The role of cardiac troponin T quantity and function in cardiac development and dilated cardiomyopathy

Background: Hypertrophic (HCM) and dilated (DCM) cardiomyopathies results from sarcomeric protein mutations, including cardiac troponin T (cTnT, TNNT2). We determined whether TNNT2 mutations cause cardiomyopathies by altering cTnT function or quantity; whether the severity of DCM is related to the ratio of mutant to wildtype cTnT; whether Ca2+ desensitization occurs in DCM; and whether absence of cTnT impairs early embryonic cardiogenesis. Methods and Findings: We ablated Tnnt2 to produce heterozygous Tnnt2+/ mice, and crossbreeding produced homozygous null Tnnt2-/-embryos. We also generated transgenic mice overexpressing wildtype (TGWT) or DCM mutant (TGK210Δ) Tnnt2. Crossbreeding produced mice lacking one allele of Tnnt2, but carrying wildtype (Tnnt2+/-/TGWT) or mutant (Tnnt2+/-/TGK210Δ) transgenes. Tnnt2+/-mice relative to wildtype had significantly reduced transcript (0.82 ± 0.06 [SD] vs. 1.00 ± 0.12 arbitrary units; p = 0.025), but not protein (1.01 ± 0.20 vs. 1.00 ± 0.13 arbitrary units; p = 0.44). Tnnt2+/-mice had normal hearts (histology, mass, left ventricular end diastolic diameter [LVEDD], fractional shortening [FS]). Moreover, whereas Tnnt2+/-/ TGK210Δ mice had severe DCM, TGK210Δ mice had only mild DCM (FS 18 ± 4 vs. 29 ± 7%; p < 0.01). The difference in severity of DCM may be attributable to a greater ratio of mutant to wildtype Tnnt2 transcript in Tnnt2+/-/TGK210Δ relative to TGK210Δ mice (2.42±0.08, p = 0.03). Tnnt2+/-/TGK210Δ muscle showed Ca2+ desensitization (pCa50 = 5.34 ± 0.08 vs. 5.58 ± 0.03 at sarcomere length 1.9 μm. p<0.01), but no difference in maximum force generation. Day 9.5 Tnnt2-/-embryos had normally looped hearts, but thin ventricular walls, large pericardial effusions, noncontractile hearts, and severely disorganized sarcomeres. Conclusions: Absence of one Tnnt2 allele leads to a mild deficit in transcript but not protein, leading to a normal cardiac phenotype. DCM results from abnormal function of a mutant protein, which is associated with myocyte Ca2+ desensitization. The severity of DCM depends on the ratio of mutant to wildtype Tnnt2 transcript. cTnT is essential for sarcomere formation, but normal embryonic heart looping occurs without contractile activity. © 2008 Ahmad et al

Physical fitness in morbidly obese patients: effect of gastric bypass surgery and exercise training

Background There is a growing consensus that bariatric surgery is currently the most efficacious and long-term treatment for clinically severe obesity. However, it remains to be determined whether poor physical fitness, an important characteristic of these patients, improves as well. The purpose of this pilot study is to investigate the effect of gastric bypass surgery on physical fitness and to determine if an exercise program in the first 4 months is beneficial. Methods Fifteen morbidly obese patients (BMI 43.0 kg/m(2)) were tested before and 4 months after gastric bypass surgery. Eight of them followed a combined endurance and strength training program. Before and after 4 months the operation, anthropometrical characteristics were measured, and an extensive assessment of physical fitness (strength, aerobic, and functional capacity) was performed. Results Large-scale weight loss through gastric bypass surgery results in a decrease in dynamic and static muscle strength and no improvement of aerobic capacity. In contrast, an intensive exercise program could prevent the decrease and even induced an increase in strength of most muscle groups. Together with an improvement in aerobic capacity, functional capacity increased significantly. Both groups evolved equally with regard to body composition (decrease in fat mass and fat-free mass). Conclusions An exercise training program in the first 4 months after bariatric surgery is effective and should be promoted, considering the fact that physical fitness does not improve by weight loss only

[Treatment goals of pulmonary hypertension].

