Hypertension in pregnancy: the most recent findings in pathophysiology, diagnosis and therapy.

Hypertension in pregnancy is a major cause of maternal, fetal and neonatal morbidity and mortality, both in developing and developed countries. That is because it is the most common pathological condition during pregnancy and its development is associated with high risk of severe complications: mother could be affected by placental abruption, cerebrovascular events, organ dysfunction and could develop disseminated intravascular coagulation, instead the foetus could be affected by intrauterine growth retardation, premature birth and intrauterine death. Aware that preeclampsia still remains an enigma for different aspects, this review aims to provide a comprehensive update of all the current literature regarding this disease. In particular, the main purpose of this review is to emphasize the most recent findings about the pathophysiology, diagnosis and submit a revision of the most recent guidelines in relation to drug therapy, with particular attention to the evaluation of risks and benefits associated with the use of various classes of the currently available drugs.

Pulmonary embolism in pregnancy.

Venous thromboembolism (VTE) is a major cause of maternal morbidity and mortality during pregnancy or early after delivery, remaining a diagnostic and therapeutic challenge in both states. The absolute incidence of pregnancy-associated VTE has been reported as 1 in 1,000 to 1 in 2,000 deliveries. With 5-6 million new births computed in Europe in 2010, the potential clinical relevance of diagnosing and treating gravidic VTE is immediately evident. Fivefold higher in a pregnant as compared with a non-pregnant woman, VTE risk is also higher in postpartum than antepartum period. Ranked absolute and relative thrombotic risk may be described in the several thrombophilic conditions experienced by women at risk, according to which specific prophylactic and therapeutic recommendations have been formulated by recent guidelines. The main purpose of the present review article was to emphasize the most recent findings and recommendations in diagnostic strategies, discussing thrombophilic risk evaluation, as well as risks and benefits of various diagnostic techniques for both mother and fetus.

Growth factors in preeclampsia: a vascular disease model. A failed vasodilation and angiogenic challenge from pregnancy onwards?

Preeclampsia is the major cause of maternofetal and neonatal morbi-mortality including intrauterine growth retardation, miscarriages and stillbirths. Inadequate vascular dilation and angiogenesis represent the crucial underlying defect of gravidic hypertension, denoting a failed response to the vasodilatory and pro-angiogenic challenge imposed by pregnancy, especially if multifetal. A similar pathogenesis appears involved in gestational diabetes. In this review we aimed to provide a hint on understanding the deeply involved angiogenic disorders which eventually culminate in utero-placental failure. The key players in these complex processes may be found in an intricate network of growth factors (GFs) and GF inhibitors, controlled by several vascular risk factors modulated by environment and genes, which eventually impact on early and late cardiovascular outcomes of mother and fetus.

Lack of Influence of the Androgen Receptor Gene CAG-Repeat Polymorphism on Clinical and Electrocardiographic Manifestations of the Brugada Syndrome in Man.

BACKGROUND: Clinical studies suggest that testosterone (T) plays an important role in the male predominance of the clinical manifestations of the Brugada syndrome (BS). However, no statistically significant correlations have been observed between T levels and electrocardiogram (ECG) parameters in the BS patients. We investigated whether the hormonal pattern and the variation within CAG repeat polymorphism in exon 1 of the androgen receptor (AR) gene, affecting androgen sensitivity, are associated with the Brugada ECG phenotype in males. METHODS AND RESULTS: 16 male patients with BS (mean age 45.06 ± 11.3 years) were studied. 12-lead ECG was recorded. Blood levels of follicle-stimulating hormone, luteinizing hormone, prolactin, testosterone, free-T, dihydrotestosterone, 17-ß-estradiol, estrone, 3-alpha-androstanediol-glucuronide, delta-4-androstenedione, dehydroepiandrosterone sulphate, progesterone, 17-hydroxyprogesterone, and sex hormone binding globulin were assayed. Genotyping of CAG repeats on DNA extracted from leukocytes was carried out. No relationship was found between hormone values and ECG parameters of BS. BS patients showed the CAG length normally recognized in the human polymorphism range and the number of CAG repeats did not correlate with the ECG pattern of BS. CONCLUSIONS: The AR CAG repeat length does not correlate with the ECG features of the patients affected by BS. The search for genes downstream AR activation as possibly responsible for the increased risk of spontaneous arrhythmias in BS males after puberty is warranted.

