Research Spotlight

Peters, Y., A. Al-Kaabi, N. J. Shaheen, A. Chak, A. Blum, R. F. Souza, M. Di Pietro, P. G. Iyer, O. Pech, R. C. Fitzgerald and P. D. Siersema (2019). “Barrett oesophagus.” Nat Rev Dis Primers 5(1): 35.

Full text of this article.

Barrett oesophagus (BE), the only known histological precursor of oesophageal adenocarcinoma (EAC), is a condition in which the squamous epithelium of the oesophagus is replaced by columnar epithelium as an adaptive response to gastro-oesophageal reflux. EAC has one of the fastest rising incidences of cancers in Western countries and has a dismal prognosis. BE is usually detected during endoscopic examination, and diagnosis is confirmed by the histological presence of intestinal metaplasia. Advances in genomics and transcriptomics have improved our understanding of the pathogenesis and malignant progression of intestinal metaplasia. As the majority of EAC cases are diagnosed in individuals without a known history of BE, screening for BE could potentially decrease disease-related mortality. Owing to the pre-malignant nature of BE, endoscopic surveillance of patients with BE is imperative for early detection and treatment of dysplasia to prevent further progression to invasive EAC. Developments in endoscopic therapy have resulted in a major shift in the treatment of patients with BE who have dysplasia or early EAC, from surgical resection to endoscopic resection and ablation. In addition to symptom control by optimization of lifestyle and pharmacological therapy with proton pump inhibitors, chemopreventive strategies based on NSAIDs and statins are currently being investigated for BE management.

Packer, M. (2019). “Major reduction in the risk of sudden cardiac death in patients with chronic heart failure with the use of drug and device combinations that favourably affect left ventricular structure.” Eur J Heart Fail May 29. [Epub ahead of print].

Full text of this article.

In 30–50% of patients with chronic heart failure, the mode of demise is sudden cardiac death. Because many (but not all) of these events are related to a sustained ventricular tachyarrhythmia, implantable cardioverter‐defibrillators (ICD) have been recommended to prevent these serious rhythm disturbances, and their use reduces the risk of sudden death by 50–70%, depending on the patient population studied. However, these devices address the lethality of a life‐threatening arrhythmia; they do not interfere with the critical pathophysiological mechanisms that cause the structural remodelling that is responsible for disease progression. Neurohormonal antagonists and cardiac resynchronization can reduce the risk of heart failure hospitalizations and pump failure deaths, but the effect of these interventions on sudden death is not well appreciated, especially the potential for a cumulative benefit when they are used in combination . . . Drugs and devices that have favourable effects on ventricular structure and geometry have remarkable effects to reduce the risk of sudden death, and the available evidence demonstrates the incremental value of each intervention in patients already receiving treatments that were previously shown in earlier trials to reduce the risk of an abrupt unexpected demise. Because of the sequencing of these studies, it is possible to estimate the cumulative advantages of combination therapy on the risk of sudden death in patients with heart failure. In a hypothetical cohort of 1000 patients with chronic heart failure and a reduced ejection fraction, ≈400 patients would be expected to die suddenly in the absence of modern‐day treatment with neurohormonal antagonists. If implantation of an ICD reduced the risk of sudden death by 60–70%, i.e. 120–160 patients would die suddenly. However, if an ICD were not implanted, the use of beta‐blockers in patients receiving an ACE inhibitor would be expected to decrease the risk of abrupt circulatory collapse by ≈40%, i.e. 240 patients would die suddenly. If these patients were also treated with a mineralocorticoid receptor antagonist and a neprilysin inhibitor, the risk of sudden death would be progressively reduced by an additional 35%, and then by 20%, thereby lowering the number of sudden deaths to 156 (with the addition of a mineralocorticoid receptor antagonist), and then to 125 patients (with the addition of a neprilysin inhibitor). (Excerpts from text, p. 1-3; no abstract available.)

Packer, M. (2019). “Effect of catheter ablation on pre-existing abnormalities of left atrial systolic, diastolic, and neurohormonal functions in patients with chronic heart failure and atrial fibrillation.” Eur Heart J May 12. [Epub ahead of print].

Full text of this article.

