Heart disease remains the most common cause of death and disability in our society. However, the face of this disease has evolved considerably in the decades since cardiovascular scientists began to understand the cellular and molecular mechanisms of its pathophysiology. Today, nearly 90% of patients hospitalized for a heart attack not only survive but also return to their normal activities and work within weeks, if not sooner — a vast improvement in outcome as compared with decades earlier. However, the evolution in the treatment of acute cardiovascular disease has also been paralleled by an increase in the number of patients with chronic debilitation due to heart failure. Despite advances in our understanding of the neurohormonal basis of heart failure, current therapies for heart failure are limited, and the need for additional therapies remains great. Protein homeostasis plays a role in the development of numerous disorders. Misfolded proteins are central in the pathophysiology of neurodegenerative diseases such as Huntington’s disease, Parkinson’s disease, and Alzheimer’s disease. In the past several years, misfolded proteins have been found to play a role in the pathophysiology of common human cardiac diseases such as pathologic cardiac hypertrophy and dilated and ischemic cardiomyopathies, leading to the suggestion that protein misfolding is a key contributor to the progression of heart failure. In this review, we explore the contribution of protein misfolding to the pathophysiology of cardiac disease, describing why these proteins become misfolded and how the innate systems that usually dispose of them break down. We then discuss how the knowledge obtained from studying protein misfolding in other diseases, such as Alzheimer’s disease, may aid us in understanding  the pathophysiological mechanisms of cardiac diseases and developing new treatments that focus on preventing or reversing protein misfolding in the heart.


Monte S. Willis & Cam Patterson
New England Journal of Medicine, Jan 31, 2013 

OBJECTIVE: To investigate the long term effect of hormone replacement therapy on cardiovascular outcomes in recently postmenopausal women.
PARTICIPANTS: 1006 healthy women aged 45-58 who were recently postmenopausal or had perimenopausal symptoms in combination with recorded postmenopausal serum follicle stimulating hormone values. 502 women were randomly allocated to receive hormone replacement therapy and 504 to receive no treatment (control). Women who had undergone hysterectomy were included if they were aged 45-52 and had recorded values for postmenopausal serum follicle stimulating hormone.
INTERVENTIONS: In the treatment group, women with an intact uterus were treated with triphasic estradiol and norethisterone acetate and women who had undergone hysterectomy received 2 mg estradiol a day. Intervention was stopped after about 11 years owing to adverse reports from other trials, but participants were followed for death, cardiovascular disease, and cancer for up to 16 years. Sensitivity analyses were carried out on women who took more than 80% of the prescribed treatment for five years.
MAIN OUTCOME MEASURE: The primary endpoint was a composite of death, admission to hospital for heart failure, and myocardial infarction.
RESULTS: At inclusion the women on average were aged 50 and had been postmenopausal for seven months. After 10 years of intervention, 16 women in the treatment group experienced the primary composite endpoint compared with 33 in the control group (hazard ratio 0.48, 95% confidence interval 0.26 to 0.87; P=0.015) and 15 died compared with 26 (0.57, 0.30 to 1.08; P=0.084). The reduction in cardiovascular events was not associated with an increase in any cancer (36 in treated group v 39 in control group, 0.92, 0.58 to 1.45; P=0.71) or in breast cancer (10 in treated group v 17 in control group, 0.58, 0.27 to 1.27; P=0.17). The hazard ratio for deep vein thrombosis (2 in treated group v 1 in control group) was 2.01 (0.18 to 22.16) and for stroke (11 in treated group v 14 in control group) was 0.77 (0.35 to 1.70). After 16 years the reduction in the primary composite outcome was still present and not associated with an increase in any cancer.

CONCLUSIONS: After 10 years of randomised treatment, women receiving hormone replacement therapy early after menopause had a significantly reduced risk of mortality, heart failure, or myocardial infarction, without any apparent increase in risk of cancer, venous thromboembolism, or stroke.

Schierbeck LL, Rejnmark L et al. 
British Medical Journal, 2012 Oct 9

The HDL hypothesis has suffered damage in the past few years. Clinical trials have shown that raising HDL cholesterol levels does not improve cardiovascular disease (CVD) outcomes. In addition, Mendelian randomization studies have shown that DNA variants that alter HDL cholesterol levels in populations are unrelated to incident CVD events. Balancing this deluge of negative data are substantial basic science data supporting the concept that raising HDL cholesterol levels reduces CVD risk. Also, functionally relevant HDL subfractions might be more important determinants of risk than overall HDL cholesterol levels. But, while wobbly, the HDL hypothesis is still standing, seemingly too big to fail owing to past intellectual, economic and psychological investments in the idea.

Dominic S. Ng, Norman C. W. Wong & Robert A. Hegele
Nature Reviews Endocrinology, 2012