Recombinant human insulin-like growth factor-1: a new cardiovascular disease treatment option?

The Insulin-like growth factor-1 (IGF-1) system is dynamic and complex, involving many binding proteins, binding-protein-related proteases, and receptors. It has emerged in time as a powerful defence to life processes of many cytotypes, tissues and systems. Mainly in body metabolism, diabetes and cardiovascular system, but also in brain and kidney, IGF-1 plays a key role in maintaining homeostasis, increasing progenitor cell potential, and improving physiologic performance both in rest and stress conditions. Its vasculoprotective and insulin sensitizing ability exerts a protective role on flow-metabolism coupling and organs function. Therapeutical human use of recombinant human IGF-1 (rhIGF-1) has been widely applied only in Laron syndrome, while being verified in many randomized controlled trials to improve glycemic control in type 1 and type 2 diabetes, and proposed in neurological disease such as amyotrophic lateral sclerosis, multiple sclerosis and Alzheimer disease. Sparse evidence exists moreover about rhIGF-1 use in insulin resistance, burns, catabolic and post-surgery states, acute and chronic renal failure, amyotrophic lateral and multiple sclerosis, brain injury, and immunoincompetence. Along with these data, results are available on cardiovascular benefit of administration of other growth factors, such as erythropoietin and vascular endothelial growth factor, or on cardiovascular side effects of growth factor antagonists such as trastuzumab in cancer therapy. We intended therefore to summarize in this review available human and animals evidence about rhIGF-1 effects on different systems with insights on rhIGF-1 cardiovascular effects. In view of its ability to improve flow-metabolism coupling, IGF-1 could indeed represent a new cardiovascular disease treatment option for many cardiac disorders such as ischemic heart disease and heart failure.

Drugs and cardiotoxicity in HIV and AIDS.

The advent of potent antiretroviral drugs in recent years has had an impressive impact on mortality and disease progression in HIV-infected patients, so that issues related to long-term effects of drugs are of growing importance. Hyperlipidemia, hyperglycemia, and lipodystrophy are increasingly described adverse effects of highly active antiretroviral therapy (HAART), in particular when protease inhibitors are used. Hyperlipidemia is strikingly associated with the use of most available protease inhibitors, with an estimated prevalence of up to 50%. Because of the short observation period and the small number of cardiovascular events, epidemiological evidence for an increased risk of coronary heart disease in HIV-infected patients treated with HAART is not adequate at present; however, it is likely that shortly more data will accumulate to quantify this risk. Before starting HAART and during treatment it is reasonable to evaluate all patients for traditional coronary risk factors, including lipid profile. Among the drugs that are currently used in HIV+ patients, antibacterials, antifungals, psychotropic drugs and anti-histamines have been associated with QT prolongation or torsade de pointe, a life-threatening ventricular arrhythmia. Among the risk factors that may precipitate an asymptomatic electrocardiographic abnormality into a dangerous arrhythmia is the concomitant use of drugs that share the CYP3A metabolic pathway. Since most protease inhibitors are potent inhibitors of CYP3A, clinicians should be aware of this potentially dangerous effect of HAART. Anthracyclines are potent cytotoxic antibiotics that have been widely used for the treatment of HIV-related neoplasms. Their cardiotoxicity is well known, ranging from benign and reversible arrhythmias to progressive severe cardiomyopathy. The increased survival and quality of life of HIV+ patients emphasize the importance of a high awareness of adverse drug-related cardiac effects.

Role of echocardiography in acute chest pain syndrome.

