Gregory I.C. Nelson

First-line treatment of left ventricular failure complicating acute myocardial infarction: a randomised evaluation of immediate effects of diuretic, venodilator, arteriodilator, and positive inotropic drugs on left ventricular function

A prospective randomised trial compared the immediate haemodynamic effects of intravenous diuretic (frusemide), venodilator (isosorbide dinitrate). arteriolar dilator (hydralazine), and positive inotropie stimulation (prenalterol) as first-line therapy for acute left ventricular (LV) failure following myocardial infarction. Forty-eight patients with transmural myocardial infarction and a pulmonary artery occluded pressure (PAOP) of >20 mm Hg were studied within 18 h of admission to a coronary care unit. Both frusemide (-4 mm Hg: p < 0.01) and isosorbide dinitrate (-6 mm Hg: p < 0.01) reduced LV filling pressure without change in cardiac index and heart rate. Although both hydralazine and prenalterol increased cardiac index (p < 0.01), the reduction in LV filling pressure (-2 mm Hg: p < 0.05) was less than with frusemide and isosorbide dinitrate. and was associated with an increased heart rate (+8 and + 13 beats min−1: p < 0.01). These data suggest that in acute heart failure following myocardial infarction the four treatment modalities could be ranked in descending order of potential benefit as follows: (a) venodilatation (isosorbide dinitrate) — decrease of LV pressure/work: (b) diuretic therapy (frusemide)— decrease of LV pressure/work offset by a transient pressor effect: (c) arteriolar dilatation (hydralazine) —decrease of LV pressure/work and of PAOP. but offset by tachycardia: and (d) positive inotropic therapy (β1-agonist prenalterol) — tachycardia and augmented LV afterload. Combination of the former and latter agents, because of their differing modes of action, should offer haemodynamic advantages over monotherapy and deserves further evaluation.

Prevalence of coronary occlusion and outcome of an immediate invasive strategy in suspected acute myocardial infarction with and without ST-segment elevation

The prevalence of flow-limiting coronary lesions at the time of presentation in patients with non-ST-segment elevation myocardial infarction (NSTEMI) is unknown. Because rational reperfusion strategies depend on early, accurate identification of coronary flow limitation, we performed coronary angiography at the time of presentation of patients with suspected NSTEMI. We also evaluated outcomes of an immediate interventional strategy. A comparison is made with suspected ST-segment elevation myocardial infarction (STEMI). Unselected consecutive patients with suspected STEMI or NSTEMI were enrolled in a prospective observational cohort study. Suspected STEMI was defined according to standard criteria. Suspected NSTEMI was identified by clinical evaluation of symptoms, electrocardiographic changes, persistence of ischemic pain for >20 minutes despite treatment, and/or hemodynamic instability. Biochemical evidence of myocardial necrosis on presentation was not mandatory. An immediate, around-the-clock invasive strategy was applied. Significant coronary lesions were found in 94% of 279 patients with suspected STEMI and in 90% of 125 patients with suspected NSTEMI, and coronary occlusion or flow limitation was present in 75% and 63% of patients, respectively. Immediate percutaneous coronary intervention was performed in 74% and 60%, respectively, and an additional 13% and 18%, respectively, had coronary artery bypass surgery during the index admission. In-hospital mortalities in the patients with suspected STEMI and NSTEMI were 4.7% and 5.6%, respectively. An additional 1.9% and 2.5% died at 6 months. The prevalence of coronary flow limitation in clinically suspected NSTEMI is almost as high as in suspected STEMI. Short- and long-term outcomes of an immediate invasive strategy are similar for the 2 conditions.

Hemodynamic effects of nifedipine during upright exercise in stable angina pectoris and either normal or severely impaired left ventricular function

The immediate effects of sublingual nifedipine (20 mg) were evaluated in 18 men with stable, exercise-related angina pectoris and angiographically confirmed coronary artery obstructions, stratified at the time of left ventricular (LV) angiography according to the degree of LV dysfunction supine at rest (Group 1: n = 9, left ventricular end-diastolic pressure [LVEDP] less than 20 mm Hg; Group 2: n = 9, LVEDP greater than 20 mm Hg). At rest, in the upright posture in both groups, nifedipine reduced the systemic vascular resistance (p less than 0.01). The systemic arterial mean (p less than 0.05) and diastolic (p less than 0.01) pressures were reduced despite an increase in the cardiac output (p less than 0.05). Heart rate was increased only in Group 1 (p less than 0.05). Pulmonary artery occluded pressure was unchanged in both groups. During upright bicycle exercise in all patients, compared to control measurements, systemic arterial pressure (p less than 0.01) and vascular resistance (p less than 0.05) were similarly reduced, while exercise cardiac output response and LV filling pressure did not change after nifedipine. Heart rate was increased in Group 1 (p less than 0.05) and decreased in Group 2 (p less than 0.05). Stroke volume during exercise after nifedipine decreased 1 ml/m2 in Group 1 (p greater than 0.05) and increased 2 ml/m2 in Group 2 (p greater than 0.05) compared to control measurements; the between-group difference in the exercise heart rate and stroke volume responses after nifedipine were significant at the 5% level.(ABSTRACT TRUNCATED AT 250 WORDS)

Hemodynamic comparison of primary venous or arteriolar dilatation and the subsequent effect of furosemide in left ventricular failure after acute myocardial infarction.

