Susan E. Howlett

Responsiveness of goal attainment scaling in a randomized controlled trial of comprehensive geriatric assessment

BACKGROUND AND OBJECTIVE Frail elderly patients have complex problems that require a multidimensional assessment and a range of treatment goals. Goal Attainment Scaling (GAS) measures multiple, individualized goals, but its responsiveness in comparative clinical trials has not been established. METHODS We assessed the responsiveness of GAS in a randomized, controlled trial of an interdisciplinary Mobile Geriatric Assessment Team (MGAT) in 265 rural frail older adults. Sensitivity to change was compared with standard measures; clinical meaningfulness was assessed in relation to a patient and a blinded physician global measure. RESULTS At 3 months follow-up, GAS was the most responsive measure (standardized response mean 1.22, Normans responsiveness statistic 0.58) compared with the Barthel Index (1.13, 0.46), Physical Self-Maintenance Scale (0.10, 0.16, 0.02), Instrumental Activities of Daily Living (0.23, 0.00), and modified Spitzer Quality of Life Index (-0.04, 0.00). CONCLUSIONS Only GAS detected clinically important change associated with the MGAT intervention in these frail elderly patients. Clinometric measures can offer a responsive means of evaluating complex interventions.

A Clinical Frailty Index in Aging Mice: Comparisons With Frailty Index Data in Humans

We previously quantified frailty in aged mice with frailty index (FI) that used specialized equipment to measure health parameters. Here we developed a simplified, noninvasive method to quantify frailty through clinical assessment of C57BL/6J mice (5–28 months) and compared the relationship between FI scores and age in mice and humans. FIs calculated with the original performance-based eight-item FI increased from 0.06±0.01 at 5 months to 0.36±0.06 at 19 months and 0.38±0.04 at 28 months (n = 14). By contrast, the increase was graded with a 31-item clinical FI (0.02±0.005 at 5 months; 0.12±0.008 at 19 months; 0.33±0.02 at 28 months; n = 14). FI scores calculated from 70 self-report items from the first wave of the Survey of Health, Ageing and Retirement in Europe were plotted as function of age (n = 30,025 people). The exponential relationship between FI scores and age (normalized to 90% mortality) was similar in mice and humans for the clinical FI but not the eight-item FI. This noninvasive FI based on clinical measures can be used in longitudinal studies to quantify frailty in mice. Unlike the performance-based eight-item mouse FI, the clinical FI exhibits key features of the FI established for use in humans.

A Procedure for Creating a Frailty Index Based on Deficit Accumulation in Aging Mice

This study developed an approach to quantify frailty with a frailty index (FI) and investigated whether age-related changes in contractions, calcium transients, and ventricular myocyte length were more prominent in mice with a high FI. The FI combined 31 variables that reflect different aspects of health in middle-aged (∼12 months) and aged (∼30 months) mice of both sexes. Aged animals had a higher FI than younger animals (FI = 0.43 ± 0.03 vs 0.08 ± 0.02, p < .001, n = 12). Myocyte hypertrophy increased by 30%-50% as the FI increased in aged animals. Peak contractions decreased more than threefold from lowest to highest FI values in aged mice (p < .037), but calcium transients were unaffected. Similar results were seen with an FI based on eight noninvasive variables identified as underlying factors. These results show that an FI can be developed for murine models and suggest that age-associated changes in myocytes are more prominent in animals with a high FI.

Contractions in guinea‐pig ventricular myocytes triggered by a calcium‐release mechanism separate from Na+ and L‐currents.

