Old age and chronic disease: is the emergency medical system the appropriate provider for the elderly?

OBJECTIVE: The use of emergency medical services increases with the age of patients. Some care providers hold on to the prejudice that these alarms are unnecessary or of a lower importance. We assessed the relation of age and age-dependent emergency characteristics, taking into consideration the ratings of emergency physicians on whether or not emergency cases were considered truly in need of emergency physician attendance. METHODS: Emergency physicians dispatched by the Berlin Fire Department evaluated for each case the necessity of emergency physician attendance. Case characteristics such as the day of the week and location of the emergency as well as patient characteristics such as age, sex, prior status, and care dependency were recorded. In addition, whether or not the physician accompanied the patient to the hospital was recorded as a parameter for emergency severity. Analysis was performed using multiple logistic regression modeling. RESULTS: During the 6-month prospective study period, 2702 cases were evaluated. Emergency medical services are used more frequently by older individuals, especially octogenarians. Emergency cases in older individuals were significantly more often rated as in need of emergency physician attendance; however, the rate of patients accompanied by the emergency physician to the hospital did not differ between the age groups. The age of patients, the primary diagnosis, the day and location of the emergency, and the presence of pre-existing dementia showed a significant impact on the necessity of physician-attended emergency missions. CONCLUSION: Despite common prejudices, emergency cases in elder patients are rated more often as in need of emergency physician attendance compared with those involving younger patients.

TRIF is a critical survival factor in viral cardiomyopathy.

TRIF is a member of the innate immune system known to be involved in viral recognition and type I IFN activation. Because IFNs are thought to play an important role in viral myocarditis, we investigated the role of TRIF in induced myocarditis in mice. Whereas C57BL/6 (wild-type) mice showed only mild myocarditis, including normal survival postinfection with coxsackievirus group B serotype 3 (CVB3), infection of TRIF(-/-) mice led to the induction of cardiac remodeling, severe heart failure, and 100% mortality (p < 0.0001). These mice showed markedly reduced virus control in cardiac tissues and cardiomyocytes. This was accompained with dynamic cardiac cytokine activation in the heart, including a suppression of the antiviral cytokine IFN-ß in the early viremic phase. TRIF(-/-) myocytes displayed a TLR4-dependent suppression of IFN-ß, and pharmacological treatment of CVB3-infected TRIF(-/-) mice with murine IFN-ß led to improved virus control and reduced cardiac inflammation. Additionally, this treatment within the viremic phase of myocarditis showed a significant long-term outcome indexed by reduced mortality (20 versus 100%; p < 0.001). TRIF is essential toward a cardioprotection against CVB3 infection.

Myeloid differentiation factor-88 contributes to TLR9-mediated modulation of acute coxsackievirus B3-induced myocarditis in vivo.

Toll-like receptor 9 (TLR9) is a member of the innate immune system and has been shown to influence myocardial function, but its role in myocarditis is hitherto unknown. We therefore investigated whether or not TLR9 plays a role in this disease in coxsackievirus B3 (CVB3)-induced myocarditis in mice. Left ventricular (LV) function, cardiac immune cell infiltration, virus mRNA, and components of the TLR9 downstream pathway were investigated in TLR9-deficient [knockout (KO)] and wild-type (WT) mice after infection with CVB3. Murine cardiac TLR9 expression was significantly increased in WT mice with acute CVB3 infection but not in WT mice with chronic myocarditis. Furthermore, in the acute phase of CVB3-induced myocarditis, CVB3-infected KO mice displayed improved LV function associated with reduced cardiac inflammation indexed by reduced amounts of immune cells compared with CVB3-infected WT mice. In contrast, in the chronic phase, LV function and inflammation were not seen to differ among the infected groups. The cardioprotective effects due to TLR9 deficiency were associated with suppression of the TLR9 downstream pathway as indexed by reduced cardiac levels of the adapter protein myeloid differentiation factor (MyD)-88 and the proinflammatory cytokine TNF-alpha. In addition, TLR9 deficiency led to an activation of the antiviral cytokine interferon-beta in the heart as a result from viral infection. In conclusion, the MyD88/TNF-alpha axis due to TLR9 activation in the heart contributes the development of acute myocarditis but not of chronic myocarditis.

Pretreatment with statin attenuates the cardiotoxicity of Doxorubicin in mice.

