Therapeutic Applications of Cannabinoids in Cardiomyopathy and Heart Failure.

A large number of cannabinoids have been discovered that could play a role in mitigating cardiac affections. However, none of them has been as widely studied as cannabidiol (CBD), most likely because, individually, the others offer only partial effects or can activate potential harmful pathways. In this regard, CBD has proven to be of great value as a cardioprotective agent since it is a potent antioxidant and anti-inflammatory molecule. Thus, we conducted a review to condensate the currently available knowledge on CBD as a therapy for different experimental models of cardiomyopathies and heart failure to detect the molecular pathways involved in cardiac protection. CBD therapy can greatly limit the production of oxygen/nitrogen reactive species, thereby limiting cellular damage, protecting mitochondria, avoiding caspase activation, and regulating ionic homeostasis. Hence, it can affect myocardial contraction by restricting the activation of inflammatory pathways and cytokine secretion, lowering tissular infiltration by immune cells, and reducing the area of infarct and fibrosis formation. These effects are mediated by the activation or inhibition of different receptors and target molecules of the endocannabinoid system. In the final part of this review, we explore the current state of CBD in clinical trials as a treatment for cardiovascular diseases and provide evidence of its potential benefits in humans.

High dose and short-term streptokinase infusion in patients with pulmonary embolism: prospective with seven-year follow-up trial.

BACKGROUND: High dose and short-term streptokinase infusion has proved to improve survival among few patients with pulmonary embolism and cardiogenic shock, without increasing hemorrhagic complications. However its efficacy and safety in terms of long follow-up and in major number of patients requires to be established. METHODS: Patients with pulmonary embolism proved through high probability V/Q lung scan, suggestive echocardiogram, or deep venous thrombosis were enrolled. All were assigned to receive 1,500,000 IU in one-hour streptokinase infusion. The primary end point was efficacy and safety of streptokinase regimen in terms of pulmonary arterial hypertension, right ventricular dysfunction, perfusion abnormalities, recurrence, mortality and hemorrhagic complications. In long-term follow-up, we assessed functional class, recurrence, chronic pulmonary arterial hypertension, postthrombotic-syndrome and mortality. RESULTS: A total of 40 consecutive patients (47.3+/-15.3 years of age) with large or massive pulmonary embolism were enrolled. In 35 patients high dose and short-term streptokinase regimen reversed acute pulmonary arterial hypertension, clinical and echocardiographic evidence of right ventricular dysfunction and improved pulmonary perfusion without increasing hemorrhagic complications. In acute phase 5 patients died, necropsy study performed in 4 patients showed massive pulmonary embolism and right ventricular myocardial infarction, without significant coronary arterial obstruction. Risk factors for mortality and recurrence were: right ventricular global hypokinesis (p<0.0001), 6 hours or over between onset symptoms and streptokinase regimen (p=0.02), severe systolic pulmonary arterial hypertension (p=0.001) right ventricular hypokinesis (p=0.001), hypoxemia (p=0.02) and right ventricular acute myocardial infarction (p<0.0001). Right ventricular hypokinesis (p=0.02) was the only independent risk factor for recurrence. In a seven-year follow-up of the original 35 patients who survived in acute phase, 2 patients were lost and 33 are alive, in functional class I, without recurrence or chronic pulmonary arterial hypertension. CONCLUSIONS: Our report indicates that among properly selected high-risk PE patients, short-term streptokinase infusion is effective and safe.

The Dressler syndrome after pulmonary embolism.

A study was conducted in 14 patients with pericardial syndrome after pulmonary embolism. The role of right ventricular myocardial injury and noncardiogenic pulmonary edema in this syndrome is considered and its existence is established.

Intrapleural fibrinolysis with streptokinase as an adjunctive treatment in hemothorax and empyema: a multicenter trial.

