The transition from juvenile to adult life is accompanied by programmed remodeling in many tissues and organs, which is key for organisms to adapt to the demand of the environment. Here we report a novel regulated alternative splicing program that is crucial for postnatnal heart remodeling in the mouse. We identify the essential splicing factor ASF/SF2 as a key component of the program, regulating a restricted set of tissue-specific alternative splicing events during heart remodeling. Cardiomyocytes deficient in ASF/SF2 display an unexpected hypercontraction phenotype due to a defect in postnatal splicing switch of the Ca(2+)/calmodulin-dependent kinase IIdelta (CaMKIIdelta) transcript. This failure results in mistargeting of the kinase to sarcolemmal membranes, causing severe excitation-contraction coupling defects. Our results validate ASF/SF2 as a fundamental splicing regulator in the reprogramming pathway and reveal the central contribution of ASF/SF2-regulated CaMKIIdelta alternative splicing to functional remodeling in developing heart.

Cypher is a member of a recently emerging family of proteins containing a PDZ domain at their NH2 terminus and one or three LIM domains at their COOH terminus. Cypher knockout mice display a severe form of congenital myopathy and die postnatally from functional failure in multiple striated muscles. Examination of striated muscle from the mutants revealed that Cypher is not required for sarcomerogenesis or Z-line assembly, but rather is required for maintenance of the Z-line during muscle function. In vitro studies demonstrated that individual domains within Cypher localize independently to the Z-line via interactions with α-actinin or other Z-line components. These results suggest that Cypher functions as a linker-strut to maintain cytoskeletal structure during contraction.

The response of cardiomyocytes to biomechanical stress can determine the pathophysiology of hypertrophic cardiac disease, and targeting the pathways regulating these responses is a therapeutic goal. However, little is known about how biomechanical stress is sensed by the cardiomyocyte sarcomere to transduce intracellular hypertrophic signals or how the dysfunction of these pathways may lead to disease. Here, we found that fourand-a-half LIM domains 1 (FHL1) is part of a complex within the cardiomyocyte sarcomere that senses the biomechanical stress-induced responses important for cardiac hypertrophy. Mice lacking Fhl1 displayed a blunted hypertrophic response and a beneficial functional response to pressure overload induced by transverse aortic constriction. A link to the Gαq (Gq) signaling pathway was also observed, as Fhl1 deficiency prevented the cardiomyopathy observed in Gq transgenic mice. Mechanistic studies demonstrated that FHL1 plays an important role in the mechanism of pathological hypertrophy by sensing biomechanical stress responses via the N2B stretch sensor domain of titin and initiating changes in the titin-and MAPK-mediated responses important for sarcomere extensibility and intracellular signaling. These studies shed light on the physiological regulation of the sarcomere in response to hypertrophic stress.

It has been almost 5 years since the publication of the 2010 hypertension guidelines of the Taiwan Society of Cardiology (TSOC). There is new evidence regarding the management of hypertension, including randomized controlled trials, non-randomized trials, post-hoc analyses, subgroup analyses, retrospective studies, cohort studies, and registries. More recently, the European Society of Hypertension (ESH) and the European Society of Cardiology (ESC) published joint hypertension guidelines in 2013. The panel members who were appointed to the Eighth Joint National Committee (JNC) also published the 2014 JNC report. Blood pressure (BP) targets have been changed; in particular, such targets have been loosened in high risk patients. The Executive Board members of TSOC and the Taiwan Hypertension Society (THS) aimed to review updated information about the management of hypertension to publish an updated hypertension guideline in Taiwan. We recognized that hypertension is the most important risk factor for global disease burden. Management of hypertension is especially important in Asia where the prevalence rate grows faster than other parts of the world. In most countries in East Asia, stroke surpassed coronary heart disease (CHD) in causing premature death. A diagnostic algorithm was proposed, emphasizing the importance of home BP monitoring and ambulatory BP monitoring for better detection of night time hypertension, early morning hypertension, white-coat hypertension, and masked hypertension. We disagreed with the ESH/ESH joint hypertension guidelines suggestion to loosen BP targets to <140/90 mmHg for all patients. We strongly disagree with the suggestion by the 2014 JNC report to raise the BP target to <150/90 mmHg for patients between 60-80 years of age. For patients with diabetes, CHD, chronic kidney disease who have proteinuria, and those who are receiving antithrombotic therapy for stroke prevention, we propose BP targets of <130/80 mmHg in our guidelines. BP targets are <140/90 mmHg for all other patient groups, except for patients ≥80 years of age in whom a BP target of <150/90 mmHg would be optimal. For the management of hypertension, we proposed a treatment algorithm, starting with life style modification (LSM) including S-ABCDE (Sodium restriction, Alcohol limitation, Body weight reduction, Cigarette smoke cessation, Diet adaptation, and Exercise adoption). We emphasized a low-salt strategy instead of a no-salt strategy, and that excessively aggressive sodium restriction to <2.0 gram/day may be harmful. When drug therapy is considered, a strategy called "PROCEED" was suggested (Previous experience, Risk factors, Organ damage, Contraindications or unfavorable conditions, Expert's or doctor's judgment, Expenses or cost, and Delivery and compliance issue). To predict drug effects in lowering BP, we proposed the "Rule of 10" and "Rule of 5". With a standard dose of any one of the 5 major classes of anti-hypertensive agents, one can anticipate approximately a 10-mmHg decrease in systolic BP (SBP) (Rule of 10) an...