The importance of reducing heart rate in cardiovascular diseases: effects of Ivabradine.

Heart rate is a major determinant of cardiac output, myocardial oxygen consumption and coronary blood flow under physiological and pathological conditions. Experimental and clinical data have demonstrated that heart rate reduction is the main mechanism for reducing ischemia, improving left ventricular function, decreasing the risk of plaque rupture and post myocardial infarction mortality. Nowadays betablockers are the best class of drugs that can lower heart rate in patients with cardiovascular diseases, but sometimes their use is limited by some contraindications. Ivabradine is a new drug that reduces the firing rate of pacemaker cells in the sinoatrial node through a different mechanism with respect to betablockers. The purpose of this review is to investigate the main trials that support Ivabradine adoption in clinical practice.

Tako-tsubo-like left ventricular dysfunction: transient left ventricular apical ballooning syndrome.

AIMS/OBJECTIVES: This review examines the 'tako-tsubo-like' syndrome or transient left ventricular apical ballooning. The aim of this review is a complete evaluation of epidemiology, clinical and instrumental features, pathophysiological mechanisms, therapy and prognosis of this syndrome. METHODS: We have evaluated the data from literature for a comprehensive consideration of multiple aspects of this syndrome. RESULTS/FINDINGS: Transient left ventricular apical ballooning typically affects women, and the clinical presentation is comparable to acute coronary syndrome with chest pain or sudden dyspnoea, changes in ECG and elevated cardiac enzymes in the absence of significant coronary stenosis, with complete resolution of wall-motion abnormalities in a period of days or weeks. This syndrome is triggered by marked psychological or physiological stress. Several pathophysiological mechanisms have been proposed, such as cathecolamine-mediated cardiotoxicity, abnormalities in coronary microvascular function and multivessel coronary vasospasm. The highest incidence of transient left ventricular apical ballooning is in the Japanese population, but it has been recently identified also in the USA and Europe. Treatment is empirical and supportive. The prognosis is generally favourable, although some deaths have been reported, usually the result of irreversible cardiogenic shock, refractory ventricular arrhythmias, or other catastrophic cardiovascular event. CONCLUSIONS/INTERPRETATIONS: We conclude by emphasising the importance of a more deeper knowledge of this syndrome for general physicians and cardiologists and it should be often considered as a possible diagnosis occurring in emergency department and in patients admitted in the Chest Pain Units with a diagnosis of coronary acute syndrome.

A quadricuspid aortic valve associated with severe aortic regurgitation and left ventricular systolic dysfunction.

We report a case of a quadricuspid aortic valve associated with severe aortic regurgitation and left ventricular systolic dysfunction.

[Homocysteine: a casual link with heart failure?]. / Omocisteina e scompenso cardiaco: un'associazione casuale?

Several studies and recent patents have demonstrated that hyperhomocysteinemia (HHCY) is an independent risk factor for congestive heart failure (CHF); it is also correlated to the severity of the disease. In literature there are some data about effects of HHCY on myocardial structure and function in animal models. These studies indicate a direct effect of HCY in promoting reactive myocardial fibrosis and systolic dysfunction, promoting miocardial redox state, endothelial and mithocondryal dysfunction, negative inotropic effect. According to some authors the HHCY is a potential ethiological factor for heart failure while according to others it is just an epiphenomenon without direct effects on myocardium. Nevertheless the literature studies show the relevant involvement of HHCY in CHF and the strong relations between HHCY plasma levels and the severity and prognosis of the disease. Regarding the potential mechanistic role of HHCY in CHF, all of these studies do not provide any mechanistic insights because of their epidemiological nature. Future studies need to explore the exact pathomechanisms of HHCY in CHF.

Cardiac arrest in a patient with a mobile right atrial thrombus in transit and amyloidosis.

Primary amyloidosis is a rare disorder in which insoluble fibers are deposited in tissue and organs, impairing their function. Cardiac involvement occurs in up to 50% of patients with primary amyloidosis. We describe a case of a 75-year-old admitted to our department after he had a sudden cardiac arrest due to massive bilateral thrombotic occlusion of the pulmonary arteries. The echocardiogram revealed many atrial thrombi swirling inside the right atrium and protruding into the tricuspid valve partly occluding it. Severe concentric hypertrophy of the left ventricle was also present with a preserved ejection fraction. The right ventricle was dilated, hypertrophic and ipokinetic with a severe tricuspidal insufficiency that permitted estimation of a severe pulmonary hypertension. All these characteristics were highly suggestive for an infiltrative form of hypertrophic cardiomyopathy. The final diagnosis was amyloidosis.

