The cellular pathophysiology of myocardial dysfunction in heart failure is multifactorial. Studies of animal models and myocardium from patients with heart failure have demonstrated abnormalities of cytosolic calcium handling, myofilament calcium sensitivity, and myocyte energetics. Many of these metabolic abnormalities have been shown to be the result of alterations in the activity or number of myocyte enzymes and transport channels that are important in excitation-contraction coupling. Several innovative techniques for measuring intracellular calcium and energy metabolites and recent advances in cell biology have helped to further our understanding of the cellular pathophysiology of heart failure. Abnormalities at several levels of the excitation-contraction coupling mechanism have been shown to be responsible for both systolic and diastolic dysfunction in the failing heart.
The goal of this study was to determine whether Ca 2+ plays a role in regulating tension development kinetics in intact cardiac muscle. In cardiac muscle, this fundamental issue of Ca 2+ regulation has been controversial. The approach was to induce steady-state tetanic contractions of intact right ventricular trabeculae from rat hearts at varying external Ca 2+ concentrations ([Ca 2+ ]) at 22°C. During tetani, cross bridges were mechanically disrupted and the kinetics of tension redevelopment were assessed from the rate constant of exponential tension redevelopment ( k tr ). There was a relationship between k tr and external [Ca 2+ ] that was similar in form to the relationship between tension and [Ca 2+ ]. Thus a close relationship also existed between k tr and tension ( r = 0.88; P < 0.001); whereas at maximal tetanic tension (saturating cytosolic [Ca 2+ ]), k tr was 16.4 ± 2.2 s −1 (mean ± SE, n = 7), at zero tension (low cytosolic [Ca 2+ ]), k tr extrapolated to 20% of maximum (3.3 ± 0.7 s −1 ). Qualitatively similar results were obtained using different mechanical protocols to disrupt cross bridges. These data demonstrate that tension redevelopment kinetics in intact cardiac muscle are influenced by the level of Ca 2+ activation. These findings contrast with the findings of one previous study of intact cardiac muscle. Activation dependence of tension development kinetics may play an important role in determining the rate and extent of myocardial tension rise during the cardiac cycle in vivo.
We asked whether thyroid hormone (T4) would improve heart function in left ventricular hypertrophy (LVH) induced by pressure overload (aortic banding). After banding for 10-22 wk, rats were treated with T4 or saline for 10-14 d. Isovolumic LV pressure and cytosolic [Ca2+] (indo-1) were assessed in perfused hearts. Sarcoplasmic reticulum Ca2+-ATPase (SERCA), phospholamban, and alpha- and beta-myosin heavy chain (MHC) proteins were assayed in homogenates of myocytes isolated from the same hearts. Of 14 banded hearts treated with saline, 8 had compensated LVH with normal function (LVHcomp), whereas 6 had abnormal contraction, relaxation, and calcium handling (LVHdecomp). In contrast, banded animals treated with T4 had no myocardial dysfunction; these hearts had increased contractility, and faster relaxation and cytosolic [Ca2+] decline compared with LVHcomp and LVHdecomp. Myocytes from banded hearts treated with T4 were hypertrophied but had increased concentrations of alpha-MHC and SERCA proteins, similar to physiological hypertrophy induced by exercise. Thus thyroid hormone improves LV function and calcium handling in pressure overload hypertrophy, and these beneficial effects are related to changes in myocyte gene expression. Induction of physiological hypertrophy by thyroid hormone-like signaling might be a therapeutic strategy for treating cardiac dysfunction in pathological hypertrophy and heart failure.
Despite an increase in frailty research in recent years, there is a lack of consensus regarding the approach to, and instrument used for, frailty measurement. Frailty measurement approaches include deficit accumulation models and frailty phenotypes. The current study evaluates a brief, self-report phenotypic frailty instrument, the Paulson-Lichtenberg Frailty Index (PLFI), against the deficit accumulation frailty index proposed by Mitnitski, Song, and Rockwood in 2004. The sample included 51 individuals over age 70 from the Vascular Aging Study. The PLFI consisted of 5 items: wasting, weakness, slowness, falls, and fatigue; frailty criteria was met if a participant endorsed three or more items. Bivariate correlation and receiver operating characteristic curve analyses were employed to compare the PLFI to a deficit accumulation frailty index, which included 40 self-reported health and health-attitude related items. Rate of frailty based on the PLFI was 14%. Mean score on the deficit accumulation model was 5.61 (SD = 4.36), and significantly varied between (t=-4.12, p<.001) non-frail (mean=4.76, SD=3.57) and frail (mean=11.18, SD=5.36) participants. PLFI scores significantly correlated with deficit accumulation frailty index scores (r = .61, p < .001). Area under the receiver operating characteristic curve = .846 (p=.004), indicating good discrimination with the PLFI between those who meet the frailty criteria and those who do not, based on items endorsed on the deficit accumulation frailty index. In sum, results suggest that the PLFI is a valid phenotypic assessment of frailty with high clinical utility given its brevity and ease of administration.