Fewer than one third of patients presenting to the emergency department with complaints of chest pain have an acute coronary syndrome. The electrocardiogram provides a specific diagnosis only in 40% of patients with acute myocardial infarction. The presence of regional wall-motion abnormalities at echocardiography in patients without known coronary artery disease is a moderate indicator of an increased likelihood of acute myocardial ischemia or myocardial infarction with a positive predictive accuracy of about 50%. More important, the absence of regional wall-motion abnormalities identifies a subset of patients unlikely to have a myocardial infarction with a negative predictive accuracy of about 95%. Echocardiography can provide incremental prognostic information to identify patients at risk of early or late cardiac events, even after consideration of clinical, historical, and electrocardiographic variables. The application of new contrast agents to echocardiography will probably allow an early and more accurate evaluation of patients with chest pain of uncertain significance.

Maternally inherited cardiomyopathy: clinical and molecular characterization of a large kindred harboring the A4300G point mutation in mitochondrial deoxyribonucleic acid.

OBJECTIVES: The purpose of this study was to describe the clinical and molecular features of a large family with maternally inherited cardiomyopathy (MICM). BACKGROUND: Recently, several mitochondrial deoxyribonucleic acid (mtDNA) point mutations have been associated with MICM. However, the distinctive clinical and morphologic features of MICM are not fully appreciated. This is partially due to the small size of the reported pedigrees, often lacking detailed clinical and laboratory information. METHODS: Clinical and genetic analysis of the family was carried out. RESULTS: Echocardiography showed mostly symmetrical hypertrophic cardiomyopathy in 10 family members. The illness had an unfavorable course. Progressive heart failure occurred in three subjects, who eventually died; one individual underwent heart transplantation. Electrocardiographic or echocardiographic signs of cardiac hypertrophy in the absence of significant clinical complaints were observed in five subjects. Neurologic examination was normal. The mutation was detected in blood from all available subjects. Abundance of mutated molecules ranged between 13% and 100% of total mtDNA genomes. The severity of the disease could not be foreseen by the proportion of mutation in blood. CONCLUSIONS: This report contributes a better description of the clinical aspects of MICM and provides important clues to distinguish it from hypertrophic cardiomyopathy. We suggest that mtDNA mutations, particularly in the transfer ribonucleic acid for isoleucin, should be systematically searched in patients with MICM. The identification of an underlying maternally inherited mitochondrial DNA defect in familial cases of cardiomyopathy may considerably influence the management and genetic counseling of affected patients.

Infective endocarditis in hypertrophic cardiomyopathy: prevalence, incidence, and indications for antibiotic prophylaxis.

BACKGROUND: The literature on infective endocarditis in hypertrophic cardiomyopathy (HCM) is virtually confined to case reports. Consequently, the risk of endocarditis in HCM remains undefined. METHODS AND RESULTS: We assessed the occurrence of endocarditis in 810 HCM patients evaluated between 1970 and 1997. Endocarditis was diagnosed in 10 patients, 2 of whom were excluded from analysis of prevalence and incidence because they were referred for acute endocarditis. At first evaluation, echocardiographic features consistent with prior endocarditis were identified in 3 of 808 patients, a prevalence of 3.7 per 1000 patients (95% CI, 0.8 to 11). Of 681 patients who were followed, 5 developed endocarditis, an incidence of 1.4 per 1000 person-years (95% CI, 0.5 to 3.2); outflow obstruction was present in each of these 5 patients and was associated with the risk of endocarditis (P=0.006). In the 224 obstructive patients, incidence of endocarditis was 3.8 per 1000 person-years (95% CI, 1.6 to 8.9) and probability of endocarditis 4. 3% at 10 years. Left atrial size was also associated with the risk of endocarditis (P=0.007). In patients with both obstruction and atrial dilatation (>/=50 mm), incidence of endocarditis increased to 9.2 per 1000 person-years (95% CI, 2.5 to 23.5). Analysis of all 10 patients with endocarditis identified outflow obstruction in each and atrial dilatation in 7. CONCLUSIONS: Endocarditis in HCM is virtually confined to patients with outflow obstruction and is more common in those with both obstruction and atrial dilatation. These results indicate that antibiotic prophylaxis is required only in patients with obstructive HCM.

The complex relation between myocardial viability and functional recovery in chronic left ventricular dysfunction.

