José A. Barrabés

Purulent pericarditis : review of a 20-year experience in a general hospital

OBJECTIVES The purpose of this study was to review the features of purulent pericarditis in patients from a general hospital during a recent 20-year period. BACKGROUND Although studies published from 1974 to 1977 suggested a changing spectrum for purulent pericarditis, this view has not been proved. METHODS We retrospectively evaluated the records of 33 patients from one general hospital who had a diagnosis of purulent pericarditis during the period 1972 to 1991. All autopsy protocols from the same period were also reviewed. In 19 patients (group I), the condition was diagnosed during life; in 14 (group II), it was identified at autopsy. RESULTS In group I, the possible sources of pericardial infection were identified in 17 patients; pneumonia (6 patients) was the most common source. Empyema was present in 10 patients; 15 had cardiac tamponade. The most common microorganisms were streptococci, pneumococci and staphylococci. Six patients developed constrictive pericarditis and required pericardiectomy. Three patients died, 1 patient was lost to follow up and 15 patients had a favorable outcome at a mean follow-up interval of 35 months. In group II, the clinical diagnoses included pneumonia (five patients) among other infections, with empyema in six patients. Purulent pericarditis was probably the direct cause of death in two patients. CONCLUSIONS In our experience, the spectrum of purulent pericarditis has not changed in recent years. Many patients do not have the classical findings of pericarditis, and diagnosis is made only at autopsy or after tamponade has developed. Empyema remains a common predisposing condition. Purulent pericarditis is still a severe disease, but its prognosis is excellent in patients who can be discharged from the hospital.

Gap Junction Uncoupler Heptanol Prevents Cell-to-Cell Progression of Hypercontracture and Limits Necrosis During Myocardial Reperfusion

BACKGROUND The objective of this study was to test the hypothesis that chemical interaction through gap junctions may result in cell-to-cell progression of hypercontracture and that this phenomenon contributes to the final extent of reperfused infarcts. METHODS AND RESULTS Cell-to-cell transmission of hypercontracture was studied in pairs of freshly isolated adult rat cardiomyocytes. Hypercontracture induced by microinjection of a solution containing 1 mmol/L Ca2+ and 2% lucifer yellow (LY) was transmitted to the adjacent cell (11 of 11 pairs), and the gap junction uncoupler heptanol (2 mmol/L) prevented transmission in 6 of 8 pairs (P=.003), with a perfect association between passage of the LY and transmission of hypercontracture. In the isolated, perfused rat heart submitted to 30 minutes of hypoxia, addition of heptanol to the perfusion media during the first 15 minutes of reoxygenation had a dose-related protective effect against the oxygen paradox, as demonstrated by a reduction of diastolic pressure and marked recovery of developed pressure (P<.001), as well as less lactate dehydrogenase release during reoxygenation (P<.001) and less contraction band necrosis (P<.001) than controls. In the in situ pig heart submitted to 48 minutes of coronary occlusion, the intracoronary infusion of heptanol during the first 15 minutes of reperfusion at a final concentration of 1 mmol/L limited myocardial shrinkage, reflecting hypercontracture (P<.05), reduced infarct size after 5 hours of reperfusion by 54% (P=.04), and modified infarct geometry with a characteristic fragmentation of the area of necrosis. Heptanol at 1 mmol/L had no significant effect on contractility of nonischemic myocardium. CONCLUSIONS These results demonstrate that hypercontracture may be transmitted to adjacent myocytes through gap junctions and that heptanol may interfere with this transmission and reduce the final extent of myocardial necrosis during reoxygenation or reperfusion. These findings are consistent with the hypothesis tested and open a new approach to limitation of infarct size by pharmacological control of gap junction conductance.