Coronary artery fistula: diagnostic role of transthoracic and transesophageal echocardiography.

Congenital coronary artery fistulas (CAFs) are rare. Some patients develop symptoms of congestive heart failure secondary to a large left-to-right shunt or myocardial ischemia from coronary artery steal in the first few years after birth. After the second decade the frequency of symptoms and complications increase. We report a case of CAF originating from the circumflex artery and draining into the coronary sinus, associated with left main coronary aneurysm. Transtho-racic and transesophageal echocardiography approach showed the origin, course, and drainage site of the CAF. This case represents a typical sample of this rare anomaly and puts into evidence the essential role of echocardiography to define and complete the angiographic diagnosis.

Plasma homocysteine levels and late outcome in patients with unstable angina.

AIM OF THE STUDY: Previous studies have suggested that total plasma homocysteine (HCY) is an important cardiovascular risk factor because of its interaction with vascular smooth muscle cells, endothelium function, plasma lipoprotein, coagulation factors and platelets. The aim of this study was to evaluate a possible relationship between HCY levels and the severity of coronary artery disease (CAD) and its prognostic value in patients with unstable angina (UA). METHODS AND RESULTS: Ninety-four patients with UA were recruited and underwent coronary angiography and in some cases myocardial revascularization. The primary end point was the severity of CAD. The clinical end points were the recurrence of UA and the compositive end point of the occurrence of cardiac death and re-hospitalization due to acute coronary syndrome. HCY levels were shown to be poorly correlated with the severity of CAD. After 48 months' of follow-up, a graded relationship between HCY levels and recurrence of UA and compositive end point was found (p < 0.001). CONCLUSIONS: In the light of events occurring during the follow-up period, it was concluded that total plasma HCY is a strong predictor of recurrence of UA.

Brain cancer mimicking an acute coronary syndrome.

The authors report the case of a 62-year-old woman admitted to hospital for episodes of chest pain with ischemic abnormalities at ECG without enzyme release. Coronography confirmed a normal coronary tree with mild ascending aortic dilatation. Subsequent diagnostic and clinical examinations resulted normal. Episodes of chest pain and dyspnea persisted over the following days. Administration of nitrates, calcium antagonist, diuretic, antidepressant agents for suspected syndrome X led to partial improvement of clinical symptoms. The patient was discharged from the hospital. A few days later she was referred to the neurology department because of an episode of transient dysarthria, hyposthenia and paresthesis localized to the right lower and upper limbs associated with chest pain. A brain computed tomography showed an expansive solid mass. Nuclear magnetic resonance imaging and stereotaxis biopsy confirmed the etiology of the lesion to be a glioblastoma. The patient died soon thereafter from respiratory and cardiocirculatory arrest.

[Raised homocysteine plasma concentration in patients with heart failure: clinical significance]. / Elevate concentrazioni plasmatiche di omocisteina in pazienti affetti da insufficienza cardiaca: significato clinico.

UNLABELLED: Elevated plasma levels of homocysteine is associated with increased risk of thrombotic and atherosclerotic vascular disease. Several studies have demonstrated that hyper-homocysteinemia is an indipendent risk factor for vascular disease and is associated to heart failure. However there are no data regarding the association between homocysteine and various objective as well as subjective measures of heart failure. We hypothesized that plasma homocysteine is associated with clinical and echocardiographic signs of heart failure. On this ground we have analysed levels of homocysteine in patients with heart failure and possible correlation between these levels and clinical-functional pattern (NYHA class and ejection fraction). METHODS: Plasma homocysteine levels were determined in 123 patients with dilated cardiomyopathy (59 males, 64 females, mean age 67+/-10 years, mean EF 31+/-11% and mean NYHA 2.4+/-0.9, 47 idiopatic and 76 postischemic cardiomyopathy) and 85 healthy control subjects (homogeneus group for sex and age). Patients with chronic renal failure, vitamin B12 and folate deficiency or factors affecting homocysteine plasma levels were escluded from this study. Homocysteine levels were determined in coded plasma samples by immunoenzimatic methods. RESULTS: Patients with heart failure had a higher homocysteine level (mcg/L) than control subjects (21.72+/-10.28 vs 12.9+/-6.86, p<0,001) both postischemic (20.89+/-9.6 vs 12.9+/-6.86, p<0,001) and idiopatic cardiomiopathy (23.0+/-11.2 vs 12.9+/-6.86, p<0,001). A significant correlation was observed between homocysteine and NYHA functional class (p<0,001), age (p<0,001), creatinine (p<0,001), colesterol (p<0,05) while no correlations were observed with hemodynamic (HR, BP), functional (ejection fraction) and other metabolic parameters (triglycerides). Serum homocysteine was lowest in control and increased with increasing NYHA class. In idiopatic cardiomiopathy the correlation between homocysteine and NYHA functional class, creatinine (p<0,001), fibrinogen (p<0,05) was confirmed; in postischemic cardiomiopathy a significant correlation with creatinine and NYHA class (p<0,001) and with triglycerides (p<0,05) was also found. CONCLUSION: Plasma homocysteine was directly related to NYHA class. This observation may underline the strong relations of plasma homocysteine to congestive heart failure. Further research is indicated to evaluate a causal or non-causal mechanism for this association.