Cardiotoxicity, which may result from intense cardiac oxidative stress and inflammation, is the main limiting factor of the anticancer therapy using doxorubicin. Because statins might exert beneficial pleiotropic cardiovascular effects, among other things, by anti-inflammatory and antioxidative mechanisms, we investigated whether or not fluvastatin pretreatment can attenuate doxorubicin-induced cardiotoxicity. Five days after a single injection of doxorubicin (20 mg/kg; i.p.), left ventricular (LV) function was measured in fluvastatin-treated (DoxStatin; 100 mg/kg/day, p.o.) and saline-treated (doxorubicin) mice (n = 8 per group) by a micro conductance catheter. Untreated mice served as controls (placebo; n = 8 per group). After measurement of cardiac function, LV tissues were analyzed by molecular biological and immunohistologic methods. Injection resulted in significantly impaired LV function (LV pressure, -29%; dp/dtmax, -45%; cardiac output, -68%; P < 0.05) when compared with placebo. This was associated with a significant increase in cardiac oxidative stress, inflammation and apoptotic mechanisms, as indicated by significant increased cardiac lipid peroxidation activity, protein expression of nitrotyrosine, tumor necrosis factor alpha and Bax (P < 0.05). In contrast, DoxStatin mice showed improved LV function (LV pressure, +24%; dp/dtmax, +87%; cardiac output, +87%; P < 0.05) when compared with untreated doxorubicin mice. This was associated with reduced cardiac expression of nitrotyrosine, enhanced expression of the mitochondrial located antioxidative SOD 2, attenuated mitochondrial apoptotic pathways, and reduced cardiac inflammatory response. Statin pretreatment attenuates doxorubicin-induced cardiotoxicity via antioxidative and anti-inflammatory effects.

Toll-like receptor-4 modulates survival by induction of left ventricular remodeling after myocardial infarction in mice.

Left ventricular (LV) remodeling is known to contribute to morbidity and mortality after myocardial infarction (MI). Because LV remodeling is strongly associated with an inflammatory response, we investigated whether or not TLR-4 influences LV remodeling and survival in a mice model of MI. Six days after MI induction, TLR4 knockout (KO)-MI mice showed improved LV function 32 and reduced LV remodeling as indexed by reduced levels of atrial natriuretic factor and total collagen as well as by a reduced heart weight to body weight ratio when compared with WT-MI mice. This was associated with a reduction of protein levels of the intracellular TLR4 adapter protein MyD88 and enhanced protein expression of the anti-hypertrophic JNK in KO-MI mice when compared with wild-type (WT)-MI mice. In contrast, protein activation of the pro-hypertrophic kinases protein kinase Cdelta and p42/44 were not regulated in KO-MI mice when compared with WT-MI mice. Improved LV function, reduced cardiac remodeling, and suppressed intracellular TLR4 signaling in KO-MI mice were associated with significantly improved survival compared with WT-MI mice (62 vs 23%; p < 0.0001). TLR4 deficiency led to improved survival after MI mediated by attenuated left ventricular remodeling.

Toll-like receptor-4 deficiency attenuates doxorubicin-induced cardiomyopathy in mice.

BACKGROUND: Cardiac inflammation and generation of oxidative stress are known to contribute to doxorubicin (Dox)-induced cardiomyopathy. Toll-like receptors (TLRs) are a part of the innate immune system and are involved in cardiac stress reactions. Since TLR4 might play a relevant role in cardiac inflammatory signalling, we investigated whether or not TLR4 is involved in Dox-induced cardiotoxicity. METHODS AND RESULTS: Five days after a single injection of Dox (20 mg/kg; i.p.), left ventricular pressure-volume loops were measured in wild-type and TLR4-deficient mice (TLR4-/-) Dox-treated and control mice. Analyses of possible pathophysiological mechanisms were performed in left ventricular tissue and isolated myocytes, respectively. Dox injection resulted in an impairment of left ventricular function and neurohumoral activation, indexed by increased ET-1 expression. This was further associated with an increase in cardiac oxidative stress, inflammation and apoptosis, as indicated by an up-regulation of cardiac lipid peroxidation, TNF-alpha expression and enhanced content of TUNEL-positive cells. In contrast, TLR4-/- Dox mice showed improved left ventricular function with reduced oxidative and inflammatory stress response including reduced cardiac apoptosis. These results were found to be associated with an increase of GATA-4 expression. CONCLUSIONS: TLR4 deficiency improves left ventricular function and attenuates pathophysiological key mechanisms in Dox-induced cardiomyopathy.

Preamplification techniques for real-time RT-PCR analyses of endomyocardial biopsies.