Preserved myocardial viability and recurrent symptomatic ischemia are the most widely accepted criteria indicating that coronary revascularization should take place in patients with postischemic left ventricular dysfunction. However, the presence of viable myocardium within the infarct zone does not necessarily imply recovery of function after coronary revascularization. The complex relation between the extent of transmural necrosis and the degree of residual perfusion within the infarct area plays an important role. However, independently of functional recovery, cell viability may have important clinical implications, since it may improve long-term prognosis by attenuating left ventricular remodeling processes. Several different methods are used to detect hibernating myocardium. Mounting evidence suggests that thallium-201 scintigraphy is most sensitive in identifying tissue viability, whereas dobutamine echocardiography is most specific in predicting functional recovery after revascularization. In between, myocardial contrast echocardiography is the only technique able to evaluate the microvascular integrity that is a condition sine qua non for both cell viability and later functional recovery. Combined information derived from these 3 different approaches might be considered as the best way to understand how the combination of contractile, viable but noncontractile, and dead tissue affect resultant function and prognosis.

Multiplane transesophageal echocardiography and stroke.

Transesophageal echocardiography (TEE) is considered a basic tool in the diagnostic and follow-up evaluation of stroke patients, since up to 40% of cerebral ischemic events are presumed to have a cardiac origin. TEE offers a superior resolution of the posterior cardiac structures, such as left atrium and appendage and atrial septum, as well as of the aorta. By means of TEE, evidence has accumulated that some cardiovascular abnormalities (left-sided thrombi, tumors and vegetative lesions, complicated plaques of the aortic arch) are associated with ischemic stroke. Nevertheless, some issues remain unresolved. Will exclusion of atrial thrombus by multiplane TEE preclude embolism after cardioversion of atrial fibrillation? If anticoagulation before and after cardioversion is needed to provide adequate protection against embolism, will TEE be indicated in all patients? Moreover, can the detection of spontaneous echo contrast or enlarged and hypokinetic left atrial appendage in atrial fibrillation modify the therapeutic strategy? Is atrial septal aneurysm (ASA) a real embolic source, particularly when a right-to-left shunt is not associated? Considering the high prevalence of patent foramen ovale (PFO) in normal subjects, how can we identify patients at higher risk of embolism? Furthermore, methodologic points have to be taken into account when we analyze data from the literature. First, most studies are retrospective; a sole prospective study demonstrated that atherosclerotic plaques >4 mm thick in the aortic arch are significant predictors of recurrent brain infarction and other cardiovascular events in patients > or =60 years of age. Second, the association between the aforementioned cardiac abnormalities (mainly ASA and PFO) and cardiogenic embolism is biased by the patient-enrollment criteria used in those studies so that their pathogenetic role has not yet been established. Prospective studies with the enrollment of appropriate control groups will be necessary to define what can be considered a marker of embolic risk; the diagnosis "cardiogenic embolism" will not be a definitive diagnosis in most cases.

Tissue-type plasminogen activator therapy versus primary coronary angioplasty: impact on myocardial tissue perfusion and regional function 1 month after uncomplicated myocardial infarction.

OBJECTIVES: This study sought to compare the impact of primary coronary angioplasty and thrombolytic therapy for acute myocardial infarction (AMI) on 1-month infarct size and microvascular perfusion. BACKGROUND: The effect of the reperfusion strategies of primary coronary angioplasty and thrombolytic therapy on microvascular integrity still remains to be determined. METHODS: Sixty-two consecutive patients with a first AMI, undergoing intravenous tissue-type plasminogen activator (t-PA) therapy (32 patients, Group I) or primary angioplasty (30 patients, Group II), were studied. Only patients with 1-month Thrombolysis in Myocardial Infarction (TIMI) flow grade 2 or 3 were selected for the study. Patients in whom primary angioplasty was unsuccessful or those with clinical evidence of failed reperfusion were excluded. Microvascular perfusion was assessed at 1 month by intracoronary injection of sonicated microbubbles. Contrast score index (CSI) and wall motion score index (WMSI) were derived using qualitative methods. RESULTS: At baseline there were no significant differences between groups for age, risk factors, time to hospital presentation, Killip class on admission, prevalence of multivessel disease or anterior infarct site, infarct area extension before reperfusion, peak creatine kinase levels and postinfarction treatment. Conversely, significant differences between groups were found at follow-up for percent residual infarct related-artery (IRA) stenosis (70 +/- 12 vs 36 +/- 14 [mean +/- SD], p = 0.0001), CSI (1.02 +/- 0.4 vs. 1.49 +/- 0.5, p = 0.0003) and WMSI (1.67 +/- 0.3 vs. 1.45 +/- 0.3, p = 0.015). In particular, in the subset of patients with TIMI grade 3 flow, a perfusion defect occurred in one or more segments subtended by the IRA in 72% of Group I versus 31% of Group II patients (p < 0.00001) and in 27% of Group I versus 8% of Group II segments (p < 0.00001). CONCLUSIONS: The present study shows, in a highly selected cohort with successful IRA recanalization, that primary angioplasty is more effective than thrombolysis in preserving microvascular flow and preventing extension of myocardial damage at 1-month after AMI.