Differential effects of beta-blockers in patients with heart failure: A prospective, randomized, double-blind comparison of the long-term effects of metoprolol versus carvedilol.

BACKGROUND: Both metoprolol and carvedilol produce hemodynamic and clinical benefits in patients with chronic heart failure; carvedilol exerts greater antiadrenergic effects than metoprolol, but it is unknown whether this pharmacological difference results in hemodynamic and clinical differences between the 2 drugs. METHODS AND RESULTS: We randomized 150 patients with heart failure (left ventricular ejection fraction

Effects of short- and long-term carvedilol administration on rest and exercise hemodynamic variables, exercise capacity and clinical conditions in patients with idiopathic dilated cardiomyopathy.

OBJECTIVES: The study evaluated the effects of short- and long-term administration of carvedilol in patients with idiopathic dilated cardiomyopathy. BACKGROUND: Carvedilol is a beta-adrenergic blocking agent with vasodilator activity that might be well tolerated in patients with heart failure. METHODS: Forty patients with idiopathic dilated cardiomyopathy treated with digoxin, furosemide and angiotensin-converting enzyme inhibitors were randomized in a double-blind manner to receive either placebo or carvedilol. Right heart hemodynamic variables were evaluated up to 8 h after short-term drug administration and, on the next day, during cardiopulmonary exercise testing before and 3 h after drug ingestion. Placebo or carvedilol was added to standard therapy, starting with a dose of 6.25 mg twice a day with weekly increments up to the maximum of 25 mg twice a day. Patients were reevaluated after 4 months by cardiopulmonary exercise testing and measurement of right heart hemodynamic variables 12 h after last drug ingestion and 3 h after drug readministration. Left ventricular ejection fraction and volume, measured by equilibrium radionuclide ventriculography, quality of life and submaximal exercise duration were assessed before and after long-term therapy. RESULTS: Compared with placebo, carvedilol produced a short-term reduction in heart rate and pulmonary artery and pulmonary wedge pressures and, after long-term administration, increased both rest and peak exercise cardiac, stroke volume and stroke work indexes, with a further reduction in right atrial, pulmonary artery and pulmonary wedge pressures. Long-term carvedilol administration also improved rest left ventricular ejection fraction (from 20 +/- 7% to 30 +/- 12%, p < 0.001), submaximal exercise capacity, quality of life and New York Heart Association functional class. No baseline variable was predictive of the response to therapy. CONCLUSIONS: Short-term carvedilol administration reduces heart rate and mean pulmonary artery and pulmonary wedge pressures, whereas it improves both long-term rest and exercise left ventricular systolic function, reduces heart failure symptoms and improves submaximal exercise tolerance in patients with idiopathic cardiomyopathy.

Use of cardiopulmonary exercise testing with hemodynamic monitoring in the prognostic assessment of ambulatory patients with chronic heart failure.

