Background-The time course and mechanisms of altered mechanoenergetics and depressed cross-bridge cycling in hypertrophied and failing myocardium are uncertain. Methods and Results-We studied mechanoenergetics in Dahl salt-sensitive (DS) rats fed high-salt diet (HS) for 6 and 12 (HS-12) weeks to produce compensated hypertrophy and failure. The slope of the end-systolic pressure-volume relation (EЈ max ) was similar in HS-6 and low-salt controls (LS-6), but reduced in HS-12 compared with controls (LS-12 ). There were no changes in troponin I or tropomyosin isoforms. However, the proportion of phosphorylated troponin T was reduced in HS-12 versus LS-12 hearts (PϽ.001). Conclusions-In DS rats, the transition to failure is associated with depressed EЈ max and increased efficiency and economy.These findings are linked to myofibrillar ATPase activity and suggest that mechanisms other than isomyosin switching are important determinants of ventricular energetics. A troponin T isoform switch is one potential mechanism.

We tested the feasibility of an isolated, balloon-in-ventricle, isovolumically contracting, crystalloid-perfused mouse heart preparation ( n = 10) for studies of cardiac mechanoenergetics using the end-systolic pressure-volume relation (ESPVR) and myocardial oxygen consumption (V˙o 2)-pressure-volume area (PVA) framework employed in larger species. The intraventricular balloon method was shown to be accurate for measurement of left ventricular volume, especially at relatively higher volumes. The ESPVR demonstrated contractility-dependent curvilinearity. Average slope of the ESPVR was 1,299 ± 369 (SD) mmHg ⋅ g ⋅ ml−1, with a volume intercept of 0.018 ± 0.006 ml. TheV˙o 2-PVA relation was well fitted by a straight line, with average slope andV˙o 2 intercept of 3.57 ± 1.31 × 10−5 ml O2 ⋅ mmHg−1 ⋅ ml−1and 0.92 ± 0.21 × 10−3 ml O2 ⋅ beat−1 ⋅ g−1, respectively. Decreasing perfusate Ca2+ concentration resulted in a decrease in the slope of the ESPVR, a decrease in theV˙o 2 intercept of theV˙o 2-PVA relation, but no significant change in its slope. Hearts from hypothyroid ( n = 8) mice demonstrated similar mechanoenergetic changes. We conclude that delineation of the ESPVR and the V˙o 2-PVA relation is feasible in the mouse heart. Our method should allow an assessment of cardiac mechanoenergetics as sophisticated as that previously possible only in larger hearts.

Background-Brain natriuretic peptide (BNP) levels are used in the evaluation of patients with heart disease, yet there is little understanding of the effect of hypoxia on natriuretic peptide secretion. Furthermore, recent data suggest that oxytocin may mediate stretch-induced atrial natriuretic peptide (ANP) secretion. Methods and Results-Ten patients with cyanotic congenital heart defects and 10 control subjects were studied. N-terminal proatrial natriuretic peptide and N-terminal probrain natriuretic peptide levels were 4-fold (Pϭ0.02) and 12-fold (Pϭ0.03) greater in cyanotic patients than in control subjects. Cyanotic patients had reduced body water compared with control subjects, although the difference did not reach statistical significance (Pϭ0.22). In a separate group of patients, cardiac myocytes were isolated from the right atrial appendage during CABG. The amount of oxygen in the buffered saline was varied to simulate hypoxia. Isolated hypoxic atrial myocytes had 43% fewer dense surface secretory granules compared with normoxic myocytes (PϽ0.0001). Immunohistochemical staining demonstrated decreased ANP and BNP in hypoxic compared with normoxic right atrial tissue. Isolated myocytes also degranulated when incubated with oxytocin (PϽ0.0001), but there was no difference in oxytocin levels in cyanotic patients compared with control subjects (Pϭ0.49). Conclusions-ANP and BNP are markedly elevated in adults with cyanotic congenital heart disease despite reduced body water. Our results show that hypoxia is a direct stimulus for ANP and BNP secretion in human cardiac myocytes. These findings may have implications for the interpretation of BNP levels in the assessment of patients with heart and lung disease.

Background-The left ventricles of both rabbits and humans express predominantly ␤-myosin heavy chain (MHC).Transgenic (TG) rabbits expressing 40% ␣-MHC are protected against tachycardia-induced cardiomyopathy, but the normal amount of ␣-MHC expressed in humans is only 5% to 7% and its functional importance is questionable. This study was undertaken to identify a myofilament-based mechanism underlying tachycardia-induced cardiomyopathy protection and to extrapolate the impact of MHC isoform variation on myofilament function in human hearts. Methods and Results-Papillary muscle strips from TG rabbits expressing 40% (TG40) and 15% ␣-MHC (TG15) and from nontransgenic (NTG) controls expressing Ϸ100% ␤-MHC (NTG40 and NTG15) were demembranated and calcium activated. Myofilament tension and calcium sensitivity were similar in TGs and respective NTGs. Force-clamp measurements revealed Ϸ50% higher power production in TG40 versus NTG40 (PϽ0.001) and Ϸ20% higher power in TG15 versus NTG15 (PϽ0.05). A characteristic of acto-myosin crossbridge kinetics, the "dip" frequency, was significantly higher in TG40 versus NTG40 (0.70Ϯ0.04 versus 0.39Ϯ0.09 Hz, PϽ0.01) but not in TG15 versus NTG15.The calculated crossbridge time-on was also significantly shorter in TG40 (102.3Ϯ14.2 ms) versus NTG40 (175.7Ϯ19.7 ms) but not in TG15 versus NTG15. Conclusions-The incorporation of 40% ␣-MHC leads to greater myofilament power production and more rapid crossbridge cycling, which facilitate ejection and relengthening during short cycle intervals, and thus protect against tachycardia-induced cardiomyopathy. Our results suggest, however, that, even when compared with the virtual absence of ␣-MHC in the failing heart, the 5% to 7% ␣-MHC content of the normal human heart has little if any functional significance. (Circ Heart Fail. 2009;2:334-341.)