Richard Sheppard

Fibrosis in heart disease: understanding the role of transforming growth factor-β1 in cardiomyopathy, valvular disease and arrhythmia

The importance of fibrosis in organ pathology and dysfunction appears to be increasingly relevant to a variety of distinct diseases. In particular, a number of different cardiac pathologies seem to be caused by a common fibrotic process. Within the heart, this fibrosis is thought to be partially mediated by transforming growth factor‐β1 (TGF‐β1), a potent stimulator of collagen‐producing cardiac fibroblasts. Previously, TGF‐β1 had been implicated solely as a modulator of the myocardial remodelling seen after infarction. However, recent studies indicate that dilated, ischaemic and hypertrophic cardiomyopathies are all associated with raised levels of TGF‐β1. In fact, the pathogenic effects of TGF‐β1 have now been suggested to play a major role in valvular disease and arrhythmia, particularly atrial fibrillation. Thus far, medical therapy targeting TGF‐β1 has shown promise in a multitude of heart diseases. These therapies provide great hope, not only for treatment of symptoms but also for prevention of cardiac pathology as well. As is stated in the introduction, most reviews have focused on the effects of cytokines in remodelling after myocardial infarction. This article attempts to underline the significance of TGF‐β1 not only in the post‐ischaemic setting, but also in dilated and hypertrophic cardiomyopathies, valvular diseases and arrhythmias (focusing on atrial fibrillation). It also aims to show that TGF‐β1 is an appropriate target for therapy in a variety of cardiovascular diseases.

Shared Genetic Predisposition in Peripartum and Dilated Cardiomyopathies

Background Peripartum cardiomyopathy shares some clinical features with idiopathic dilated cardiomyopathy, a disorder caused by mutations in more than 40 genes, including TTN, which encodes the sarcomere protein titin. Methods In 172 women with peripartum cardiomyopathy, we sequenced 43 genes with variants that have been associated with dilated cardiomyopathy. We compared the prevalence of different variant types (nonsense, frameshift, and splicing) in these women with the prevalence of such variants in persons with dilated cardiomyopathy and with population controls. Results We identified 26 distinct, rare truncating variants in eight genes among women with peripartum cardiomyopathy. The prevalence of truncating variants (26 in 172 [15%]) was significantly higher than that in a reference population of 60,706 persons (4.7%, P=1.3×10(-7)) but was similar to that in a cohort of patients with dilated cardiomyopathy (55 of 332 patients [17%], P=0.81). Two thirds of identified truncating variants were in TTN, as seen in 10% of the patients and in 1.4% of the reference population (P=2.7×10(-10)); almost all TTN variants were located in the titin A-band. Seven of the TTN truncating variants were previously reported in patients with idiopathic dilated cardiomyopathy. In a clinically well-characterized cohort of 83 women with peripartum cardiomyopathy, the presence of TTN truncating variants was significantly correlated with a lower ejection fraction at 1-year follow-up (P=0.005). Conclusions The distribution of truncating variants in a large series of women with peripartum cardiomyopathy was remarkably similar to that found in patients with idiopathic dilated cardiomyopathy. TTN truncating variants were the most prevalent genetic predisposition in each disorder.

Sex differences in the effectiveness of angiotensin receptor blockers and angiotensin converting enzyme inhibitors in patients with congestive heart failure — A population study

Angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) have been shown to improve survival in patients with congestive heart failure (CHF). We wish to determine whether there are sex‐related differences in the optimal treatment of congestive heart failure.

Intracoronary Radiotherapy for Restenosis

On November 3, 2000, the Food and Drug Administration (FDA) granted approval for two devices that deliver intracoronary radiotherapy for in-stent restenosis. Given this approval, it is possible tha...

Cardiotoxicity of Cancer Therapeutics: Current Issues in Screening, Prevention, and Therapy