The hemodynamic effect of venous dilatation (intravenous isosorbide dinitrate [ISDN]) and arteriolar dilatation (intravenous hydralazine), both as firstline treatment and then combined with intravenous furosemide, were evaluated in a randomized, between-group comparison in 20 men with severe acute left-sided cardiac failure after myocardial infarction (MI). Both ISDN (50 to 200 micrograms/kg/hour) (Group 1) and hydralazine (0.15 mg/kg) (Group 2) reduced systemic arterial pressure (p less than 0.05) and vascular resistance (p less than 0.05). Pulmonary artery occluded pressure was reduced (p less than 0.01) only by ISDN, whereas heart rate (p less than 0.01), cardiac output (p less than 0.01) and stroke volume (p less than 0.05) were increased only after hydralazine. After ISDN, furosemide (1 mg/kg) decreased left-sided cardiac filling pressure by 1 mm Hg (p greater than 0.05), whereas after hydralazine, furosemide in a similar dose reduced pulmonary artery occluded pressure by 5 mm Hg (p less than 0.01). In both groups of patients, furosemide transiently increased systemic arterial pressure (p less than 0.05). Cardiac output was reduced (p less than 0.05) and systemic vascular resistance increased (p less than 0.05) in Group 1 patients after furosemide. Similar changes in both variables in Group 2 patients did not attain statistical significance. In conclusion, ISDN-induced venous dilatation is preferable to primary arteriolar dilatation by hydralazine as first-line treatment in acute left-sided cardiac failure. However, hydralazine and furosemide in combination were equally effective in reducing pulmonary artery occluded pressure and increasing cardiac output. The influences of each regimen on prognosis await further investigation.

The effects on left ventricular performance of verapamil and metoprolol singly and together in exercise-induced angina pectoris

Concurrent therapy with the calcium channel blocker, verapamil, and the beta-blocking group of compounds is usually felt to be clinically contraindicated due to the formers potent dromotropic and negative inotropic actions. The basis of this assumption was examined in a rest and exercise hemodynamic study of the effects of verapamil and the cardioselective beta-blocking drug, metoprolol, in 22 patients with stable angina pectoris and angiographically confirmed coronary artery disease. In a randomized study, 11 patients were assessed following intravenous verapamil (16 mg) alone, 11 following intravenous metoprolol (10 mg) alone, and all 22 were assessed on combination therapy. The plasma levels achieved at the time of each hemodynamic assessment were in the therapeutic range. At rest, verapamil alone significantly lowered systemic arterial pressure and vascular resistance; metoprolol alone lowered heart rate and increased systemic vascular resistance without change in systemic arterial pressure. Combination therapy reduced systemic arterial pressure and heart rate without change in cardiac output and systemic vascular resistance. During upright bicycle exercise, the changes were directionally similar. Depression of cardiac function (i.e., reduced cardiac output at increased pulmonary artery occluded pressure) occurred following metoprolol but not following verapamil; the addition of verapamil did not accentuate the depression of function induced by metoprolol. These results suggested that in patients with stable coronary artery disease, without manifest conduction system abnormality, the cardiac depressant actions of verapamil were countered by its vasodilator properties.(ABSTRACT TRUNCATED AT 250 WORDS)

Procedural and in-patient outcomes in patients aged 80 years or older undergoing contemporary primary percutaneous coronary intervention

