Current perspectives on defining and mitigating frailty in relation to critical illness.

Up to half of ICU survivors, many of whom were premorbidly well, will have residual functional and/or cognitive impairment and be vulnerable to future health problems. Frailty describes vulnerability to poor resolution of homeostasis after a stressor event but it is not clear whether the vulnerability seen after ICU correlates with clinical measures of frailty. In clinical practice, the scales most commonly used in critically ill patients are based on the assessment of severity and survival. Identification and monitoring of frailty in the ICU may be an alternative or complimentary approach, particularly if it helps explain vulnerability during the recovery and rehabilitation period. The purpose of this review is to discuss the use of tools to assess frailty status in the critically ill, and consider their importance in clinical practice. Amongst these, we consider biomarkers with potential to identify patients at greater or lesser risk of developing post-ICU vulnerability.

Influence of intermittent fasting on myocardial infarction-induced cardiac remodeling.

BACKGROUND: Information on the role of intermittent fasting (IF) on pathologic cardiac remodeling is scarce. We compared the effects of IF before and after myocardial infarction (MI) on rat cardiac remodeling and survival. METHODS: Wistar rats were intermittently fasted (food available every other day) or fed ad libitum for 12 weeks and then divided into three groups: AL - fed ad libitum; AL/IF - fed AL before MI and IF after MI; and IF - fed IF before and after MI. Echocardiogram was performed before MI and 2 and 12 weeks after surgery. Isolated hearts were evaluated in Langendorff preparations. RESULTS: Before surgery, body weight (BW) was lower in IF than AL. Final BW was lower in AL/IF and IF than AL. Perioperative mortality did not change between AL (31.3%) and IF (27.3%). Total mortality was lower in IF than AL. Before surgery, echocardiographic parameters did not differ between groups. Two weeks after surgery, MI size did not differ between groups. Twelve weeks after MI, left ventricular (LV) diastolic posterior wall thickness was lower in AL/IF and IF than AL. The percentage of variation of echocardiographic parameters between twelve and two weeks showed that MI size decreased in all groups and the reduction was higher in IF than AL/IF. In Langendorff preparations, LV volume at zero end-diastolic pressure (V0; AL: 0.41 ± 0.05; AL/IF: 0.34 ± 0.06; IF: 0.28 ± 0.05 mL) and at 25 mmHg end-diastolic pressure (V25; AL: 0.61 ± 0.05; AL/IF: 0.54 ± 0.07; IF: 0.44 ± 0.06 mL) was lower in AL/IF and IF than AL and V25 was lower in IF than AL/IF. V0/BW ratio was lower in IF than AL and LV weight/V0 ratio was higher in IF than AL. Myocyte diameter was lower in AL/IF and IF than AL (AL: 17.3 ± 1.70; AL/IF: 15.1 ± 2.21; IF: 13.4 ± 1.49 µm). Myocardial hydroxyproline concentration and gene expression of ANP, Serca 2a, and α- and ß-myosin heavy chain did not differ between groups. CONCLUSION: Intermittent fasting initiated before or after MI reduces myocyte hypertrophy and LV dilation. Myocardial fibrosis and fetal gene expression are not modulated by feeding regimens. Benefit is more evident when intermittent fasting is initiated before rather than after MI.

Early rather than delayed administration of lisinopril protects the heart after myocardial infarction in rats.

BACKGROUND: ACE inhibitors have shown beneficial results in several studies after myocardial infarction (MI). However, these studies have shown conflicting results about the ideal starting time of the ACE inhibitors administration after MI and the importance of infarct size. OBJECTIVES: This study was designed to assess the long-term effects of lisinopril on mortality, cardiac function, and ventricular fibrosis after MI, in rats. METHODS: Lisinopril (20 mg/kg/day) was given on day 1 or 21 days after coronary occlusion in small or large infarctions. RESULTS: The mortality rate was reduced by 39 % in early treatment and 30 % in delayed treatment in comparison to the untreated rats. Early treatment reduced cardiac dysfunction in small MIs; however, delayed treatment did not. No statistical difference was observed among the groups for large MIs. No statistical difference was observed among the groups with large or small MIs on myocardial hydroxyproline concentration. CONCLUSIONS: Both early and delayed treatments with lisinopril increased survival. Treatment exerts no marked effects on fibrosis; early treatment has exerted beneficial influences on cardiac function whereas delayed treatment had no consistent effects. The protective effect of lisinopril is detectable only in small (< 40 % of LV) MIs.