BACKGROUND: Due to the limited RNA amounts from endomyocardial biopsies (EMBs) and low expression levels of certain genes, gene expression analyses by conventional real-time RT-PCR are restrained in EMBs. We applied two preamplification techniques, the TaqMan(R) PreAmp Master Mix (T-PreAmp) and a multiplex preamplification following a sequence specific reverse transcription (SSRT-PreAmp). RESULTS: T-PreAmp encompassing 92 gene assays with 14 cycles resulted in a mean improvement of 7.24 +/- 0.33 Ct values. The coefficients for inter- (1.89 +/- 0.48%) and intra-assay variation (0.85 +/- 0.45%) were low for all gene assays tested (<4%). The PreAmp uniformity values related to the reference gene CDKN1B for 91 of the investigated gene assays (except for CD56) were -0.38 +/- 0.33, without significant differences between self-designed and ABI inventoried Taqman(R) gene assays. Only two of the tested Taqman(R) ABI inventoried gene assays (HPRT-ABI and CD56) did not maintain PreAmp uniformity levels between -1.5 and +1.5. In comparison, the SSRT-PreAmp tested on 8 self-designed gene assays yielded higher Ct improvement (9.76 +/- 2.45), however was not as robust regarding the maintenance of PreAmp uniformity related to HPRT-CCM (-3.29 +/- 2.40; p < 0.0001), and demonstrated comparable intra-assay CVs (1.47 +/- 0.74), albeit higher inter-assay CVs (5.38 +/- 2.06; p = 0.01). Comparing EMBs from each 10 patients with dilated cardiomyopathy (DCM) and inflammatory cardiomyopathy (DCMi), T-PreAmp real-time RT-PCR analyses revealed differential regulation regarding 27 (30%) of the investigated 90 genes related to both HPRT-CCM and CDKN1B. Ct values of HPRT and CDKN1B did not differ in equal RNA amounts from explanted DCM and donor hearts. CONCLUSION: In comparison to the SSRT-PreAmp, T-PreAmp enables a relatively simple workflow, and results in a robust PreAmp of multiple target genes (at least 92 gene assays as tested here) by a mean Ct improvement around 7 cycles, and in a lower inter-assay variance in RNA derived from EMBs. Preliminary analyses comparing EMBs from DCM and DCMi patients, revealing differential regulation regarding 30% of the investigated genes, confirm that T-PreAmp is a suitable tool to perform gene expression analyses in EMBs, expanding gene expression investigations with the limited RNA/cDNA amounts derived from EMBs. CDKN1B, in addition to its function as a reference gene for the calculation of PreAmp uniformity, might serve as a suitable housekeeping gene for real-time RT-PCR analyses of myocardial tissues.

Comparison of myocardial reperfusion in patients undergoing percutaneous coronary intervention in ST-segment elevation acute myocardial infarction with versus without diabetes mellitus (from the EMERALD Trial).

Diabetes mellitus is strongly associated with increased cardiovascular morbidity and mortality in patients with ST-segment elevation myocardial infarction. It is unknown whether myocardial perfusion is decreased in diabetic compared with nondiabetic patients after primary percutaneous coronary intervention (PCI), which may contribute to their worse prognosis. We compared myocardial perfusion and infarct sizes between diabetic and nondiabetic patients undergoing PCI for acute ST-segment elevation myocardial infarction in the EMERALD trial. EMERALD was a prospective, randomized, multicenter study evaluating distal embolic protection during primary PCI in ST-segment elevation myocardial infarction. End points included final myocardial blush grade, complete ST-segment resolution (STR) 30 minutes after PCI, and final infarct size as determined by technetium-99m single proton emission computed tomography measured between days 5 and 14. Of 501 patients, 62 (12%) had diabetes mellitus. Diabetic patients had impaired myocardial perfusion after PCI as measured by myocardial blush grade 0/1 (34% vs 16%, p = 0.002) and lower rates of complete 30-minute STR (45% vs 65%, p = 0.005). Infarct size (median 20% vs 11%, p = 0.005), development of new onset severe congestive heart failure (12% vs 4%, p = 0.016), and 30-day mortality (10% vs 1%, p <0.0001) were also greater in diabetic patients. After multivariate adjustment, diabetes remained associated with lack of complete STR and mortality at 6 months. Use of distal protection devices did not improve outcomes in diabetic or nondiabetic patients. In conclusion, in patients with ST-segment elevation myocardial infarction undergoing primary PCI, diabetes is independently associated with decreased myocardial reperfusion, larger infarct, development of congestive heart failure, and decreased survival.

Impact of time to treatment on myocardial reperfusion and infarct size with primary percutaneous coronary intervention for acute myocardial infarction (from the EMERALD Trial).