6zet\u2013 Pulmoner hipertansiyon alan\u131ndaki \uf6nemli geli\u15fmelerden sonra, en \uf6nemli g\uf6revlerden biri uzun d\uf6nem sonu\ue7larla ili\u15fkili kinik tedavi hedeflerini belirleme gereksinimidir. Modifiye New York Kalp Cemiyeti fonksiyonel s\u131n\u131f I veya II, 380 metreden fazla 6 dakika y\ufcr\ufcme mesafesine ula\u15fma, ekokardiyografide sa\u11f ventrik\ufcl boyutunun ve fonksiyonunun normalle\u15fmesi, B-tip natri\ufcretik peptit d\ufczeyinin azalmas\u131 ya da normalle\u15fmesi ve sa\u11f atriyal bas\u131nc\u131n\u131n 8 mmHg\u2019den d\ufc\u15f\ufck ve kardiyak indeksin 2,5 L/dk/m2 \u2019den b\ufcy\ufck olmas\u131 g\ufcncel hedeflerdir. Bununla birlikte, egzersiz kapasitesi ve sa\u11f kalp fonksiyonu gibi uzun d\uf6nem sonu\ue7larla daha fazla ili\u15fkili olan parametreleri hedefleyen daha g\ufc\ue7l\ufc ve net s\u131n\u131rlarla \ue7izen \u201ce\u15fi\u11fin\u201d daha y\ufcksek tutulmas\u131 gerekti\u11fi a\ue7\u131k hale gelmektedir; 6zellikle, manyetik rezonans g\uf6r\ufcnt\ufcleme ve BNP/N-terminal pro B tip natri\ufcretik peptit gibi do\u11fru ve noninvaziv olarak sa\u11f ventrik\ufcl fonksiyonunu belirleyen testler, temel belirleyiciler ve tedavi hedefleri olarak hizmet etmek i\ue7in umut verici g\uf6stergeler olarak ortaya \ue7\u131kmaktad\u131r. Ayr\u131ca, sonu\ue7lar \ufczerine odakl\u131 \ue7al\u131\u15fmalar tek ba\u15f\u131na hi\ue7bir testin g\ufcvenilir bir \u15fekilde uzun vadeli prognostik belirte\ue7 olarak kullan\u131lamayaca\u11f\u131n\u131 ve birle\u15fik tedavi hedeflerinin uzun d\uf6nem sonu\ue7lar\u131n\u131n daha iyi \uf6ng\uf6rd\ufcrece\u11fini g\uf6sterdi. Yeniden d\ufczenlenen tedavi hedeflerinin \u15funlar oldu\u11fu ileri s\ufcr\ufclm\ufc\u15ft\ufcr: Modifiye New York Kalp Cemiyeti fonksiyonel s\u131n\u131f I veya II, 65380 ve 440 m aras\u131ndaki 6 dakika y\ufcr\ufcme mesafesi, kardiyopulmoner egzersiz testi-15 ml/d/kg\u2019dan fazla tepe oksijen t\ufcketim \uf6l\ue7\ufcm\ufc ve 45 l/dak\u2019dan az karbondioksit i\ue7in solunum e\u15fde\u11feri, normale yak\u131n BNP de\u11feri, ile normal/normale yak\u131n sa\u11f ventrik\ufcl boyut ve fonksiyonlar\u131n\u131 g\uf6steren ekokardiyografi ve/veya kardiyak manyetik rezonans g\uf6r\ufcnt\ufcleme ve 8 mmHg\u2019den az sa\u11f atriyal bas\u131n\ue7la ve 2,5-3 l/dak/m\ub2\u2019den fazla kardiyak indeksle birlikte sa\u11f ventrik\ufcl fonksiyonunun normalle\u15fti\u11fini g\uf6steren hemodinamik parametreler. (J Am Coll Cardiol 2013;62:D73\u201381)With significant therapeutic advances in the field of pulmonary arterial hypertension, the need to identify clinically relevant treatment goals that correlate with long-term outcome has emerged as 1 of the most critical tasks. Current goals include achieving modified New York Heart Association functional class I or II, 6-min walk distance &gt;380 m, normalization of right ventricular size and function on echocardiograph, a decreasing or normalization of B-type natriuretic peptide (BNP), and hemodynamics with right atrial pressure &lt;8 mm Hg and cardiac index &gt;2.5 L/dk/m2. However, to more effectively prognosticate in the current era of complex treatments, it is becoming clear that the "bar" needs to be set higher, with more robust and clearer delineations aimed at parameters that correlate with long-term outcome; namely, exercise capacity and right heart function. Specifically, tests that accurately and noninvasively determine right ventricular function, such as cardiac magnetic resonance imaging and BNP/N-terminal pro-B-type natriuretic peptide, are emerging as promising indicators to serve as baseline predictors and treatment targets. Furthermore, studies focusing on outcomes have shown that no single test can reliably serve as a long-term prognostic marker and that composite treatment goals are more predictive of long-term outcome. It has been proposed that treatment goals be revised to include the following: modified New York Heart Association functional class I or II, 6-min walk distance 380 to 440 m, cardiopulmonary exercise test-measured peak oxygen consumption &gt;15 ml/min/kg and ventilatory equivalent for carbon dioxide &lt;45 l/min/l/min, BNP level toward "normal," echocardiograph and/or cardiac magnetic resonance imaging demonstrating normal/near-normal right ventricular size and function, and hemodynamics showing normalization of right ventricular function with right atrial pressure &lt;8 mm Hg and cardiac index &gt;2.5 to 3.0 l/min/m2. (J Am Coll Cardiol 2013;62:D73-81) \ua92013 by the American College of Cardiology Foundation