The critical role of the left atrium (LA) in cardiovascular homoeostasis is mediated by its reservoir, conduit, systolic, and neurohormonal functions. Atrial fibrillation is generally a reflection of underlying disease of the LA, especially in patients with heart failure. Disease-related LA remodelling leads to a decline in both atrial contractility and distensibility along with an impairment in the control of neurohormonal systems that regulate intravascular volume. Catheter ablation can lead to further injury to the atrial myocardium, as evidenced by post-procedural troponin release and tissue oedema. The cardiomyocyte loss leads to replacement fibrosis, which may affect up to 30-35% of the LA wall. These alterations further impair atrial force generation and neurohormonal functions; the additional loss of atrial distensibility can lead to a ‘stiff LA syndrome’, and the fibrotic response predisposes to recurrence of the atrial arrhythmia. Although it intends to restore LA systole, catheter ablation often decreases the chamber’s transport functions. This is particularly likely in patients with long-standing atrial fibrillation and pre-existing LA fibrosis, especially those with increased epicardial adipose tissue (e.g. patients with obesity, diabetes and/or heart failure with a preserved ejection fraction). Although the fibrotic LA in these individuals is an ideal substrate for the development of atrial fibrillation, it may be a suboptimal substrate for catheter ablation. Such patients are not likely to experience long-term restoration of sinus rhythm, and catheter ablation has the potential to worsen their haemodynamic and clinical status. Further studies in this vulnerable group of patients are needed.

Packer, M. (2019). “Critical Role of the Epicardium in Mediating Cardiac Inflammation and Fibrosis in Patients With Type 2 Diabetes.” Diabetes Obes Metab May 30. [Epub ahead of print].

Full text of this article.

The metabolic derangements in type 2 diabetes afflict nearly every organ in the body. Although physicians have traditionally focused on the effects on the retina, kidneys and peripheral nerves, the most serious consequences of the disease are seen in the cardiovascular system.

Packer, M. (2019). “Compelling First-Line Drug and Device Therapies for the Prevention of Sudden Death in Patients With Chronic Heart Failure and a Reduced Ejection Fraction Who Are Candidates for an Implantable Cardioverter-Defibrillator.” Circ Arrhythm Electrophysiol Jun; 12(6): e007430. Epub 2019 Jun 4.

Full text of this article.

Sudden unexpected death is a devastating event in patients with chronic heart failure and a reduced ejection fraction, accounting for 30% to 50% of all deaths in this disorder. In 50% to 70% of sudden deaths, the abrupt circulatory collapse results from a sustained ventricular tachyarrhythmia, typically in a patient who had not experienced the rhythm disturbance previously. However, in the remaining 30% to 50%, sudden death appears to result from acute mechanical failure of the left ventricle, which is reflected on the surface ECG as asystole, bradyarrhythmia, or electromechanical dissociation. The former event (ie, sustained ventricular tachycardia or fibrillation) is typically seen in patients with mild symptoms and underlying coronary artery disease, and once detected, can be treated with an implantable cardioverter-defibrillator (ICD). In contrast, the latter event is primarily hemodynamic rather than electrical in nature, is seen disproportionately in those with advancing symptoms or with a nonischemic cardiomyopathy, and is not responsive to an ICD. The existence of 2 distinct pathways for sudden cardiac death explains why ICDs do not prevent all episodes of sudden death in patients with chronic heart failure. Depending on the population studied, ICDs reduce the risk of an abrupt demise by 30% to 70%. The effect of ICDs on all-cause mortality depends on the prevalence of sudden deaths in the population. In patients with class III–IV symptoms or meaningful comorbidities, sudden death represents a smaller proportion of all deaths, and ICDs do not significantly decrease all-cause mortality. Whether the terminal event is primarily electrical or mechanical in nature, the common underlying substrate for sudden cardiac death is a severely remodeled left ventricle, which is markedly dilated, replete with interstitial fibrosis, and distended by elevated cardiac filling pressures. The worsening of remodeling not only contributes to repeated hospitalizations for heart failure and death from circulatory insufficiency, but it also creates the structural and pathophysiological prerequisites for acute electrical and mechanical instability. (Excerpt from text, p. 1; no abstract available.)