Effect of inhibition of Na+/Ca2+ exchanger at the time of myocardial reperfusion on hypercontracture and cell death

OBJECTIVE There is recent evidence that Ca(2+) influx via reverse mode Na(+)/Ca(2+) exchange (NCX) at the time of reperfusion can contribute to cardiomyocyte hypercontracture. However, forward NCX is essential for normalization of [Ca(2+)](i) during reperfusion, and its inhibition may be detrimental. This study investigates the effect of NCX inhibition with KB-R7943 at the time of reperfusion on cell viability. METHODS The effect of several concentrations of KB-R7943 added at reperfusion was studied in Fura-2 loaded quiescent cardiomyocytes submitted to 40 min of simulated ischemia (NaCN 2 mM, pH 6.4), and in rat hearts submitted to 60 min of ischemia. [Ca(2+)](i) and cell length were monitored in myocytes, and functional recovery and LDH release in isolated hearts. From these experiments an optimal concentration of KB-R7943 was identified and tested in pigs submitted to 48 min of coronary occlusion and 2 h of reperfusion. RESULTS In myocytes, KB-R7943 at concentrations up to 15 microM reduced [Ca(2+)](i) rise and the probability of hypercontracture during re-energization (P<0.01). Nevertheless, in rat hearts, the effects of KB-R7943 applied during reperfusion after 60 min of ischemia depended on concentration and timing of administration. During the first 5 min of reperfusion, KB-R7943 (0.3-30 microM) induced a dose-dependent reduction in LDH release (half-response concentration 0.29 microM). Beyond 6 min of re-flow, KB-R7943 had no effect on LDH release, except at concentrations > or = 15 microM, which increased LDH. KB-R7943 at 5 microM given during the first 10 min of reflow reduced contractile dysfunction (P=0.011), LDH release (P=0.019) and contraction band necrosis (P=0.014) during reperfusion. Intracoronary administration of this concentration during the first 10 min of reperfusion reduced infarct size by 34% (P=0.033) in pigs submitted to 48 min of coronary occlusion. CONCLUSIONS These results are consistent with the hypothesis that during initial reperfusion NCX activity results in net reverse mode operation contributing to Ca(2+) overload, hypercontracture and cell death, and that NCX inhibition during this phase is beneficial. Beyond this phase, NCX inhibition may impair forward mode-dependent Ca(2+) extrusion and be detrimental. These findings may help in the design of therapeutic strategies against lethal reperfusion injury, with NCX as the target.

Prognostic value of lead aVR in patients with a first non-ST-segment elevation acute myocardial infarction.

Background—ST-segment elevation in lead aVR has been associated with severe coronary artery lesions in patients with acute coronary syndromes, but the prognostic significance of this finding is unknown. Methods and Results—We analyzed the initial ECG in 775 consecutive patients admitted to our center with a first acute myocardial infarction without ST-segment elevation in leads other than aVR or V1. The rates of in-hospital death in patients without (n=525) and with 0.05 to 0.1 mV (n=116) or ≥0.1 mV (n=134) of ST-segment elevation in lead aVR were 1.3%, 8.6%, and 19.4%, respectively (P <0.001). After adjustment for the baseline clinical predictors and for ST-segment depression on admission, the odds ratios for death in the last 2 groups were, respectively, 4.2 (95% CI, 1.5 to 12.2) and 6.6 (95% CI, 2.5 to 17.6). The rates of recurrent ischemic events and heart failure during hospital stay also increased in a stepwise fashion among the groups, whereas creatine kinase–MB levels were similar. Among the 437 patients that were catheterized within 6 months, the prevalence of left main or 3-vessel coronary artery disease in the 3 groups was 22.0%, 42.6%, and 66.3%, respectively (P <0.001). Conclusions—Lead aVR contains important short-term prognostic information in patients with a first non–ST-segment elevation acute myocardial infarction. Because the poorer outcome predicted by ST-segment elevation in lead aVR seems to be related to a more severe coronary artery disease, an early invasive approach might be especially beneficial in patients presenting with this finding.

Changes in Hospital Mortality Rates in 425 Patients With Acute ST-Elevation Myocardial Infarction and Cardiac Rupture Over a 30-Year Period