To test the efficacy of intrapleural fibrinolytic therapy in patients with loculated pleural effusions, we conducted an open, prospective, and multicenter trial among five hospitals in Mexico. We enrolled patients with hemothorax or empyema, clotted and/or loculated, that was not resolved through conventional pleural drainage with chest tube and antibiotics in patients with empyema. All patients received repeated doses of 250,000 IU of streptokinase through chest tube. Effectiveness criteria were before and after intrapleural streptokinase (IPSK) drainage, and poststreptokinase radiographic and respiratory function test improvement. Forty-eight patients were studied; there were 30 patients with empyemas, 14 with hemothorax, and 4 patients with malignant pleural effusions without lung trapping. Successful fibrinolysis was obtained in 44 patients, with complete resolution of the pleural collection and adequate radiologic and spirometric improvement. In three of four patients with multiloculated malignant hemothorax with high-yielding pleural drainage, IPSK allowed successful lysis of loci and an adequate pleurodesis was achieved. Only four patients required surgical treatment. The overall success rate in our series was 92%, similar to previous reports. The results in this first prospective and multicentric trial suggest that intrapleural fibrinolysis is an effective and safe adjunctive treatment in patients with heterogeneous pleural coagulated and loculated collections to restore the pulmonary function assessed by respiratory function tests and can obviate surgery in most cases.

[Thrombolysis in unstable angina. A perspective before and after TIMI IIIB]. / Trombolisis en angina inestable. Una perspectiva antes y después del TIMI IIIB.

To identify the utility and security of thrombolytic therapy in unstable angina, we performed: a) retrospective analysis of controlled trials through computers system and cross references; b) analysis of TIMI IIIB trial to identify variables that explain, why thrombolytic therapy was unsuccessful; c) analysis of our clinical experience. For the three models of research, variables of primary and secondary effectivity were designed. Twenty two controlled trials with 3,544 patients were analyzed, the variables of primary effectivity suggest that in patients with unstable angina with sustained and recurrent clinical and electrocardiographic manifestations of acute ischemia, the use thrombolytic therapy could produce benefit, if the main mechanism is an intracoronary thrombus and if it is associated with maximum pharmacologic treatment and anticoagulation in acute phase. In the TIMI IIIB trial, variables that explain unsuccessful thrombolytic therapy were identified. The clinical experience in 17 patients with high risk unstable angina that received streptokinase in accelerated and standard infusion, proved success in 100% of the cases by improvement of ischemia, avoidance of infarction and recurrence, without hemorrhagic complications, without mortality. The results suggest, that in unstable angina with high clinical suspicion of disruption and thrombogenesis, refractory acute ischemia, jeopardized myocardium, and hemodynamic unstability, thrombolytic therapy could be an alternative that eliminates acute ischemia, as a bridge to the use in a second time of a definitive therapy. These data require in our environment revalidation with controlled trials and inclusion of more patients.

[Rescue thrombolysis with repeated doses of streptokinase in acute myocardial infarct. A preliminary report]. / Trombolisis de rescate con dosis repetidas de estreptoquinasa en el infarto agudo del miocardio. Reporte preliminar.

In patients with persistent acute ischemia and early reocclusion after thrombolytic therapy, the available therapeutic options are optimum drug pharmacologic treatment or a mechanical revascularization. Recently, repeated doses of the same thrombolytic agent used (rescue thrombolysis) have been considered. We report our experience in seven patients with acute myocardial infarction treated with conventional streptokinase dose, within the first 6 hs after onset of the symptoms, and whom due to persistent myocardial ischemia or early reocclusion, hemodynamic instability, significative area of myocardium at risk, failure of maximal doses of conventional therapeutic and inaccessibility for performed mechanical revascularization, a second dose of streptokinase was successfully employed in the early (1:45 to 2:30 hs) and late (48 to 50:00 hs) phase, without hemorrhagic complications and without hypersensitivity effects. In every case rescue thrombolysis allowed to limit the time of ischemia and the extension of the myocardial infarction, demonstrated by indirect clinical criteria, improvement in hemodynamic instability and in the ventricular ejection fraction, that can be considered as a postinfarction myocardial function index, as well as by the reduced in-hospital mortality. These findings suggest that in patients with acute myocardial infarction treated with thrombolytic therapy, and persistent acute ischemia or early reocclusion, a second dose of streptokinase could be a safe and effective therapeutic option. Our successful results will lead to a prospective trial.