Combined use of dobutamine echocardiography and myocardial contrast echocardiography in predicting regional dysfunction recovery after coronary revascularization in patients with recent myocardial infarction.

BACKGROUND: Myocardial contrast echocardiography and dobutamine echocardiography have recently emerged as potentially useful clinical tools to detect reversible myocardial dysfunction. However, the relative accuracy of these two techniques in predicting regional wall motion improvement after coronary interventions is still unclear. The aim of the present study was to compare their diagnostic value in predicting functional recovery after coronary revascularization in patients with recent acute myocardial infarction. METHODS AND RESULTS: Twenty-four patients with acute myocardial infarction underwent myocardial contrast echocardiography and dobutamine echocardiography within 2 weeks of hospital admission. Infarct zone contrast score and wall motion score indexes were derived in each patient. Infarct-related artery revascularization was performed before hospital discharge in all selected patients. Resting echocardiography was repeated 3 months after revascularization, and regional function recovery was analysed. The degree of wall motion score improvement at 3-month follow-up and the percentage of positive responses to dobutamine echo were greater (P < 0.001 and P < 0.002, respectively) in patients with a higher baseline contrast score (> or = 0.50). Conversely, no significant changes were observed either during dobutamine echo or after revascularization in the group of patients without residual perfusion within the infarct area. Diagnostic agreement between both techniques in predicting reversible dysfunction was high (81% of segments). The sensitivity and negative predictive value in predicting functional outcome were 100% (95% confidence interval [CI], 87% to 100%) and 100% (95% CI, 93% to 100%) by contrast echo, and 85% (95% CI, 66% to 96%) and 93% (95% CI, 84% to 98%) by dobutamine echo. The specificity and positive predictive value were 90% (95% CI, 80% to 96%) and 81% (95% CI, 64% to 93%) by contrast echo, and 88% (95% CI, 78% to 95%) and 76% (95% CI, 58% to 90%) by dobutamine echo. The combination of myocardial contrast and dobutamine echocardiography positive responses improved specificity and positive predictive value in detecting functional recovery after revascularization to 100% (95% CI, 94% to 100%) and 100% (95% CI, 85% to 100%), respectively. However, the sensitivity and negative predictive value slightly decreased with the use of both methods (85% [95% CI, 66% to 96%)] and (93%[95% CI, 85% to 98%)], respectively. CONCLUSIONS: In patients with recent myocardial infarction, reversible dysfunction after coronary revascularization and the response to dobutamine infusion are strictly dependent on microvascular integrity. However, microvascular perfusion does not always imply functional recovery after coronary revascularization. The integration with dobutamine echo results seems particularly helpful to further improve myocardial contrast echo specificity and positive predictive values.

Prognosis of asymptomatic patients with hypertrophic cardiomyopathy and nonsustained ventricular tachycardia.

