepressant properties, and repolarization changes. Low systemic vascular resistance and bradycardia are also commonly seen in cirrhosis and can be aggravated by beta-blocker use. These physiologic changes all contribute to the potential for cardiovascular complications, particularly with the altered hemodynamic stresses that LT patients face in the immediate post-operative period. Post-transplant reperfusion may result in cardiac death due to a multitude of causes, including arrhythmia, acute heart failure, and myocardial infarction. Recognizing the hemodynamic challenges encountered by LT patients in the perioperative period and how these responses can be exacerbated by underlying cardiac pathology is critical in developing recommendations for the pre-operative risk assessment and management of these patients. The following provides a review of the cardiovascular challenges in LT candidates, as well as evidence-based recommendations for their evaluation and management.

Predictive Value of Dobutamine Stress Echocardiography for Coronary Artery Disease Detection in Liver Transplant Candidates

Patients with obstructive coronary artery disease (CAD) undergoing orthotopic liver transplantation (OLT) are at increased risk of poor outcomes. The accuracy of dobutamine stress echocardiography (DSE) to detect obstructive CAD is not well established in this population. We retrospectively identified patients with end‐stage liver disease who underwent both DSE and coronary angiography as part of risk stratification prior to OLT. One hundred and five patients had both DSE and angiography, of whom 14 had known CAD and 27 failed to reach target heart rate during DSE. Among the remaining 64 patients (45 men; average age 61 ± 8 years) DSE had a low sensitivity (13%), high specificity (85%), low positive predictive value (PPV) (22%) and intermediate negative predictive value (NPV) (75%) for obstructive CAD. DSE as a screening test for obstructive CAD in OLT candidates has a poor sensitivity. The frequent chronotropic incompetence and low sensitivity in patients who achieve target heart rate, even in those with multiple cardiovascular disease risk factors, suggest that alternative or additional methods of risk stratification are necessary.

Istaroxime, a first in class new chemical entity exhibiting SERCA-2 activation and Na–K-ATPase inhibition: a new promising treatment for acute heart failure syndromes?

Acute heart failure syndromes (AHFS) are associated with the rapid onset of heart failure (HF) signs and symptoms. Hospitalizations for AHFS continue to rise and are associated with significant mortality and morbidity. Several pharmacological agents are currently approved for the treatment of AHFS, but their use is associated with an increase in short-term mortality. There is a need for new agents that can be given in the acute setting with increased efficacy and safety. Istaroxime is a unique agent with both inotropic and lusitropic properties which is currently being studied for the treatment of AHFS. Istaroxime inhibits the sodium–potassium adenosine triphosphatase (ATPase) and stimulates the sarcoplasmic reticulum calcium ATPase isoform 2 (SERCA-2) thereby improving contractility and diastolic relaxation. Early data from human studies reveal that istaroxime decreases pulmonary capillary wedge pressure (PCWP) and possibly improves diastolic function without causing a significant change in heart rate (HR), blood pressure, ischemic or arrhythmic events. Most commonly reported side effects were related to gastrointestinal intolerance and were dose related. In conclusion, istaroxime is a novel agent being investigated for the treatment of AHFS whose mechanism of action and cellular targets make it a promising therapy. Further studies with longer infusion times in patients with hypotension are required to confirm its efficacy and safety.

Coronary multidetector computed tomographic angiography to evaluate coronary artery disease in liver transplant candidates: methods, feasibility and initial experience.

Aims In patients undergoing orthotopic liver transplantation (OLT), coronary artery disease (CAD), obstructive and nonobstructive, is associated with high morbidity and mortality. In OLT candidates, stress testing for detecting ischemia is often inaccurate, and this patient population often has relative contraindications for cardiac catheterization. The objective of this study was to describe the methods, assess the feasibility and determine the extent and severity of CAD in OLT candidates without a prior history of CAD using coronary multidetector computer tomographic angiography (MDCTA). Methods Sixty-five OLT candidates without known CAD underwent coronary MDCTA with dual source cardiac computed tomography (Siemens Definition). Coronary arteries were divided into 17 segments based on American Heart Association guidelines and evaluated independently by two blinded reviewers. Image quality of coronary MDCTA was assessed on a four-point Likert scale (0 = poor, 1 = fair, 2 = good, and 3 = excellent). Atherosclerotic lesions were evaluated for severity [mild (0–50%), moderate (51–70%), and severe (71–100%)], morphology, extent, location and consistency. Results Image quality was graded as good or excellent in 73.8%. In this cohort of OLT candidates without known CAD, 9% had normal coronary arteries, 58% had mild CAD and 34% had moderate to severe CAD. Plaque severity and burden scores were high. Conclusion The prevalence of asymptomatic CAD is high in OLT candidates. Coronary MDCTA is feasible in OLT candidates and appears to be a useful technique to diagnose occult CAD in this patient population.

Clinical assessment of acute heart failure syndromes: emergency department through the early post-discharge period

Acute heart failure syndromes (AHFS) are defined as a rapid change in heart failure signs and symptoms in patients with chronic or de novo heart failure, who require urgent or emergent therapy.w1 w2 These symptoms are predominantly the result of systemic and pulmonary congestion due to elevated left ventricular (LV) filling pressures. AHFS are known to occur in patients with preserved or reduced LV ejection fraction (LVEF) and are an increasingly common cause of hospitalisation and mortality in the USA and worldwide.w3 In the USA, heart failure as the primary or secondary cause resulted in almost 3.6 million hospitalisations annually with an estimated cost of

Digoxin for the treatment of chronic and acute heart failure syndromes

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Rationale and design of the hemodynamic, echocardiographic and neurohormonal effects of istaroxime, a novel intravenous inotropic and lusitropic agent: a randomized controlled trial in patients hospitalized with heart failure (HORIZON-HF) trial.