Effects of losartan on ventricular remodeling in experimental infarction in rats.

OBJECTIVE: To evaluate the effects of losartan on ventricular remodeling and on survival after myocardial infarction in rats. METHODS: After surgical occlusion of left coronary artery, 84 surviving male Wistar rats were divided into two groups: LO treated with losartan (20mg/kg/day, n=33) and NT (n=51), without medication. After 3 months, we analyzed mortality; ventricular to body mass ratio (VM /BM); myocardial hydroxyproline concentration (HOP); isovolumetric pressure, +dp/dt, -dp/dt, and diastolic volume/left ventricle mass ratio (VO/LV). RESULTS: Mortality was: LO = 22 %, and NT = 47 % (p<0.05). Ventricular mass,(VM/BM, mg/g) was 4.14 +/- 0.76 and 3.54+/-0.48, in the NT and LO groups, respectively (p<0.05). HOP (median) was 4.92 upsilong/mg in the LO and 5.54 upsilong/g in the NT group (p>0.05). The V0/LV values (median) were 0.24 mL/g in group LO and 0.31 mL/g in group NT (p<0.05) compared to NT group. There were no differences between the groups for +dp/dt and -dp/dt parameters. CONCLUSION: 1. The use of losartan myocardial infarction causes an attenuation of ventricular remodeling, bringing about an increased survival, an attenuation of ventricular hypertrophy and dilation, and an improvement of the isovolumetric pressure; 2. the treatment does not modify the myocardial collagen concentration.

Combination therapy with angiotensin converting enzyme inhibition and AT1 receptor inhibitor on ventricular remodeling after myocardial infarction in rats.

BACKGROUND: There are limited data regarding the effects of angiotensin II receptor blockade after myocardial infarction (MI). In addition, whether combined angiotensin converting enzyme (ACE) inhibitor and angiotensin II type I (AT(1)) receptor antagonist may be superior to either drug alone on ventricular remodeling remains unclear. The goal of this study was to determine if the cardiac effects of the combined administration of an ACE inhibitor and AT(1) receptor antagonist are greater than those produced by either of these agents administered individually after MI. METHODS AND RESULTS: After MI, rats were divided into 4 groups: 1) untreated animals, 2) lisinopril treatment (20 mg/kg/day), 3) losartan treatment (20 mg/kg/day), and 4) lisinopril plus losartan treatment. After 3 months, the cardiac parameters studied were: mortality, fibrosis (hydroxyproline), hypertrophy (ventricular weight/body weight ratio [VW/BW]), left ventricular enlargement (volume at end-diastolic pressure equaled zero/body weight ratio [V0/BW]), and ventricular function (isovolumetric developed pressure, dp/dt, -dp/dt). A lowest mortality rate in the animals treated with the combination of both ACE inhibitor and AT(1) receptor antagonist was observed. Although lisinopril and losartan significantly decreased VW/BW ratio, when administered concomitantly, VW/BW ratio was lower than when either agent was administered individually. There were no differences in right ventricle hydroxyproline concentration. Only combination therapy decreased V0/BW ratio. The treatment with lisinopril plus losartan resulted in increases in the development of pressure versus untreated group; without alteration in dp/dt and -dp/dt. CONCLUSIONS: The combination of the AT(1) receptor blockade and ACE inhibitor is more effective than individual treatment on ventricular remodeling and survival after MI in rats.

Endothelin-A receptor antagonism during acute myocardial infarction in rats.