OBJECTIVES: We studied whether direct assessment of the hemodynamic response to exercise could improve the prognostic evaluation of patients with heart failure (HF) and identify those in whom the main cause of the reduced functional capacity is related to extracardiac factors. BACKGROUND: Peak exercise oxygen consumption (VO2) is one of the main prognostic variables in patients with HF, but it is influenced also by many extracardiac factors. METHODS: Bicycle cardiopulmonary exercise testing with hemodynamic monitoring was performed, in addition to clinical evaluation and radionuclide ventriculography, in 219 consecutive patients with chronic HF (left ventricular ejection fraction, 22 +/- 7%; peak VO2, 14.2 +/- 4.4 ml/kg/min). RESULTS: During a follow-up of 19 +/- 25 months, 32 patients died and 6 underwent urgent transplantation with a 71% cumulative major event-free 2-year survival. Peak exercise stroke work index (SWI) was the most powerful prognostic variable selected by Cox multivariate analysis, followed by serum sodium and left ventricular ejection fraction, for one-year survival, and peak VO2 and serum sodium for two-year survival. Two-year survival was 54% in the patients with peak exercise SWI < or = 30 g x m/m2 versus 91% in those with a SWI >30 g x m/m2 (p < 0.0001). A significant percentage of patients (41%) had a normal cardiac output response to exercise with an excellent two-year survival (87% vs. 58% in the others) despite a relatively low peak VO2 (15.1 +/- 4.7 ml/kg/min). CONCLUSIONS: Direct assessment of exercise hemodynamics in patients with HF provides additive independent prognostic information, compared to traditional noninvasive data.

Adult human heart microvascular endothelial cells are permissive for non-lytic infection by human cytomegalovirus.

OBJECTIVE: Human cytomegalovirus (CMV) infection has been linked to chronic heart disease. The mechanism of CMV dissemination to the heart remains unknown. CMV antigens and nucleic acid sequences have been detected in endothelial cells (ECs) in vivo, and ECs are fully permissive hosts to CMV replication in vitro. This report examines the characteristics of CMV replication in primary cultures of human heart microvascular ECs (HHMECs). METHODS: Capillary ECs were isolated from heart tissue biopsies of six patients at the time of heart surgery. HHMECs were infected with CMV and viral antigens were detected by immunofluorescence assay using monoclonal antibodies as specific reagents. Cytokine and chemokine release in the supernatant of sham- and CMV-infected cells was quantitated by ELISA. Reverse transcriptase-polymerase chain reaction (RT-PCR) was used to analyse expression of mRNA for adhesion molecules. RESULTS: CMV was found to productively infect HHMECs without cytolytic effects. Infected cultures released high levels of pro-inflammatory chemokines and enhanced their adhesion molecule expression. CONCLUSIONS: Our data provide new insights into the mechanism of CMV dissemination to the heart, signalling the need for further investigation of the pathogenetic role of this virus in cardiac disorders.

Effects of acute and chronic ibopamine administration on resting and exercise hemodynamics, plasma catecholamines and functional capacity of patients with chronic congestive heart failure.

The effects of acute and chronic ibopamine treatment on resting and exercise hemodynamics, exercise capacity and plasma catecholamines were evaluated in 25 patients with chronic heart failure, using a double-blind, parallel, placebo-controlled design. During 2 months of therapy with either placebo or ibopamine (100 mg, 3 times daily), 1 patient was withdrawn from each group for worsening heart failure, New York Heart Association functional class improved in 4 patients on ibopamine and in 1 on placebo, and furosemide dose could be decreased in 4 on ibopamine and in no patient on placebo. Acute ibopamine administration induced, in comparison with placebo, a significant increase of cardiac and stroke volume indexes both at rest and peak exercise, with a reduction of systemic vascular resistance. These hemodynamic changes were maintained also after chronic therapy, with no evidence of tolerance development. Exercise capacity (evaluated as peak exercise duration and oxygen consumption, and ventilatory threshold) did not significantly change. Resting and peak exercise norepinephrine plasma levels were significantly reduced after both acute and chronic ibopamine administration. Thus, the hemodynamic and neurohumoral effects of ibopamine make this drug potentially useful for the chronic treatment of congestive heart failure.

Exercise hyperventilation chronic congestive heart failure, and its relation to functional capacity and hemodynamics.

The ventilatory response to exercise was evaluated in 26 normal sedentary men and 68 patients with chronic heart failure using the slope of the relation between minute ventilation (VE) and carbon dioxide production (VCO2). All subjects underwent maximal upright bicycle cardiopulmonary exercise testing; 33 patients also underwent right-sided cardiac catheterization. The slope of VE/VCO2 was calculated by linear regression analysis using data from all the exercise tests and the first 60% of exercise duration; a high correlation was seen between these results (r = 0.83; p less than 0.001). The slope of VE/VCO2 was significantly, though weakly, related to peak exercise work load, oxygen consumption and ventilatory threshold (r = -0.49, -0.56 and -0.49, respectively), several peak exercise hemodynamic parameters and peak exercise dead space/tidal volume ratio (r = 0.70). With use of multivariate analysis, the only independent determinants of the slope were peak exercise dead space/tidal volume ratio and cardiac index. Thus, in patients with heart failure, exercise hyperventilation can contribute to the impairment of functional capacity and can be considered a compensatory response to abnormal hemodynamics and lung blood distribution in order to keep blood gas concentrations normal.