[Acute infarct of the right ventricle secondary to a massive pulmonary thromboembolism]. / Infarto agudo del ventrículo derecho secundario a tromboembolia pulmonar masiva.

The hemodynamic and cardiovascular responses to a massive pulmonary embolism are: severe pulmonary hypertension, right ventricular failure and cardiogenic shock. The irreversible state of the latest condition and mortality could be due to a secondary right ventricle myocardial infarction, an entity which was first described in 1949. We report a necropsy case with massive pulmonary embolism and as a relevant finding a recent right ventricular myocardial infarction without significant obstructive coronary lesions. The relevance of right ventricle myocardial infarction as a major risk factor for mortality, its clinical and hemodynamic profile as well as the ischemic phenomena, are analyzed. It is emphasized also the importance of an early lysis of thrombus to rescue myocardium and to preserve right ventricle viability. This could be the first case reported in Mexico, in which the relationship between massive pulmonary embolism and right ventricle myocardial infarction is demonstrated as a determinant factor for mortality.

Streptokinase and Heparin versus Heparin Alone in Massive Pulmonary Embolism: A Randomized Controlled Trial.

To test the efficacy of thrombolytic therapy in massive pulmonary embolism, we conducted a prospective randomized controlled trial. Eight patients were randomized to receive either 1,500,000 IU of streptokinase in 1 hour through a peripheral vein followed by heparin or heparin alone. All patients had major risk factors for deep vein thrombosis (DVT) and were considered to have high clinical suspicion for pulmonary embolism (PE). At baseline all patients had a similar degree of systemic arterial hypotension, pulmonary arterial hypertension, and right ventricular dysfunction. The time of onset of cardiogenic shock in both groups was comparable (2.25 +/- 0.5 hours in the streptokinase group and 1.75 +/- 0.96 hours in the heparin group). The four patients who were randomized to streptokinase improved in the first hour after treatment, survived, and in 2 years of follow-up are without pulmonary arterial hypertension. All four patients treated with heparin alone died from 1 to 3 hours after arrival at the emergency room (p = 0.02). Post-thrombolytic therapy the diagnosis of PE was sustained in the streptokinase group by high probability V/Q lung scans and proven DVT. A necropsy study performed in three patients in the heparin group showed massive pulmonary embolism and right ventricular myocardial infarction, without significant coronary arterial obstruction. The results indicate that thrombolytic therapy reduces the mortality rate of massive acute pulmonary embolism.

[The correlation of atrial natriuretic peptide values with those of renin, angiotensin and aldosterone in hypertension patients below and above 50]. / Correlación de valores de péptido natriurético auricular con los de renina, angiotensina y aldosterona en pacientes hipertensos menores y mayores de 50 años.

A comparison of ANP and RAA. In 6 healthy subjects < 50 y, 5 healthy subjects > 50 y, 44 patients with essential hypertension < 50 y, and 41 patients with essential hypertension > 50 y, was performed. ANP values in healthy subjects < 50 y, were means = 44 +/- 7 PG/ml, and means = 87.33 +/- 14 PG/ml in those > 50 y. (P < 0.01). 80% of hypertensives < 50 y, had normal values of ANP (means = 63.8 +/- 10 PG/ml) and 20% high values (means = 131 +/- 6 PG/ml) (P < 0.001). 70% of hypertensives > 50 y, had high ANP values (means = 260 +/- 114 PG/ml) and 30% normal values (means = 75 +/- 5 PG/ml) (P < 0.001). Values for RAA were low or normal in 96% of cases with high ANP values (P < 0.001), and 100% of the cases with high RAA values, had low or normal ANP values. (P < 0.0001). This correlation had an statistically significant value for groups over 50 years (high ANP values, low RAA values) (P < 0.001) and high RAA values with low or normal ANP values in groups below 50 y (P < 0.001). We observed no significant correlation between ANP values and LVH. According to our results, essential hypertensives < 50 y, have low or normal ANP values in the majority of cases (P < 0.001). Essential hypertensives over 50 y. Have high ANP values also in the majority of cases (P < 0.001). As previously reported, an inversely proportional ratio between RAA and ANP was found in our study. The significance of ANP in regulating blood pressure in the elderly is considered.