Background— Possible changes in the incidence and outcome of cardiac rupture in patients with ST-elevation myocardial infarction over a long period of time have not been investigated. Methods and Results— The incidence of cardiac rupture in ST-elevation myocardial infarction patients and its mortality rate were investigated during a 30-year period divided into 5 intervals (1977 to 1982, 1983 to 1988, 1989 to 1994, 1995 to 2000, and 2001 to 2006). Of a total of 6678 consecutive patients, 425 experienced a free wall rupture (280 with cardiac tamponade: 227 with electromechanical dissociation and 53 with hypotension) or a septal rupture (145). After the exclusion of referrals from other centers (n=44), the incidence of definite cardiac rupture (septal rupture, anatomic evidence of free wall rupture, or electromechanical dissociation) declined progressively (6.2% in 1977 to 1982 to 3.2% in 2001 to 2006; P<0.001) in parallel with a progressive use of reperfusion therapy (0% to 75.1%; P<0.001). In addition, among patients with cardiac rupture, there was a progressive fall in the rate of death (94% to 75%; P<0.001) despite a trend toward increasing age (66±8 to 75±8 years; P<0.054) in conjunction with better control of systolic blood pressure at 24 hours (130±24 versus 110±18 mm Hg; P<0.001); an increased use of reperfusion therapy (0% to 59%; P<0.001), β-blockers (0% to 45%; P<0.001), angiotensin-converting enzyme inhibitors (0% to 38%; P<0.001), and aspirin (0% to 96%; P<0.001); and a lower use of heparin (99% to 67%; P<0.001). Conclusion— The decline in the incidence in cardiac rupture and its rate of death over the last 30 years appears to be associated with the increasing use of reperfusion strategies and adjunct medical therapy.

Prevention of ischemic rigor contracture during coronary occlusion by inhibition of Na+–H+ exchange

OBJECTIVE To determine the effect of Na(+)-H+ exchange blockade on ischemic rigor contracture and reperfusion-induced hypercontracture. METHODS Thirty-six pigs were submitted to 55 min of coronary occlusion and 5 h reperfusion. Myocardial segment length analysis with ultrasonic microcrystals was used to detect ischemic rigor (reduction in passive segment length change) and hypercontracture (reduction in end-diastolic length). RESULTS Pretreatment with the new, highly selective Na(+)-H+ exchange inhibitor HOE642 before occlusion reduced ischemic rigor (P < 0.05), attenuated segment shrinkage (P < 0.05) during subsequent reperfusion, dramatically reduced infarct size (P < 0.0001) and attenuated arrhythmias (P < 0.01). Inhibition of Na(+)-H+ exchange only during reperfusion by means of direct intracoronary infusion of HOE642 into the area at risk prevented reperfusion arrhythmias but had no effect on final infarct size, while treatment with intravenous HOE642 immediately before reperfusion had no detectable effects. CONCLUSION These results indicate that inhibition of Na(+)-H+ exchange during ischemia is necessary to limit myocardial necrosis secondary to transient coronary occlusion, and that this action could by mediated by a protective effect against ischemic contracture. Inhibition of Na(+)-H+ exchange only during reperfusion has a partial and transient beneficial effect, but only when the inhibitor reaches the area at risk before reflow.

Intravenous administration of the natriuretic peptide urodilatin at low doses during coronary reperfusion limits infarct size in anesthetized pigs

OBJECTIVE It has been shown that cGMP content is reduced in post-ischemic myocardium, and that stimulation of cGMP synthesis prevents cardiomyocyte hypercontracture and cell death in vitro. This study was aimed at determining whether administration of the natriuretic peptide urodilatin (URO) at the time of reperfusion could limit myocardial cell death secondary to transient coronary occlusion. METHODS The relation between cGMP content in reperfused myocardium and the extent of cell death was investigated in isolated rat hearts (n=62) receiving different URO concentrations during initial reperfusion. The dose of intravenous URO necessary to obtain the targeted increase in cGMP in reperfused myocardium was investigated in ten pigs submitted to transient coronary occlusion (CO), and the effect of two selected doses of URO on infarct size was investigated in 22 pigs. RESULTS cGMP was severely reduced in post-ischemic rat hearts. Addition of 0.01 microM URO during the first 15 min of reperfusion had no effect on myocardial cGMP content, functional recovery or LDH release in hearts submitted to 40 or 60 min of ischemia. At 0.05 microM, URO increased myocardial cGMP to 111% of values in normoxic hearts, improved functional recovery (P=0.01) and reduced peak LDH released by 40% (P=0.02). The beneficial effect of urodilatin was abolished by ANP receptor inhibition. At 1 microM, URO increased cGMP in reperfused myocardium to 363% of normoxic controls and had no beneficial effect. In pigs allocated to 47 min of CO and 5 min of reperfusion, cGMP was markedly reduced in reperfused myocardium. Intravenous URO at 10 ng/kg per min during the first 25 min of reperfusion normalized myocardial cGMP after 5 min of reflow (95% of control myocardium), and reduced infarct size by 40% (P=0.04). At 50 ng/kg per min, urodilatin increased myocardial cGMP in reperfused myocardium to 335% of control myocardium and failed to significantly reduce infarct size (46 vs. 66%, P=0.125). None of these doses had detectable hemodynamic effects. CONCLUSIONS Intravenous low-dose URO at the time of reperfusion normalizes myocardial cGMP and limits necrosis. Large doses of URO increasing myocardial cGMP well over normal values may lack this beneficial effect.