1. Unloaded cell shortening and membrane currents were examined in isolated guinea‐pig ventricular myocytes at 37 degrees C using video edge detection and single‐electrode voltage clamp. 2. Inward Na+ currents were eliminated by lidocaine, tetrodotoxin, replacement of extracellular Na+ with choline chloride or sucrose, or by voltage inactivation of Na+ channels. In the absence of Na+ current, the threshold for contraction was approximately ‐50 or ‐55 mV. 3. Verapamil (5 microM) and nifedipine (2 microM) failed to inhibit contractions at negative membrane potentials when positive conditioning pulses were used to maintain intracellular Ca2+ stores via Na(+)‐Ca2+ exchange. In contrast, 200 microM Ni2+ inhibited these contractions. 4. Contractions were abolished when the extracellular solution was nominally Ca2+ free. However, contractions were restored by as little as 50 microM extracellular Ca2+. 5. Ryanodine (30 nM) completely abolished contractions initiated by depolarizing steps from ‐65 to ‐40 mV, but had minimal effects on contractions initiated by depolarizing steps from ‐40 to +5 mV. Subtraction of contraction‐voltage relations determined in the presence of ryanodine from control relations revealed a ryanodine‐sensitive component of contraction. This component activated at ‐55 mV and reached a plateau near ‐25 mV. 6. The amplitudes of contractions initiated by depolarizing steps from ‐40 mV were directly proportional to the magnitude of Ca2+ current (ICa). In contrast, contractions initiated by steps from either ‐55 or ‐65 mV were not proportional to ICa. These contractions appeared at potentials negative to the threshold for L‐type Ca2+ current, increased to a plateau at more positive potentials and did not decrease at potentials at which ICa decreased. 7. Subtraction of the contraction‐voltage relationship determined from a membrane potential of ‐40 mV from that at ‐55 mV revealed a component of contraction with a negative activation threshold whose amplitude was not proportional to inward current. The shape of this relationship was virtually identical to that of the ryanodine‐sensitive component of contraction. 8. This study identifies a component of contraction associated with Ca2+ release from sarcoplasmic reticulum (SR) which can be separated from other mechanisms of contraction on the basis of membrane potential. Our observations suggest that this voltage‐dependent release mechanism is a true trigger mechanism which activates a portion of cardiac contraction which is attributable to SR Ca2+ release.

Standard laboratory tests to identify older adults at increased risk of death

BackgroundOlder adults are at an increased risk of death, but not all people of the same age have the same risk. Many methods identify frail people (that is, those at increased risk) but these often require time-consuming interactions with health care providers. We evaluated whether standard laboratory tests on their own, or added to a clinical frailty index (FI), could improve identification of older adults at increased risk of death.MethodsThis is a secondary analysis of a prospective cohort study, where community dwelling and institutionalized participants in the Canadian Study of Health and Aging who also volunteered for blood collection (n = 1,013) were followed for up to six years. A standard FI (FI-CSHA) was constructed from data obtained during the clinical evaluation and a second, novel FI was constructed from laboratory data plus systolic and diastolic blood pressure measurements (FI-LAB). A combined FI included all items from each index. Predictive validity was tested using Cox proportional hazards analysis and discriminative ability by the area under receiver operating characteristic (ROC) curves.ResultsOf 1,013 participants, 51.3% had died by six years. The mean baseline value of the FI-LAB was 0.27 (standard deviation 0.11; range 0.05 to 0.63), the FI-CSHA was 0.25 (0.11; 0.02 to 0.72), and the combined FI was 0.26 (0.09; 0.06 to 0.59). In an age- and sex-adjusted model, with each increment in the FI-LAB, the hazard ratios increased by 2.8% (95% confidence interval 1.02 to 1.04). The hazard ratios for the FI-CSHA and the combined FI were 1.02 (1.01 to 1.03) and 1.04 (1.03 to 1.05), respectively. The FI-LAB and FI-CSHA remained independently associated with death in the face of the other. The areas under the ROC curves were 0.72 for FI-LAB, 0.73 for FI-CSHA and 0.74 for the combined FI.ConclusionsAn FI based on routine laboratory data can identify older adults at increased risk of death. Additional evaluation of this approach in clinical settings is warranted.

Sex differences in mechanisms of cardiac excitation-contraction coupling in rat ventricular myocytes.