Endothelin levels are increased in rats with experimentally induced myocardial infarction. The purpose of this study was to determine whether endothelin-A (ET(A)) receptor antagonism alters ventricular remodeling and the development of heart failure after myocardial infarction (MI). We administered 10 mg/kg/day of A-127722 to rats post-MI for 6 weeks. A hemodynamic study was performed and passive pressure-volume curves obtained. In rats without infarcts, ET(A) receptor antagonist (n = 8; vehicle, n = 5) had no effect. However, in rats with infarcts ET(A) antagonism (n=14, MI = 35%; vehicle: n = 19, MI = 32%) reduced systemic arterial and LV systolic (but not end-diastolic) pressures and shifted the pressure-volume relationship to the right. Because LV mass was not changed, the volume-to-mass ratio was increased and was correlated inversely with the ability of the LV to maximally develop pressure. This increase in volume at low distending pressures was also coupled with a tendency (P < 0.06) for reduced scar thickness, suggesting that early initiation of an ET(A) receptor antagonism increased infarct expansion. The reduction in blood pressure offset the increase in volume such that wall stresses were unchanged, as was LV mass. The early use of ET(A) receptor antagonism in the rat model of myocardial infarction did not beneficially alter LV remodeling.

Effects of lisinopril on experimental ischemia in rats. Influence of infarct size.

OBJECTIVE - Angiotensin-converting enzyme inhibitors (ACEIs) have gained importance in preventing or attenuating the process of ventricular remodeling after myocardial infarction. The significance of infarct size in regard to the response to ACEIs, however, is controversial. This study aimed to analyze the effects of lisinopril on mortality rate, cardiac function, degree of cardiac hypertrophy and fibrosis in rats with different infarct sizes. METHODS - Lisinopril (20 mg/kg/day) dissolved in drinking water was administered to rats immediately after coronary artery occlusion. After being sacrificed, the infarcted animals were divided into two groups: one group of animals with small infarcts (< 40% of the left ventricle) and another group of animals with large infarcts (> 40% of the left ventricle). RESULTS - The mortality rate was 31.7% in treated rats and 47% in the untreated rats. There was no statistical difference between the groups with small and large infarcts in regard to myocardial concentration of hydroxyproline. In small infarcts, the treatment attenuated the heart dysfunction characterized by lower levels of blood pressure and lower values of the first derivative of pressure and of the negative derivative of pressure. The degree of hypertrophy was also attenuated in small infarcts. In regard to large infarcts, no differences between the groups were observed. CONCLUSION - Treatment with the ACEIs had no effect on mortality rate and on the amount of fibrosis. The protective effect of lisinopril on heart function and on the degree of hypertrophy could only be detected in small infarcts

Left ventricular adaptation to chronic pressure overload induced by inhibition of nitric oxide synthase in rats.

Recent studies have indicated that chronic inhibition of nitric oxide synthase induces arterial hypertension without myocardial hypertrophy. We investigated the mechanisms of left ventricular (LV) adaptation to this condition. Also, we analyzed the effect of the angiotensin-converting enzyme inhibitor (ACEI), lisinopril, in this experimental model of ventricular pressure overload. Fifty-eight Wistar rats received eight weeks of treatment with either NW-nitro-L-arginine-methyl ester (L-NAME group, n = 19), lisinopril (LISINOPRIL group, n = 19) or the combination of both drugs (LNAMELIS group, n = 20). All results were compared to age and sex matched untreated rats (CONTROL group, n = 18). Tail-cuff blood pressure rose significantly in L-NAME treated rats (195 +/- 29 mm Hg) compared to the CONTROL (141 +/- 12 mm Hg), LISINOPRIL (97 +/- 13 mm Hg), and LNAMELIS (113 +/- 16 mm Hg) groups. There was no myocardial hypertrophy in the chronically hypertensive rats. The ventricular unstressed volume was significantly reduced in the L-NAME group (0.119 +/- 0.027 mL) compared to the CONTROL (0.158 +/- 0.026 mL) indicating a disproportional reduction in ventricular volume related to the myocardial mass. The chamber size modification resulted in a systolic stress which was comparable to the CONTROL even though the isovolumetric systolic pressure was higher. The systolic functional data indicated preserved myocardial contractility in L-NAME. LV compliance was increased in the LISINOPRIL group and myocardial passive stiffness was lower in all treated rats compared to CONTROL. We conclude that LV. adaptation to chronic pressure overload without hypertrophy involves changes in chamber geometry and myocardial diastolic mechanical properties. Also, ACEI fully prevents L-NAME induced hypertension, reduces myocyte cross-sectional area, and myocardial passive stiffness. The combination of L-NAME plus lisinopril decreases the load independent index of myocardial contractility.