Nuclear magnetic resonance‐based metabolomics predicts exercise‐induced ischemia in patients with suspected coronary artery disease

The purpose of this study was to develop a 1H‐nuclear magnetic resonance metabolomic approach capable of predicting the occurrence of exercise‐induced ischemia in patients with suspected coronary artery disease and to identify the metabolite patterns that contribute most importantly to the prediction. In 31 patients with suspected effort angina and without previous myocardial infarction, serum was obtained just prior to a stress single‐photon emission computed tomography. Serum NMR spectra were acquired with pulse‐and‐acquire and T2‐edited sequences. The region between 0.50 and 4.25 ppm was used for analysis. Twenty‐two patients had reversible myocardial perfusion defects and nine did not. Both groups had similar age and clinical profile, except for more smokers and diabetics in the ischemia group, and attained a similar peak heart rate. The best separation was achieved with long T2‐edited spectra, 84% of patients being correctly classified based on the partial least square discriminant analysis. The main contributors to discrimination were lactate, glucose, as well as methyl and methylene moieties of lipids and long‐chain amino acids. Metabolomic analysis of serum can predict exercise‐inducible ischemia in patients with suspected coronary artery disease. This capability could be useful in screening and risk stratification of patients with coronary risk factors. Magn Reson Med 60:27–32, 2008.

Ischaemic conditioning and targeting reperfusion injury: a 30 year voyage of discovery

To commemorate the auspicious occasion of the 30th anniversary of IPC, leading pioneers in the field of cardioprotection gathered in Barcelona in May 2016 to review and discuss the history of IPC, its evolution to IPost and RIC, myocardial reperfusion injury as a therapeutic target, and future targets and strategies for cardioprotection. This article provides an overview of the major topics discussed at this special meeting and underscores the huge importance and impact, the discovery of IPC has made in the field of cardiovascular research.

Myocardial segment shrinkage during coronary reperfusion in situ. Relation to hypercontracture and myocardial necrosis.

We have investigated the changes in myocardial segment length induced by reperfusion, and their relation to myocyte hypercontracture and contraction band necrosis. Regional wall function was monitored by ultrasonic gauges in 39 pigs submitted to 48-min occlusion of the left anterior descending coronary artery (LAD) and 6 h of reperfusion. Infarct size (triphenyltetrazolium reaction), the extent of contraction band necrosis (quantitative histology) and myocardial water content (desiccation) were measured. Reperfusion induced a marked reduction in end-diastolic length of the LAD segment in all animals, maximal within 15 min after reflow. After 30 min of reperfusion, end-diastolic length of the LAD segment remained below the basal value in 15 animals. The 15 animals that showed shrinkage of the reperfused segment did not differ from the remaining animals in heart rate, aortic pressure, or control segment variables, but had larger infarcts (mean ± SEM: 32.1 ± 5.4 vs 12.1 ± 3.2% of the area at risk,P = 0.003). There was an inverse correlation between end-diastolic length of the LAD segment after 30 min of reperfusion and infarct percentage (r = -0.72) or the extent of contraction band necrosis (r = -0.71). End-diastolic length reduction was more pronounced in larger infarcts despite a more severe myocardial oedema. Neither systolic shortening of the LAD segment nor end-diastolic length or systolic shortening of the control segment, or haemodynamic variables after 30 min of reperfusion correlated to infarct percentage or to the extent of contraction band necrosis. It is concluded that myocardial segment shrinkage during reperfusion reflects myocyte hypercontracture leading to contraction band necrosis.