In the context of modern cancer chemotherapeutics, cancer survivors are living longer and being exposed to potential comorbidities related to non-cancer side effects of such treatments. With close monitoring of cancer patients receiving potentially cardiotoxic medical therapies, oncologists, and cardiologists alike are identifying patients in both clinical and subclinical phases of cardiovascular disease related to such chemotherapies. Specifically, cardiotoxicity at the level of the myocardium and potential for the development of heart failure are becoming a growing concern with increasing survival of cancer patients. Traditional chemotherapeutic agents used commonly in the treatment of breast cancer and hematologic malignancies, such as anthracyclines and HER-2 antagonists, are well known to be associated with cardiovascular sequelae. Patients often present without symptoms and an abnormal cardiac imaging study performed as part of routine evaluation of patients receiving cardiotoxic therapies. Additionally, patients can present with signs and symptoms of cardiovascular disease months to years after receiving the chemotherapies. As the understanding of the physiology underlying the various cancers has grown, therapies have been developed that target specific molecules that represent key aspects of physiologic pathways responsible for cancer growth. Inhibition of these pathways, such as those involving tyrosine kinases, has lead to the potential for cardiotoxicity as well. In view of the potential cardiotoxicity of specific chemotherapies, there is a growing interest in identifying patients who are at risk of cardiotoxicity prior to becoming symptomatic or developing cardiotoxicity that may limit the use of potentially life-saving chemotherapy agents. Serological markers and novel cardiac imaging techniques have become the source of many investigations with the goal of screening patients for pre-clinical cardiotoxicity. Additionally, studies have been performed.

Heart rate recovery – a potential marker of clinical outcomes in heart failure patients receiving beta-blocker therapy

BACKGROUND Heart rate recovery (HRR) within the first few minutes of graded exercise has been associated with impaired clinical outcomes in patients being evaluated for coronary artery disease. HRR is abnormal in patients with heart failure (HF), but has not been associated with clinical outcomes in these patients. The objective of the present study was to determine whether HRR following cardiopulmonary exercise testing (CPET) correlates with peak oxygen consumption (VO(2)), and whether it impacts clinical outcomes, including HF hospitalizations and total mortality, or the need for cardiac transplantation. METHODS CPET was performed in 78 patients referred to the Montreal Heart Institute (Montreal, Quebec) with congestive HF between January 2000 and December 2002. All patients had New York Heart Association class II or III HF with a left ventricular ejection fraction of 45% or lower. Mean (+/- SD) age was 53+/-11 years and left ventricular ejection fraction was 27+/-9%. Forty-four per cent had ischemic cardiomyopathy, 88% received beta-blockers and 79% received angiotensin-converting enzyme inhibitors. HRR was defined as the difference from peak exercise HR to HR measured at specific time intervals. HRR was calculated 30 s, 60 s, 90 s and 120 s after exercise. RESULTS Mean peak VO(2) was 18.0+/-5.3 mL/kg/min, resting HR was 74+/-13 beats/min and peak HR was 119+/-22 beats/min. HRR measured was 10+/-9 beats/min after 30 s, 20+/-12 beats/min after 60 s, 25+/-15 beats/min after 90 s and 30+/-13 beats/min after 120 s. At 90 s, patients with an HRR below 24 beats/min were more likely to have an HF hospitalization at five-year follow-up (eight hospitalizations [22.2%] versus two hospitalizations [2.7%]; P=0.0134). There was a correlation between peak VO(2) and HRR 90 s and 120 s after completion of the exercise test (r=0.40 after 90 s, P=0.001, and r=0.41 after 120 s, P=0.008). CONCLUSIONS In patients with HF, blunted HRR 90 s and 120 s after CPET correlate with peak VO(2) and are associated with increased risk of worsening HF. HRR is easily measured and a useful marker for morbidity in patients with HF.

Angiotensin II Receptor Blockers for the Treatment of Heart Failure: A Class Effect?

Study Objective. To examine the class effect of angiotensin II receptor blockers (ARBs) on mortality in patients with heart failure who were aged 65 years or older.

Right Ventricular Function in Peripartum Cardiomyopathy at Presentation Is Associated With Subsequent Left Ventricular Recovery and Clinical Outcomes

Background—Peripartum cardiomyopathy has variable disease progression and left ventricular (LV) recovery. We hypothesized that baseline right ventricular (RV) size and function are associated with LV recovery and outcome. Methods and Results—Investigations of Pregnancy-Associated Cardiomyopathy was a prospective 30-center study of 100 peripartum cardiomyopathy women with LV ejection fraction (LVEF) <45% within 13 weeks after delivery. Baseline RV function was assessed by echocardiographic end-diastolic area, end-systolic area, fractional area change, tricuspid annular plane excursion, and RV speckle-tracking longitudinal strain. LV recovery was defined as LVEF of ≥50% at 1 year, persistent severe LV dysfunction as LVEF of ⩽35%, and major events as death, transplant, or LV assist device implantation. RV measurements were feasible for 90 of the 96 patients (94%) with echocardiograms available. Mean baseline LVEF was 36±9%. RV fractional area change was <35% in 38% of patients. Of 84 patients with 1-year follow-up data, 63 (75%) had LV recovery and 11 (13%) had LVEF of ⩽35% or a major event (4 LV assist devices and 2 deaths). Tricuspid annular plane excursion and RV strain did not predict outcome. Baseline RV fractional area change by multivariable analysis was independently associated with subsequent LV recovery and clinical outcome. Conclusions—Peripartum cardiomyopathy patients had a high incidence of LV recovery, but a significant minority had persistent LV dysfunction or a major clinical event by 1 year. RV function per echocardiographic fractional area change at presentation was associated with subsequent LV recovery and clinical outcomes and thus is prognostically important.