AIMS Patients aged ≥80 years are often excluded or under-represented in trials assessing treatment modalities in STEMI. We assessed in-patient outcomes in elderly patients undergoing contemporary primary PCI (PPCI). METHODS AND RESULTS From Sept 2005 to July 2011 patients undergoing PPCI in our centre were identified. Demographic details, procedural data and in-patient outcomes were collated. Those aged ≥80 years were compared with those aged <80 years. In the study period 1,218 patients required PPCI, of which 224(18.4%) were ≥80 years. The elderly cohort were more likely to be female (44.3% vs. 20.3%; p<0.001), and have significant comorbidities. Times from first medical contact until TIMI 3 flow were similar between the two groups (medien 102 min vs. 109 min; p=0.19). There was no difference in rates of PCI success (97.3% vs. 98.3%; p=0.24), drug-eluting stent use (63.5% vs. 63.3%; p=1.00) and number of stents used. In-patient outcomes were worse in the elderly cohort with significantly higher rates of death (11.2% vs. 3.7%; p<0.001) and acute kidney injury (12.9% vs. 4.0%; p<0.001), with a trend towards more post-procedure cardiovascular accidents (CVA), access site complications and reinfarction. Length of stay was significantly longer in the elderly cohort (median days 5 vs. 3; p<0.001). CONCLUSIONS Important demographic differences exist in very elderly patients presenting with STEMI compared to younger patients though procedural data and PCI success rates are similar between the two groups. Those aged ≥80 years have significantly worse in-patient outcomes though death rates are not as high as historical data suggests.

A randomised study of the haemodynamic changes induced by venodilatation and arteriolar dilatation singly and together in left ventricular failure complicating acute myocardial infarction.

A randomised between-group study of the immediate haemodynamic effects of venodilatation by intravenous isosorbide dinitrate infusion (50–200 μg/kg/h) and arteriolar dilatation by intravenous hydralazine bolus (0.15 mg/kg) given either in random sequence (Groups 1 and 2; n = 12) or simultaneously (Group 3; n = 6) was undertaken in 18 men with radiographic and haemodynamic evidence (left ventricular [LV] filling pressure greater than 20 mm Hg) of LV failure 6–19 h following acute myocardial infarction. Control measurements (1 h) preceded either two consecutive 90-min treatment periods (Groups 1 and 2) or a single 90-min period (Group 3). Given independently, both drugs reduced systemic arterial pressure and vascular resistance, whereas only isosorbide dinitrate reduced LV filling pressure and only hydralazine increased cardiac output and stroke volume. Isosorbide dinitrate/hydralazine in combination significantly reduced LV filling pressure, systolic and diastolic arterial pressure, and total systemic vascular resistance. Cardiac output, stroke volume, and heart rate were increased. In conclusion, combined arteriolar dilatation and venodilatation appears to be of greater haemodynamic benefit than either alone, if the fall in mean systemic pressure does not compromise peripheral perfusion.

Cardiac Thrombi in Stress (Tako-Tsubo) Cardiomyopathy: More Than an Apical Issue?

To the Editor: A 61-year-old postmenopausal woman has presented 3 times within 4 years with acute tako-tsubo cardiomyopathy (TTC). Each admission was precipitated by a heated argument and characterized by severe central chest pain, anterior ST-segment elevation, and elevated serum troponin levels; however, angiography revealed normal coronary arteries. Inotropic and noninvasive ventilatory support was required on all 3 occasions and intubation on 1 occasion. Left ventricular (LV) apical thrombus complicated the first episode but resolved with anticoagulation. Rapid normalization of LV systolic function on echocardiography, as well as resolution of the ST-segment elevation on electrocardiography, was observed after each presentation. During the patients latest admission, coronary angiography (on day 10) revealed a large and mobile LV apical thrombus (Figure 1, top). This thrombus had not been observed on transthoracic echocardiography performed 6 days before angiography, and it had developed despite administration of aspirin and subcutaneous heparin and in the absence of atrial fibrillation on continuous monitoring. FIGURE 1. Top, Left ventricular apical thrombus (circle) as seen by ventriculography (day 10 of most recent admission). Bottom, Left ventricular apical thrombus (circle) and left atrial appendage thrombus (arrow) as seen on cardiac magnetic resonance imaging (day ... Cardiac magnetic resonance imaging was performed to exclude alternative myocardial pathology. A scan obtained on day 12 showed normalization of LV systolic function with no late gadolinium enhancement. However, in addition to the apical thrombus in the LV, the scan revealed a large thrombus in the left atrial appendage (LAA) (Figure 1, bottom, supplemental video). Echocardiographic assessment of left atrial (LA) function at presentation was suggestive of transient LA enlargement and dysfunction (Table). Screening for thrombophilia was negative. TABLE. Echocardiographic Left Atrial Parameters During the Acute and Recovery Phase of Tako-Tsubo Cardiomyopathy Left ventricular apical thrombus formation is a known complication of TTC and has been reported in up to 8% of case series,1 with potential for embolic sequelae. To our knowledge, this is the first published report of LAA thrombus complicating TTC independent of atrial fibrillation. We hypothesize that the following mechanisms are important contributors to thrombus formation in the setting of acute TTC: Catecholamine excess–induced platelet activation and aggregation. Plasma catecholamine levels have been found to be higher at presentation in patients with TTC than in those with ST-segment elevation myocardial infarction.2 Both norepinephrine and epinephrine have been shown to induce platelet activation.3 Catecholamine-mediated endothelial and cardiomyocyte injury. Surges of catecholamines may induce cardiac myocyte injury via cyclic adenosine monophosphate–mediated calcium overload4 or indirectly due to catecholamine-induced endothelial dysfunction and associated damage to underlying myocytes.5 Myocytes in the LV apex are thought to be particularly sensitive to excessive levels of catecholamines, partly as a result of the higher endothelial to myocardial ratio.6 Our finding of an LAA thrombus suggests that myocytes in the left atrium may also be sensitive to the pathological milieu of TTC. Atrial dysfunction may be compounded by increased atrial filling pressures secondary to increases in LV end-diastolic pressure. Consistent with this and the current case, patients with TTC have been shown to have worse LA function compared with those with ST-segment elevation myocardial infarction.7 Although the occurrence of the LV apical thrombus in the episode of TTC we describe was most likely caused by acute ventricular wall akinesis, we suggest that increased platelet activation and aggregability due to catecholamine release in conjunction with LA stretch and subsequent endothelial injury may also act as contributory factors that favor thrombus development. The global nature of these factors may explain thrombosis in other cardiac chambers, such as the LAA as described in our case. Given the prothrombotic state that characterizes TTC episodes, a review of anticoagulation protocols for this condition may be warranted.