The use of sacubitril/valsartan is not endorsed by practice guidelines for use in patients with New York Heart Association class IV heart failure with a reduced ejection fraction because of limited clinical experience in this population.
Objective
To compare treatment with sacubitril/valsartan treatment with valsartan in patients with advanced heart failure and a reduced ejection fraction and recent New York Heart Association class IV symptoms.
Design, Setting, and Participants
A double-blind randomized clinical trial was conducted; a total of 335 patients with advanced heart failure were included. The trial began on March 2, 2017, and was stopped early on March 23, 2020, owing to COVID-19 risk.
Intervention
Patients were randomized to receive sacubitril/valsartan (target dose, 200 mg twice daily) or valsartan (target dose, 160 mg twice daily) in addition to recommended therapy.
Main Outcomes and Measures
The area under the curve (AUC) for the ratio of N-terminal pro–brain natriuretic peptide (NT-proBNP) compared with baseline measured through 24 weeks of therapy.
Results
Of the 335 patients included in the analysis, 245 were men (73%); mean (SD) age was 59.4 (13.5) years. Seventy-two eligible patients (18%) were not able to tolerate sacubitril/valsartan, 100 mg/d, during the short run-in period, and 49 patients (29%) discontinued sacubitril/valsartan during the 24 weeks of the trial. The median NT-proBNP AUC for the valsartan treatment arm (n = 168) was 1.19 (IQR, 0.91-1.64), whereas the AUC for the sacubitril/valsartan treatment arm (n = 167) was 1.08 (IQR, 0.75-1.60). The estimated ratio of change in the NT-proBNP AUC was 0.95 (95% CI 0.84-1.08;P = .45). Compared with valsartan, treatment with sacubitril/valsartan did not improve the clinical composite of number of days alive, out of hospital, and free from heart failure events. Aside from a statistically significant increase in non–life-threatening hyperkalemia in the sacubitril/valsartan arm (28 [17%] vs 15 [9%];P = .04), there were no observed safety concerns.
Conclusions and Relevance
The findings of this trial showed that, in patients with chronic advanced heart failure with a reduced ejection fraction, there was no statistically significant difference between sacubitril/valsartan and valsartan with respect to reducing NT-proBNP levels.
A simple mathematical model describing the dynamic connection between Ca2+ and force generation in intact skeletal muscle from the frog has been developed from isometric force responses to cytosolic Ca2+ concentration ([Ca2+]c) transients during tetanic and twitch contractions. The main element of the model is a two-state cross-bridge cycle characterized by the fractional rate of cross-bridge attachment (f(app)) and the fractional rate of cross-bridge detachment (g*). While g* is constant, f(app) is time varying and regulated by both [Ca2+]c and force. Having only four adjustable parameters, the model is mathematically unique, thereby allowing precise parameter estimation from the dynamic Ca2+ and force data. The model should be useful for developing insights into the relative importance for force generation and relaxation of 1) the size and shape of the Ca2+ transient, 2) the sensitivity of the fractional rate of cross-bridge attachment to both the [Ca2+]c and the force responses, and 3) the fractional rate of cross-bridge detachment, which is insensitive to both Ca2+ and force.
Many studies published in 1994 significantly added to our understanding of the pathophysiology of heart failure at the cellular and subcellular level. This field continues to advance using different but complementary approaches. One approach is to study human myocardium, thereby providing data that is directly relevant to clinical disease. Another approach is to study mouse myocardium, taking advantage of transgenic technology to alter gene expression and directly study cause-and-effect relationships. Additionally, other animal models of heart failure (eg, pressure overload, volume overload, and paced tachycardia) continue to provide important information. Abnormalities of calcium cycling, myofilament sensitivity to calcium, cross-bridge kinetics, the myocyte cytoskeleton, and energetics have all been observed in animal models or failing human myocardium. The cellular and molecular basis for these abnormalities is now being explored. This understanding is essential for developing novel treatment strategies that may one day include gene therapy.