Intracoronary brachytherapy for the prevention of restenosis after percutaneous coronary revascularization.

PURPOSE The purpose of this article is to review the current literature pertaining to intracoronary brachytherapy for the prevention of restenosis after percutaneous coronary revascularization (PCR). METHODS English-language articles were identified through a MEDLINE search (January 1984 to January 2003) using the keywords brachytherapy, radioactive stents, and coronary arteries. In addition, pertinent reference citations from relevant articles were reviewed. RESULTS Restenosis after PCR is a complex process, thought to be due to a combination of vessel wall remodeling and neointimal proliferation. To date, catheter-based delivery of intracoronary brachytherapy has been found to prevent vessel wall remodeling and causes a reduction in the proliferation of the neointima. Neointimal proliferation, as measured by mean neointimal area, was reduced in all animal studies (range 26%-91%). In contrast, animal studies examining radioactive stents demonstrated an increase in neointimal proliferation, suggesting that they may not be helpful at preventing post-PCR restenosis. All human studies using catheter-based intracoronary brachytherapy for in-stent restenosis have employed either beta (beta) or gamma (gamma) radiation sources with variable doses of radiation (range 7-56 Grays [Gy]). Restenosis occurred in 12% to 40% of patients in nonrandomized studies, and clinical events occurred in 13% to 50% of patients. To date, there have been 7 published randomized trials in humans comparing catheter-based intracoronary brachytherapy to placebo, with a total of 1047 patients. The dose of radiation in the trials ranged from 14 Gy to 30 Gy. During follow-up, 8% to 33% of patients who received brachytherapy had restenosis versus 39% to 64% of patients receiving placebo. Clinical events occurred in 19% to 50% among patients who received brachytherapy versus 29% to 79% among patients receiving placebo. The majority of human studies examining radioactive stents do not demonstrate a reduction in restenosis in patients post-PCR. There are no randomized trials examining radioactive stents in humans. CONCLUSION Nonrandomized studies of radioactive stents suggest they are not effective at preventing in-stent restenosis. In contrast, data from animal and human studies suggest that catheter-based intracoronary brachytherapy can prevent in-stent restenosis and reduce clinical events post-PCR.

Access to heart failure care post emergency department visit: Do we meet established benchmarks and does it matter?

BACKGROUND The Canadian Cardiology Society recommends that patients should be seen within 2 weeks after an emergency department (ED) visit for heart failure (HF). We sought to investigate whether patients who had an ED visit for HF subsequently consult a physician within the current established benchmark, to explore factors related to physician consultation, and to examine whether delay in consultation is associated with adverse events (AEs) (death, hospitalization, or repeat ED visit). METHODS Patients were recruited by nurses at 8 hospital EDs in Québec, Canada, and interviewed by telephone within 6 weeks of discharge and subsequently at 3 and 6 months. Clinical variables were extracted from medical charts by nurses. We used Cox regression in the analysis. RESULTS We enrolled 410 patients (mean age 74.9 ± 11.1 years, 53% males) with a confirmed primary diagnosis of HF. Only 30% consulted with a physician within 2 weeks post-ED visit. By 4 weeks, 51% consulted a physician. Over the 6-month follow-up, 26% returned to the ED, 25% were hospitalized, and 9% died. Patients who were followed up within 4 weeks were more likely to be older and have higher education and a worse quality of life. Patients who consulted a physician within 4 weeks of ED discharge had a lower risk of AEs (hazard ratio 0.59, 95% CI 0.35-0.99). CONCLUSION Prompt follow-up post-ED visit for HF is associated with lower risk for major AEs. Therefore, adherence to current HF guideline benchmarks for timely follow-up post-ED visit is crucial.