[High doses and the rapid infusion of streptokinase for the treatment of massive pulmonary thromboembolism]. / Dosis altas e infusión rápida de estreptoquinasa para el tratamiento de tromboembolia pulmonar masiva.

We report the case of a 65 year old woman with no prior cardiac or pulmonary disease, who suffered pulmonary embolism (PE); diagnosis was made on the basis of the existence of risk factors, clinical, radiographic and electrocardiographic features, and a lung scan with perfusion defects and normal ventilation. PE was considered massive because the patient developed acute respiratory failure that required tracheal intubation and mechanical ventilation as well as obstructive shock, electrocardiographic and echocardiographic data of right ventricle overload, and pulmonary hypertension, with pulmonary artery pressure of 38 mmHg. She received an initial treatment with high doses (1,500,000 UI) and rapid infusion (1 hr) of intravenous streptokinase (SK) followed by heparin anticoagulation. Thereafter the hemodynamic disturbances improved and pulmonary artery pressure post-thrombolysis was 23 mmHg. In this report SK at high doses and rapid infusion showed effectiveness and security. We emphasize the usefulness of echocardiography as a diagnostic aid in patients with a previously healthy cardiopulmonary system, as well as the possible role of electrocardiogram as an early indicator of pulmonary reperfusion. This could be the first report of successful thrombolysis with high doses and rapid infusion of SK in massive PE.

Single-dose sublingual nifedipine as the only treatment in hypertensive urgencies and emergencies.

One hundred and eighteen patients with hypertensive urgencies and emergencies and diastolic blood pressure (DBP) at least 120 mm Hg by the cuff method were seen at the Emergency Care Department; none had received calcium channel blockers during the previous twelve hours. Patients with DBP of 120 to 139 mm Hg received 10 mg of sublingual nifedipine; patients with left ventricular hypertrophy or failure, renal disease, hypertensive encephalopathy, angina, papilledema, or a DBP over 140 mm Hg received 20 mg of the drug. The criterion for control was the achievement of a DBP of 100 mm Hg or less within sixty minutes of receiving sublingual nifedipine and maintenance of the effect until discharge. Control was achieved in all patients; a sixty-three-year-old man died of a brain hemorrhage after pulmonary edema and a DBP of 210 had been controlled; the other 117 were discharged to their attending physicians, either as outpatients or to a hospital ward. No patient developed hypotension, clinical or electrocardiographic signs of myocardial ischemia, or clinical signs of neurologic dysfunction. Practical, fast, safe, and dependable control of hypertensive urgencies and emergencies has made sublingual nifedipine the treatment of choice of such patients in the Emergency Care Department.

Dressler-like syndrome after pulmonary embolism and infarction.

Among 195 patients with pulmonary embolism admitted to our hospital, three men and three women, 16 to 65 years old, developed a pericardial syndrome five to 15 days after the onset of pulmonary embolism and infarction. Other known causes of pericarditis were ruled out by clinical history and ancillary methods. The six patients had a pericardial rub, fever, anemia, leukocytosis, and increasing sedimentation rate; four had a pericardial effusion; two had a pleural effusion. One patient, with coexisting heart disease, died after another episode of pulmonary embolism; in the other five, oral corticosteroids induced complete remission of the pericardial syndrome. This type of pericarditis deserves wider recognition.