Recent updates on therapeutic targeting of lipoprotein(a) with RNA interference.

PURPOSE OF REVIEW: RNA interference (RNAi)-based therapies that target specific gene products have impacted clinical medicine with 16 FDA approved drugs. RNAi therapy focused on reducing plasma lipoprotein(a) [Lp(a)] levels are under evaluation. RECENT FINDINGS: RNAi-based therapies have made significant progress over the past 2 decades and currently consist of antisense oligonucleotides (ASO) and small interfering RNA (siRNA). Chemical modification of the RNA backbone and conjugation of siRNA enables efficient gene silencing in hepatocytes allowing development of effective cholesterol lowering therapies. Multiple lines of evidence suggest a causative role for Lp(a) in atherosclerotic cardiovascular disease, and recent analyses indicate that Lp(a) is more atherogenic than low density lipoprotein- cholesterol (LDL-C). These findings have led to the 'Lp(a) hypothesis' that lowering Lp(a) may significantly improve cardiovascular outcomes. Four RNAi-based drugs have completed early phase clinical trials demonstrating >80% reduction in plasma Lp(a) levels. Phase 3 clinical trials examining clinical outcomes with these agents are currently underway. SUMMARY: Currently, four RNAi-based drugs have been shown to be effective in significantly lowering plasma Lp(a) levels. Clinical outcome data from phase 3 trials will evaluate the Lp(a) hypothesis.

Food for Thought or Feeding a Dogma? Diet and Coronary Artery Disease: a Clinician's Perspective.

PURPOSE OF REVIEW: To provide an overview of nutrition studies evaluating the association of dietary saturated fat and meat intake with the development of coronary artery disease (CAD) and discuss implications of recent data. RECENT FINDINGS: Recent studies have led to the re-evaluation of the role of saturated fat in CAD. Randomized controlled trials (RCTs) support Mediterranean diet to reduce cardiovascular risk. Recent data revealed significant association of intake of meat or poultry with increased risk, but fish consumption was associated with lower risk of incident CAD. In this review, we provide a brief overview of the studies and data that have led to the re-evaluation of the link between saturated fat and CAD. Due to conflicting data from long-term prospective cohort studies and significant heterogeneity, associations of unprocessed meat with CAD are less clear compared to the role of processed meat. Pooled data from prospective cohort studies have overcome some of these limitations and show association of both processed and unprocessed meat and poultry intake but not fish consumption with incident CAD. These findings were also validated recently in a large UK Biobank prospective study. While recognizing the limitations of these cohort studies, we discuss relevant landmark RCTs. We finally consider the challenges with RCTs in nutrition research to improve the quality of evidence and need for evidence-based dietary guidelines with respect to saturated fat intake from a clinical perspective.

Femoral arterial closure using ProGlide® is more efficacious and cost-effective when ambulating early following cardiac catheterization.

OBJECTIVE: This was a prospective, single-center study evaluating the efficacy and cost-effectiveness of early ambulation (within 30 min) following femoral artery closure with the ProGlide® suture-mediated vascular closure device (PD) in patients undergoing diagnostic cardiac catheterization compared with manual compression. BACKGROUND: It is unclear whether early ambulation with ProGlide is safe or is associated with patient satisfaction and cost savings as compared with manual compression (MC). METHODS AND RESULTS: Inclusion criteria were met in 170 patients (85 PD and 85 MC patients). Patients ambulated 20 ft. within 30 min (PD) or after the requisite 4 h recumbent time (MC) if feasible. Primary endpoint was time-to-ambulation (TTA) following device closure. We also directly compared the safety of closure, times-to-hemostasis (TTH), -ambulation (TTA) and -discharge (TTD) with MC and, using a fully allocated cost model, performed cost analysis for both strategies. Multivariate analysis was used to determine predictors of patient satisfaction. The primary endpoint of safe, early ambulation was achieved following closure (mean of 27.1 ± 14.9 min; 95% confidence interval [CI] 25.2-30.2). Predictors of patient satisfaction in the PD group were absence of pain during closure, decreased TTA, and drastic reductions in TTD; the latter contributed indirectly to significant cost savings in the PD group (1250.3 ± 146.4 vs. 2248.1 ± 910.2 dollars, respectively; P < 0.001) and incremental cost savings by strategy also favored closure over MC ($84,807). CONCLUSIONS: ProGlide is safe and effective for femoral artery closure in patients who ambulate within 30 min after cardiac catheterization; translating into improved patient satisfaction and substantial cost savings.

The Macklin effect causing a pneumopericardium.

Pleuropericarditis is a common clinical entity that has been reported in association with several diseases. However, pleuropericarditis following blunt thoracic trauma is very rare and difficult to diagnose. Here we present a case of a young man who presented to the emergency department with acute shortness of breath following a motor vehicle accident. He was found to have a pleuro-pericardial communication worsened by barotrauma, resulting in tension pneumopericardium.

Identification of mouse genes with highly specific expression patterns in differentiated intestinal epithelium.

BACKGROUND & AIMS: Few genes that regulate intestinal epithelium development, homeostasis, or function are known. We reasoned that potential candidate regulators of these processes could be identified based on their activation during intestinal epithelium development and their subsequent specific and restricted expression. METHODS: Genes were identified by differential display and microarray analyses, further selected according to sequence and UniGene expression profiles, and analyzed by RNA in situ hybridization of mouse fetal and adult intestines and in intestinal polyp tissue. RESULTS: Five genes with unknown physiological function predominantly or exclusively expressed in the intestinal epithelium were identified. Their expression is activated at distinct times during intestinal development and maturation and is maintained in highly specific, spatially distinct patterns in the adult intestinal epithelium. Two of the genes were up-regulated in intestinal tumors, 1 was down-regulated, and 2 were apparently unaltered. CONCLUSIONS: Based on sequence and expression, the identified genes represent good candidates for regulators of intestinal epithelium integrity or function. Their expression patterns suggest a morphologically not obvious molecular regionalization of the intestinal epithelium along the crypt villus axis. This approach should be an efficient means to identify novel genes required for intestinal epithelium homeostasis and function.