Components of excitation-contraction (E-C) coupling were compared in ventricular myocytes isolated from 3-mo-old male and female rats. Ca(2+) concentrations (fura-2) and cell shortening (edge detector) were measured simultaneously (37 degrees C). Membrane potential and ionic currents were measured with microelectrodes. Action potentials were similar in male and female myocytes, but contractions were smaller and slower in females. In voltage-clamped cells, peak contractions were smaller in females than in males (5.1 +/- 0.7% vs. 7.7 +/- 0.8% diastolic length, P < 0.05). Similarly, Ca(2+) transients were smaller in females than in males and the rate of rise of the Ca(2+) transient was slower in females. Despite smaller contractions and Ca(2+) transients in females, Ca(2+) current density was similar in both groups. Sarcoplasmic reticulum Ca(2+) content, assessed with caffeine, did not differ between the sexes. However, E-C coupling gain (rate of Ca(2+) release/Ca(2+) current) was smaller in females than in males (157.0 +/- 15.6 vs. 338.4 +/- 54.3 (nM/s)/(pA/pF), P < 0.05). To determine whether the reduced gain in female cells was due to changes in unitary Ca(2+) release, spontaneous Ca(2+) sparks were evaluated (fluo-4, 37 degrees C). Spark frequencies and widths were similar in both groups, but spark amplitudes were smaller in females than in males (0.56 +/- 0.01 vs. 0.64 +/- 0.01 DeltaF/F(0), P < 0.05). Spark durations also were shorter in females than in males (full duration at half-maximum = 14.86 +/- 0.17 vs. 16.25 +/- 0.27 ms, P < 0.05). These observations suggest that decreases in the size and duration of Ca(2+) sparks contributes to the decrease in E-C coupling gain in female myocytes. Thus, differences in cardiac contractile function arise, in part, from differences in unitary Ca(2+) release between the sexes.

Sex differences in mechanisms of cardiac excitation–contraction coupling

The incidence and expression of cardiovascular diseases differs between the sexes. This is not surprising, as cardiac physiology differs between men and women. Clinical and basic science investigations have shown important sex differences in cardiac structure and function. The pervasiveness of sex differences suggests that such differences must be fundamental, likely operating at a cellular level. Indeed, studies have shown that isolated ventricular myocytes from female animals have smaller and slower contractions and underlying calcium transients compared to males. Recent evidence suggests that this arises from sex differences in components of the cardiac excitation–contraction coupling pathway, the sequence of events linking myocyte depolarization to calcium release from the sarcoplasmic reticulum and subsequent contraction. The concept that sex hormones may regulate intracellular calcium at the level of the cardiomyocyte is important, as levels of these hormones decline in both men and women as the incidence of cardiovascular disease rises. This review focuses on the impact of sex on cardiac contraction, in particular at the cellular level, and highlights specific components of the excitation–contraction coupling pathway that differ between the sexes. Understanding sex hormone regulation of calcium homeostasis in the heart may reveal new avenues for therapeutic strategies to treat cardiac dysfunction and cardiovascular diseases.

Age-associated changes in excitation-contraction coupling are more prominent in ventricular myocytes from male rats than in myocytes from female rats