Assessment of peak oxygen consumption, lactate and ventilatory thresholds and correlation with resting and exercise hemodynamic data in chronic congestive heart failure.

To determine the clinical value of respiratory gas analysis during exercise, oxygen consumption (VO2) at peak exercise and at lactate and ventilatory threshold was assessed in 34 patients with chronic heart failure who underwent maximal exercise testing with expiratory gas monitoring and serial determinations of mixed venous lactate and hemodynamics by Swan-Ganz catheterization. A lactate threshold, defined as the point of abrupt increment of blood lactate, could be identified in every patient; the ventilatory threshold, detected on the basis of the respiratory changes, was found in 26 patients (77%). Lactate and ventilatory thresholds were significantly related to each other (r = 0.94; p less than 0.001) and to peak VO2 (r = 0.89; p less than 0.001 in both). Among the resting hemodynamic measurements, peak VO2 was significantly related only to total pulmonary resistances (r = -0.35). Among the parameters at maximal exercise, it was positively related to cardiac index, stroke work, stroke volume index and mean arterial pressure (r = 0.89, 0.74, 0.74 and 0.56, respectively) and inversely related to systemic vascular and total pulmonary resistances (r = -0.74 and -0.63). Using multivariate stepwise regression analysis only maximal cardiac index and, to a lesser degree, total pulmonary resistance were related to peak VO2. Similar correlations were found between the hemodynamics and the lactate and ventilatory threshold. Thus, peak VO2, lactate and ventilatory thresholds can be detected in most patients with chronic heart failure. These parameters are highly correlated to each other and bear similar relations to the hemodynamic response to exercise. The cardiac index is the main central hemodynamic determinant of exercise capacity.

Improvement in exercise capacity after correction of anemia in patients with end-stage renal failure.

Changes in exercise tolerance occurring after correction of anemia with recombinant human erythropoietin in a group of patients with end-stage renal failure were evaluated. Ten patients, aged 29 +/- 11 years, on chronic hemodialysis treatment, with no associated diseases, were evaluated by cardiopulmonary bicycle exercise testing and M-mode, 2-dimensional and pulsed doppler echocardiography before and after anemia correction. After 1 and 3 months of therapy, hemoglobin plasma levels increased from 5.9 +/- 1.2 to 7.7 +/- 1.3 and 9.9 +/- 1.4 g/dl, with a concomitant increase in peak oxygen consumption (VO2) from 21.4 +/- 4.3 to 24.4 +/- 4.3 and 26.6 +/- 4.6 ml/kg/min and of VO2 at the ventilatory threshold from 15.0 +/- 3.7 to 17.3 +/- 3.7 and 16.8 +/- 3.4 ml/kg/min. After 3 months of therapy, systolic blood pressure significantly decreased both at peak exercise (159 +/- 35 to 134 +/- 22 mm Hg) and ventilatory threshold (140 +/- 27 to 123 +/- 19 mm Hg), whereas cardiac index at rest decreased from 3.3 +/- 0.7 to 2.8 +/- 0.5 liters/min/m2 and heart rate from 77 +/- 12 to 70 +/- 10 beats/min. However, no significant relation was found between hemoglobin plasma levels and peak VO2, whereas a significant relation was found between hemoglobin concentration and cardiac index at rest.

Diagnostic features of body surface potential maps in patients with myocardial ischemia and normal resting 12-lead electrocardiograms.

Body surface maps recorded from 35 ischemic patients with normal resting 12-lead electrocardiograms were compared with those obtained from 36 age- and sex-matched normal subjects. From instantaneous maps of each subject 187 variables were derived relating to the configuration (80 variables) and magnitude (104 variables) of the potential distribution and duration of the electrocardiographic intervals (3 variables). By using stepwise discriminant analysis we selected 3 variables whose linear combination enabled us to correctly allocate 91% of the study population (jacknife procedure; specificity 92%, sensitivity 91%). To substantiate the validity of the results the discriminant function was tested on a new independent population consisting of 27 ischemic patients and 54 normal subjects from another laboratory. A proper allocation was obtained in 86% of the cases (specificity 87%, sensitivity 85%). The large number of correctly classified ischemic patients and the repeatability of the results indicate that the adopted criteria are good markers of ischemic heart disease.