56 billion (£25–£35 billion, €28–€40 billion). In other developed countries, total expenditures on heart failure ranges between 1–2% of the total healthcare budget, with ∼75% due to hospitalisation for heart failure. Hospitalisation for AHFS independently portends a poor prognosis.w4–w7 Despite multiple trials aimed at improving outcomes, post-discharge event (death or rehospitalisation) rates can be as high as 20–30% within the subsequent 60–90 day period and 50% at 1 year.w8 1 AHFS present with a wide range of signs and symptoms, often in the setting of other cardiovascular diseases such as coronary artery disease (CAD), hypertension, valvular heart disease, atrial fibrillation, as well as other non-cardiac conditions, including renal dysfunction, pulmonary disease, anaemia, and diabetes.w2 Current practice guidelines recommend the selective use of biomarkers as well as non-invasive and invasive techniques for the initial assessment of AHFS. However, the selection and timing of tests are not well delineated.2 w9 This document proposes a consensus recommendation regarding a complete assessment of patients initially presenting to the emergency department with AHFS through hospitalisation (figure 1) and the early post-discharge period. Three phases of assessment are proposed: (1) immediate (emergency department); (2) in-hospital; and (3) …

Normalization of ejection fraction and resolution of symptoms in chronic severe heart failure is possible with modern medical therapy: clinical observations in 11 patients.

Digitalis preparations have been used for centuries. Digoxin is an agent that is readily available, can be administered acutely and long-term, intravenously or orally, is safe and may be beneficial in both acute and chronic heart failure (HF). It may be an ideal drug for the treatment of acute heart failure syndromes and warrants further investigation in large clinical trials. The role of digoxin in acute and chronic HF was discussed at the 2008 European Society of Cardiology Working Group on Acute Cardiac Care Meeting held in Versailles, France from 25–28 October 2008. This report represents a summary of the presentation at this meeting.

The effects of eplerenone on length of stay and total days of heart failure hospitalization after myocardial infarction in patients with left ventricular systolic dysfunction.

Background:Current inotropes have inodilator properties and, although are frequently used in acute heart failure syndromes, do not improve outcomes, likely from reduction in systolic blood pressure and increasing in arrhythmias, causing worsened myocardial ischemia and end-organ damage. Istaroxime is a novel agent that, in animal models, has both inotropic (inhibition of the Na/K ATPase channel) and lusitropic (stimulation of sarcoplasmic reticulum calcium ATPase activity) effects. HORIZON-HF is designed to test the hypothesis that istaroxime is effective in improving central hemodynamics and left ventricular (LV) function, without lowering systolic blood pressure, increasing heart rate, and worsening renal function or myocardial necrosis. Methods and Results:This was a phase 2, randomized, double-blind, placebo-controlled, multicenter dose escalation exploratory study comparing 3 different doses of istaroxime to placebo in patients with LV systolic dysfunction (LV ejection fraction ≤ 35%) admitted to the hospital with worsening HF. Three cohorts of 40 patients each were randomized after an initial stabilization period of <48 h 3:1 to istaroxime 0.5, 1.0, or 1.5 μg/kg/min versus placebo infused over 6 h, with increasing doses after each cohort. The primary endpoint was change in pulmonary capillary wedge pressure from baseline, whereas secondary endpoints were improvement in other hemodynamic parameters, changes in echocardiographic assessment of LV systolic and diastolic function, neurohonal activation, renal function, and myocardial integrity. Pharmacokinetics and safety were also recorded. Conclusions:The novel inotropic and lusitropic agent, istaroxime, was tested in acute heart failure syndromes using a comprehensive assessment of cardiovascular function in addition to hemodynamic measurements.

Acute heart failure syndromes: Epidemiology, risk stratification and prognostic factors

This report describes the normalization of left ventricular ejection fraction and resolution of signs and symptoms of chronic and severe heart failure in both male and female patients (mean age 54 years) treated with standard medical therapy. These observations were made in 11 patients with idiopathic dilated cardiomyopathy treated in a single cardiology practice, who had evidence of myocardial “viability” (dysfunctional but noncontractile myocardium that has the potential for improvement in function) as assessed by cardiac magnetic resonance imaging, low-dose dobutamine echocardiography, or nuclear imaging. These patients were treated with standard available therapies including β-blockers, angiotensin-converting enzyme inhibitors, digoxin, and potassium and non-potassium-sparing diuretics. The average ejection fraction at presentation was 17% ± 9% which improved to 59% ± 5%. All patients improved to New York Heart Association functional class I with available therapy. The majority of patients received micronutrient supplementation with coenzyme Q10, vitamin B1, and amino acids, which target the pathways of cardiac metabolism and may aid in the restoration of cardiac function. This case series demonstrates that normalization of cardiac function is possible with standard therapy and the importance of assessing myocardial viability in all patients with heart failure and reduced ejection fraction. Given the unique metabolic needs of the failing heart, the role of micronutrients in combination with standard therapy warrants further investigation.