BACKGROUND: In the early 1980s, studies performed in highly selected referral patients with hypertrophic cardiomyopathy reported a strong association between the presence of brief episodes of ventricular tachycardia (VT) on ambulatory ECG monitoring and sudden death. These observations led to antiarrhythmic treatment in many patients with hypertrophic cardiomyopathy and brief episodes of VT. In recent years, however, a growing awareness of the potential arrhythmogenic effects of antiarrhythmic medications has raised doubts regarding such a therapeutic approach, particularly in less selected and lower-risk patient populations. METHODS AND RESULTS: In the present study, we examined the prognostic significance of nonsustained VT in a population of 151 patients with hypertrophic cardiomyopathy who were asymptomatic or had only mild symptoms at the time of their initial ambulatory ECG recording. Of the 151 study patients, 42 had episodes of VT and 109 did not. The runs of VT ranged from 3 to 19 beats, with 35 patients (83%) having < 10 beats. The number of runs of VT ranged from 1 to 12 in 24 hours, with 36 patients (86%) having < or = 5 episodes of VT. Thus, in most patients, the episodes of VT were brief and infrequent. Follow-up averaged 4.8 years. Of the 151 study patients, 6 died suddenly, 3 in the group with VT and 3 in the group without VT. Two other patients, both in the group without VT, died of congestive heart failure. The total cardiac mortality rate was 1.4% per year in the patients with VT (95% CI, 0.4% to 3.5%) and 0.9% in those without VT (95% CI, 0.4% to 2.0%; P = .43). The relative risk of cardiac death for patients with VT was 1.4 compared with patients without VT (95% CI, 0.6 to 6.1). The sudden death rate was 1.4% per year in the patients with VT (95% CI, 0.4% to 3.5%) and 0.6% in those without VT (95% CI, 0.2% to 1.5%; P = .24). The relative risk of sudden death for patients with VT compared with those without VT was 2.4 (95% CI, 0.5 to 11.9). Of the 151 patients included in the study, 88 (58%) remained asymptomatic and were not treated with cardioactive medications during follow-up. Of these 88 patients, 20 were in the group with VT and 68 in the group without VT. None of these patients died. CONCLUSIONS: Our results show that cardiac mortality is low in patients with hypertrophic cardiomyopathy who are asymptomatic or only mildly symptomatic and have brief and infrequent episodes of VT on ambulatory ECG monitoring. Our findings also suggest that brief and infrequent episodes of VT should not be considered, per se, an indication for antiarrhythmic treatment in such patients.

Influence of residual perfusion within the infarct zone on the natural history of left ventricular dysfunction after acute myocardial infarction: a myocardial contrast echocardiographic study.

OBJECTIVES: This study used myocardial contrast echocardiography to investigate the extent of residual perfusion within the infarct zone in a select group of patients with recently reperfused myocardial infarction and evaluated its influence on the ultimate infarct size. BACKGROUND: Limited information is available on the status of myocardial perfusion within postischemic dysfunctional segments at predischarge and on its influence on late regional and global functional recovery. METHODS: Twenty patients with acute myocardial infarction were selected for the study. Patients met the following inclusion criteria: 1) single-vessel coronary artery disease; 2) patency of infarct-related artery with persistent postischemic dysfunctional segments at predischarge; 3) stable clinical condition up to 6 months after hospital discharge. All selected patients underwent coronary angiography and myocardial contrast echocardiography before hospital discharge and repeated the echocardiographic examination 6 months later. Patients were grouped according to the pattern of contrast enhancement in predischarge dysfunctional segments. RESULTS: In nine patients (group I), the length of segments showing abnormal contraction coincided with that of the contrast defect segments. In the remaining 11 patients (group II), postischemic dysfunctional segments were partly or completely reperfused. There was no difference between the two groups in asynergic segment length at predischarge (7.3 +/- 2.5 vs. 7.2 +/- 4.3 cm, p = NS). At follow-up study, asynergic segment length was significantly reduced in group II patients, whereas no changes were observed in group I patients (from 7.2 +/- 4.3 to 4.7 +/- 3.7 cm, p < 0.005; and from 7.3 +/- 2.5 to 7.5 +/- 2.9 cm, p = NS, respectively). CONCLUSIONS: Among patients with a predischarge patent infarct-related artery, further improvement in regional and global function may be expected during follow-up when residual perfusion in the infarct zone is present.