Rest and exercise hemodynamic effects of sequential alpha-1-adrenoceptor (trimazosin) and beta-adrenoceptor (propranolol) antagonism in essential hypertension

The efficacy of acute beta blockade in essential hypertension is limited by reflex vasoconstriction. The aim of this study was to determine whether the latter response was modified by prior selective alpha-1-adrenoceptor blockade. A single-blind, within-patient, placebo-controlled evaluation of the immediate hemodynamic effects of sequential alpha-1 (trimazosin)- and beta (propranolol)-adrenoceptor blockade was undertaken in 10 men (34 to 58 years) with previously untreated essential hypertension. The study commenced with a 4-minute control period of constant-load (600 to 900 kpm/min) upright bicycle exercise, and measurements were made before (control) and 30 minutes after intravenous trimazosin (2 mg/kg) and exercise was then repeated; measurements at rest were again made 4 minutes after intravenous propranolol (0.2 mg/kg) before a final exercise period. Trimazosin at rest reduced systolic and diastolic arterial pressure and systemic vascular resistance without change in heart rate, cardiac output, or left ventricular (LV) filling pressure. During upright bicycle exercise the reductions in blood pressure were sustained without change in their rest-to-exercise increments. Other circulatory variables did not differ from control values. At rest the addition of propranolol further reduced systolic arterial pressure. Heart rate and cardiac output fell and systemic vascular resistance increased to its pretreatment control value. During exercise the changes at rest were sustained and the rest-to-exercise increments in blood pressure, heart rate, and cardiac output were reduced. LV filling pressure was significantly increased. In conclusion, alpha-1-adrenoceptor blockade modified the adverse effects of acute beta blockade at rest but not during exercise.

Increasing proportion of ST elevation myocardial infarction patients with coronary atherosclerosis poorly explained by standard modifiable risk factors

Aims Identification and management of the Standard Modifiable Cardiovascular Risk Factors (SMuRFs; hypercholesterolaemia, hypertension, diabetes and smoking) has substantially improved cardiovascular disease outcomes. However, cardiovascular disease remains the leading cause of death worldwide. Suspecting an evolving pattern of risk factor profiles in the ST elevation myocardial infarction (STEMI) population with the improvements in primary care, we hypothesized that the proportion of ‘SMuRFless’ STEMI patients may have increased. Methods/results We performed a single centre retrospective study of consecutive STEMI patients presenting from January 2006 to December 2014. Over the study period 132/695 (25%) STEMI patients had 0 SMuRFs, a proportion that did not significantly change with age, gender or family history. The proportion of STEMI patients who were SMuRFless in 2006 was 11%, which increased to 27% by 2014 (odds ratio 1.12 per year, 95% confidence interval: 1.04–1.22). The proportion of patients with hypercholesterolaemia decreased (odds ratio 0.92, 95% confidence interval 0.86–0.98), as did the proportion of current smokers (odds ratio 0.93, 95% confidence interval 0.86–0.99), with no significant change in the proportion of patients with diabetes and hypertension. SMuRF status was not associated with extent of coronary disease; in-hospital outcomes, or discharge prescribing patterns. Conclusion The proportion of STEMI patients with STEMI poorly explained by SMuRFs is high, and is significantly increasing. This highlights the need for bold approaches to discover new mechanisms and markers for early identification of these patients, as well as to understand the outcomes and develop new targeted therapies.