Early identification of asymptomatic subjects at increased risk of heart failure and cardiovascular events: progress and future directions.

Increasing evidence for a latent, preclinical phase of cardiac pathology prior to the development of symptomatic heart failure has fuelled interest in the potential of developing a screening program for early disease detection and intervention. Cardiac biomarkers have shown promise in identifying subjects with significant left ventricular dysfunction and more recently to assist in cardiovascular risk stratification. However, a number of questions remain regarding the use of these biomarkers for screening purposes. In particular, appropriate cut-off levels and adjustment for individual patient characteristics still need to be established and further cost-effectiveness studies are required before screening programs can be undertaken. Given the enormous and increasing burden of cardiac failure worldwide, the potential of these biomarkers to identify those at greatest risk of the condition, either alone or as part of a hybrid screening strategy is of great interest to the cardiology community. The aim of this review is to outline evidence behind the argument for screening, discuss the remaining barriers to its development and implementation and highlight potential areas for future research.

Most individuals with treated blood pressures above target receive only one or two antihypertensive drug classes.

BACKGROUND: A significant proportion of individuals taking antihypertensive therapies fail to achieve blood pressures <140/90 mmHg. In order to develop strategies for improved treatment of blood pressure, we examined the association of blood pressure control with antihypertensive therapies and clinical and lifestyle factors in a cohort of adults at increased cardiovascular risk. METHODS: A cross-sectional study of 3994 adults from Melbourne and Shepparton, Australia enrolled in the SCReening Evaluation of the Evolution of New Heart Failure (SCREEN-HF) study. Inclusion criteria were age ≥60 years with one or more of self-reported ischaemic or other heart disease, atrial fibrillation, cerebrovascular disease, renal impairment or treatment for hypertension or diabetes for ≥2 years. Exclusion criteria were known heart failure or cardiac abnormality on echocardiography or other imaging. The main outcome measures were the proportion of participants receiving antihypertensive therapy with blood pressures ≥140/90 mmHg and the association of blood pressure control with antihypertensive therapies and clinical and lifestyle factors. RESULTS: Of 3623 participants (1975 men and 1648 women) receiving antihypertensive therapy, 1867 (52%) had blood pressures ≥140/90 mmHg. Of these 1867 participants, 1483 (79%) were receiving only one or two antihypertensive drug classes. Blood pressures ≥140/90 mmHg were associated with increased age, male sex, waist circumference and log amino-terminal-pro-B-type natriuretic peptide levels. CONCLUSIONS: Most individuals with treated blood pressures above target receive only one or two antihypertensive drug classes. Prescribing additional antihypertensive drug classes and lifestyle modification may improve blood pressure control in this population of individuals at increased cardiovascular risk.

Large left ventricular metastasis causing left ventricular outflow tract obstruction and haemolysis.

Although post-mortem studies would suggest that cardiac metastases occur frequently, many of these metastases remain clinically silent. However, symptomatic lesions may also remain unrecognized due to overshadowing by other symptoms of the primary malignancy. Patients undergoing treatment for cancer are not routinely screened using echocardiography, unless their chemotherapeutic regimen includes cardiotoxic agents. The current era of research and development of targeted biological agents (such as trastuzumab and epidermal growth factor receptor inhibitors) for cancer may lead to prolonged survival of oncology patients. In future, metastases that were once rare may become increasingly recognized as these new treatments augment the natural history of the disease. There have been several case reports of small, asymptomatic left ventricular metastases, but clinically significant ventricular metastases are very rare. There are no reports in the current literature of a symptomatic ventricular metastasis, occurring in the absence of other metastatic disease. We report an unusual case of a large solitary ventricular metastasis, leading to left ventricular outflow tract obstruction and haemodynamic compromise. Echocardiographic imaging led to the diagnosis of a recurrence of soft-tissue fibrosarcoma 9 years after original resection.

The DEAD box helicase, Dhh1p, functions in mRNA decapping and interacts with both the decapping and deadenylase complexes.

A major pathway of mRNA turnover in eukaryotic cells initiates with deadenylation, leading to mRNA decapping and subsequent 5' to 3' exonuclease digestion. We show that a highly conserved member of the DEAD box family of helicases, Dhh1p, stimulates mRNA decapping in yeast. In dhh1delta mutants, mRNAs accumulate as deadenylated, capped species. Dhh1p's effects on decapping only occur on normal messages as nonsense-mediated decay still occurs in dhh1delta mutants. The role of Dhh1p in decapping appears to be direct, as Dhh1p physically interacts with several proteins involved in mRNA decapping including the decapping enzyme Dcp1p, as well as Lsm1p and Pat1p/Mrt1p, which function to enhance the decapping rate. Additional observations suggest Dhh1p functions to coordinate distinct steps in mRNA function and decay. Dhh1p also associates with Pop2p, a subunit of the mRNA deadenylase. In addition, genetic phenotypes suggest that Dhh1p also has a second biological function. Interestingly, Dhh1p homologs in others species function in maternal mRNA storage. This provides a novel link between the mechanisms of decapping and maternal mRNA translational repression.

Multiple portions of poly(A)-binding protein stimulate translation in vivo.

Translational stimulation of mRNAs during early development is often accompanied by increases in poly(A) tail length. Poly(A)-binding protein (PAB) is an evolutionarily conserved protein that binds to the poly(A) tails of eukaryotic mRNAs. We examined PAB's role in living cells, using both Xenopus laevis oocytes and Saccharomyces cerevisiae, by tethering it to the 3'-untranslated region of reporter mRNAs. Tethered PAB stimulates translation in vivo. Neither a poly(A) tail nor PAB's poly(A)-binding activity is required. Multiple domains of PAB act redundantly in oocytes to stimulate translation: the interaction of RNA recognition motifs (RRMs) 1 and 2 with eukaryotic initiation factor-4G correlates with translational stimulation. Interaction with Paip-1 is insufficient for stimulation. RRMs 3 and 4 also stimulate, but bind neither factor. The regions of tethered PAB required in yeast to stimulate translation and stabilize mRNAs differ, implying that the two functions are distinct. Our results establish that oocytes contain the machinery necessary to support PAB-mediated translation and suggest that PAB may be an important participant in translational regulation during early development.

mRNA stabilization by poly(A) binding protein is independent of poly(A) and requires translation.

Translation and mRNA stability are enhanced by the presence of a poly(A) tail. In vivo, the tail interacts with a conserved polypeptide, poly(A) binding protein (Pab1p). To examine Pab1p function in vivo, we have tethered Pab1p to the 3' UTR of reporter mRNAs by fusing it to MS2 coat protein and placing MS2 binding sites in the 3' UTR of the reporter. This strategy allows us to uncouple Pab1p function from its RNA binding activity. We show that mRNAs that lack a poly(A) tail in vivo are stabilized by Pab1p, and that the portions of Pab1p required for stabilization are genetically distinct from those required for poly(A) binding. In addition, stabilization by Pab1p requires ongoing translation of the mRNA. We conclude that the primary, or sole, function of poly(A) with respect to mRNA stability is simply to bring Pab1p to the mRNA, and that mRNA stabilization is an intrinsic property of Pab1p. The approach we describe may be useful in identifying and assaying 3' UTR regulatory proteins, as it uncouples analysis of function from RNA binding.