The impact of time to treatment on outcomes after primary percutaneous coronary intervention (PCI) is controversial, and there are few data about time to treatment and infarct size. The EMERALD trial randomly assigned 501 high-risk patients with ST-elevation myocardial infarction undergoing primary PCI to stenting with or without GuardWire (Medtronic, Santa Rosa, California) distal protection. Infarct size using sestamibi imaging at 5 to 14 days and clinical outcomes were examined by time to treatment. There were no differences in outcomes between distal protection and control patients. Shorter time to reperfusion (<2 vs 2 to 3 vs >3 to 4 vs >4 hours) was associated with smaller infarct size (2% vs 9% vs 12% vs 11%, p=0.026), trends for better myocardial blush (p=0.08), and lower 6-month mortality rates (0% vs 0% vs 2.4% vs 5.3%, p=0.06). Incremental delays in reperfusion after 2 hours had little impact on infarct size. Shorter time to reperfusion impacted on infarct size in patients with anterior infarction (0% vs 17% vs 20.5% vs 30.5%, p=0.026), but not nonanterior infarction (3% vs 7% vs 7.5% vs 10%, p=0.23, p=0.022 for interaction). In conclusion, very early reperfusion with primary PCI is associated with smaller infarct size and has a much greater impact in anterior versus nonanterior infarction. Incremental delays in reperfusion after 2 hours have less effect on infarct size. These data have implications regarding the triage of patients for primary PCI.

Distal microcirculatory protection during percutaneous coronary intervention in acute ST-segment elevation myocardial infarction: a randomized controlled trial.

CONTEXT: Atheromatous and thrombotic embolization during percutaneous coronary intervention (PCI) in acute myocardial infarction is common and may result in microcirculatory dysfunction, the prevention of which may improve reperfusion success, reduce infarct size, and enhance event-free survival. OBJECTIVE: To determine whether protection of the distal microcirculation from thromboembolic debris liberated during primary PCI results in improved reperfusion and decreased infarct size. DESIGN, SETTING, AND PATIENTS: Prospective randomized controlled trial at 38 academic and community-based institutions in 7 countries enrolling 501 patients aged 18 years or older with ST-segment elevation myocardial infarction (STEMI) presenting within 6 hours of symptom onset and undergoing primary PCI or rescue intervention after failed thrombolysis. INTERVENTIONS: Patients were randomized between May 20, 2002, and November 21, 2003, to receive PCI with a balloon occlusion and aspiration distal microcirculatory protection system vs angioplasty without distal protection. MAIN OUTCOME MEASURES: Coprimary end points were ST-segment resolution (STR) measured 30 minutes after PCI by continuous Holter monitoring and infarct size measured by technetium Tc 99m sestamibi imaging between days 5 and 14. Secondary end points included major adverse cardiac events. RESULTS: Among 252 patients assigned to distal protection, aspiration was performed in 97% (242/251), all angioplasty balloon inflations were fully protected in 79% (193/245), and visible debris was retrieved from 73% (182/250). Complete STR was achieved in a similar proportion reperfused with vs without distal protection (63.3% [152/240] vs 61.9% [148/239], respectively; absolute difference, 1.4% [95% confidence interval, -7.7% to 10.5%; P = .78]), and left ventricular infarct size was similar in both groups (median, 12.0% [n = 229] vs 9.5% [n = 208], respectively; P = .15). Major adverse cardiac events at 6 months occurred with similar frequency in the distal protection and control groups (10.0% vs 11.0%, respectively; P = .66). CONCLUSIONS: A distal balloon occlusion and aspiration system effectively retrieves embolic debris in most patients with acute STEMI undergoing emergent PCI. Nonetheless, distal embolic protection did not result in improved microvascular flow, greater reperfusion success, reduced infarct size, or enhanced event-free survival.

The cardiac mechanical stretch sensor machinery involves a Z disc complex that is defective in a subset of human dilated cardiomyopathy.

Muscle cells respond to mechanical stretch stimuli by triggering downstream signals for myocyte growth and survival. The molecular components of the muscle stretch sensor are unknown, and their role in muscle disease is unclear. Here, we present biophysical/biochemical studies in muscle LIM protein (MLP) deficient cardiac muscle that support a selective role for this Z disc protein in mechanical stretch sensing. MLP interacts with and colocalizes with telethonin (T-cap), a titin interacting protein. Further, a human MLP mutation (W4R) associated with dilated cardiomyopathy (DCM) results in a marked defect in T-cap interaction/localization. We propose that a Z disc MLP/T-cap complex is a key component of the in vivo cardiomyocyte stretch sensor machinery, and that defects in the complex can lead to human DCM and associated heart failure.