[Effect of lisinopril on cardiac parameters and mortality after myocardial infarction in rats]. / Efeito do lisinopril sobre parâmetros cardíacos e mortalidade no infarto experimental em ratos.

PURPOSE: To analyse the effect of early (< 24h) administration of lisinopril on ventricular remodeling and mortality after myocardial infarction (MI) in rats. METHODS: Wistar rats weighing 200-250 g were submitted to ligation of the left coronary artery (LCA) and divided into three groups: SHAM (S, n = 9); infarcted and lisinopril (20mg/kg/day) treated rats (L, n = 38); infarcted and non-treated animals (NT, n = 24). Three months later, the cardiac function was studied in isolated heart preparation according to the Langendorff technique. Starling curves were constructed using fluid injection in the left ventricular balloon, which permitted to alter the diastolic pressure range from 0 to 30mmHg by means of pressure increments of 5mmHg. Body weight (BW), right ventricular weight (RVW), and RVW/BW were also determined. RESULTS: Three months after the surgery, the comparative mortality rate among groups was: S = 0; L = 34.4% and NT = 54.4% (p > 0.05, for L vs NT). In infarctions < 40% of the left ventricle (LV), the RVW/BW relation was S = L < NT (p < 0.05); the left ventricular systolic pressure was S > L > NT (p < 0.05). In infarctions > 40% of LV, the RVW/BW relation was S < L = NT (p < 0.05). For the Starling curves, the results were S > L > NT (p < 0.05). CONCLUSION: In our model lisinopril did not interfere with post-infarction mortality of rats, although decreasing the mortality risk in 49%, in the treated group. The drug also altered the remodeling process, preventing hypertrophy and systolic disfunction after MI, mainly in infarctions < 40% of LV.

[Influence of mannitol added to the nutrient solution on the mechanical performance and on the degree of myocardial edema of isolated hearts of rats]. / Influência do acréscimo de manitol à solução nutriente no desempenho mecânico e no grau de edema miocárdico de corações isolados de ratos.

PURPOSE: To analyse the influence of mannitol added to Krebs-Henseleit (KH) solution on the myocardium edema and myocardial function. METHODS: Isolated rat heart under isovolumetric contractions studied according to Langendorff's technique were perfused with KH solution at constant flow during 90 min. The coronary perfusion pressure, diastolic and systolic pressures were recorded at every 15 min. At the end of the experiment, myocardium water content was measured in hearts perfused with KH solution (group I, n = 9) and in hearts perfused with KH solution plus 8mM mannitol (group II, n = 8). These results were compared to non-perfused control heart (n = 9). RESULTS: Myocardial water content was statistically higher in group I (80.8 +/- 1.3%) compared to group II (78.1 +/- 0.7%) and control group (75.5 +/- 0.5%). Systolic arterial pressure was statistically higher in group I (86.2 +/- 11.5mmHg) compared to group II (72.7 +/- 21.1mmHg). There was no difference in the diastolic pressure between the two groups. Coronary perfusion pressure (Pp) increased progressively during the experiment in both groups. However, Pp was lower in group II than in group I. CONCLUSION: Mannitol added to KH solution significantly attenuates the myocardium edema in the isolated perfused rat heart.