We evaluated effects of age on components of excitation-contraction (EC) coupling in ventricular myocytes from male and female rats to examine sex differences in mechanisms responsible for age-related contractile dysfunction. Myocytes were isolated from anesthetized young adult (approximately 3 mo) and aged (approximately 24 mo) Fischer 344 rats. Ca(2+) concentrations and contractions were measured simultaneously (37 degrees C, 2 Hz). Fractional shortening declined with age in males (6.7 +/- 0.6% to 2.4 +/- 0.4%; P < 0.05), as did peak Ca(2+) transients (47.7 +/- 4.6 to 28.1 +/- 2.1 nM; P < 0.05) and Ca(2+) current densities (-7.7 +/- 0.7 to -6.2 +/- 0.5 pA/pF; P < 0.05). Although sarcoplasmic reticulum (SR) Ca(2+) content was similar regardless of age in males, EC coupling gain declined significantly with age to 55.8 +/- 7.8% of values in younger males. In contrast with results in males, contraction and Ca(2+) transient amplitudes were unaffected by age in females. Ca(2+) current density declined with age in females (-7.5 +/- 0.5 to -5.1 +/- 0.7 pA/pF; P < 0.05), but SR Ca(2+) content actually increased dramatically (49.0 +/- 7.5 to 147.3 +/- 28.5 nM; P < 0.05). Even so, EC coupling gain was not affected by age in female myocytes. Age also promoted hypertrophy of male myocytes more than female myocytes. Age and sex differences in EC coupling were largely maintained when conditioning pulse frequency was increased to 4 Hz. Contractions, Ca(2+) transients, and EC coupling gain were also smaller in young females than in young males. Thus age-dependent changes are more prominent in myocytes from males than females. Increased SR Ca(2+) content may compensate for reduced Ca(2+) current to preserve contractile function in aged females, which may limit the detrimental effects of age on cardiac contractile function.

Effects of ischemia and reperfusion on isolated ventricular myocytes from young adult and aged Fischer 344 rat hearts.

This study examined the impact of age on contractile function, Ca(2+) homeostasis, and cell viability in isolated myocytes exposed to simulated ischemia and reperfusion. Ventricular myocytes were isolated from anesthetized young adult (3 mo) and aged (24 mo) male Fischer 344 rats. Cells were field-stimulated at 4 Hz (37 degrees C), exposed to simulated ischemia, and reperfused with Tyrode solution. Cell shortening and intracellular Ca(2+) were measured simultaneously with an edge detector and fura-2. Cell viability was assessed by Trypan blue exclusion. Ischemia (20-45 min) depressed amplitudes of contraction equally in isolated myocytes from young adult and aged animals. The degree of postischemic contractile depression (stunning) was comparable in both groups. Ca(2+) transient amplitudes were depressed in early reperfusion in young adult and aged cells and then recovered to preischemic levels in both groups. Cell viability also declined equally in reperfusion in both groups. In short, some cellular responses to simulated ischemia and reperfusion were similar in both groups. Even so, aged myocytes exhibited a much greater and more prolonged accumulation of diastolic Ca(2+) in ischemia and in early reperfusion compared with myocytes from younger animals. In addition, the degree of mechanical alternans in ischemia increased significantly with age. The observation that there is an age-related increase in accumulation of diastolic Ca(2+) in ischemia and early reperfusion may account for the increased sensitivity to ischemia and reperfusion injury in the aging heart. The occurrence of mechanical alternans in ischemia may contribute to contractile dysfunction in ischemia in the aging heart.

New horizons in frailty: ageing and the deficit-scaling problem

All the current frailty measures count deficits. They differ chiefly in which items, and how many, they consider. These differences are related: if a measure considers only a few items, to define broad risks those items need to integrate across several systems (e.g. mobility or function). If many items are included, the cumulative effect of small deficits can be considered. Even so, it is not clear just how small deficits can be. To better understand how the scale of deficit accumulation might impact frailty measurement, we consider how age-related, subcellular deficits might become macroscopically visible and so give rise to frailty. Cellular deficits occur when subcellular damage has neither been repaired nor cleared. With greater cellular deficit accumulation, detection becomes more likely. Deficit detection can be done by either subclinical (e.g. laboratory, imaging, electrodiagnostic) or clinical methods. Not all clinically evident deficits need cross a disease threshold. The extent to which cellular deficit accumulation compromises organ function can reflect not just what is happening in that organ system, but deficit accumulation in other organ systems too. In general, frailty arises in relation to the number of organ systems in which deficits accumulate. This understanding of how subcellular deficits might scale has implications for understanding frailty as a vulnerability state. Considering the cumulative effects of many small deficits appears to allow important aspects of the behaviour of systems close to failure to be observed. It also suggests the potential to detect frailty with less reliance on clinical observation than current methods employ.