Blood pressure control in resistant hypertension: new therapeutic options

Resistant hypertension, namely the hypertensive state characterized by the inability of multiple antihypertensive drug interventions to lower blood pressure to goal levels, represents a condition frequently detected in clinical practice. Its main features are represented by its heterogeneous etiology as well as its very high cardiovascular risk. This latter peculiarity has implemented the research for new approaches to the treatment of the disease. This article will focus on two of them, namely carotid baroreceptor electric stimulation and the renal denervation procedure. Clinical studies and large-scale clinical trials are presently ongoing with the aim of defining the long-term efficacy and safety profile of the two interventions.     

ST1926, a novel and orally active retinoid-related molecule inducing apoptosis in myeloid leukemia cells: modulation of intracellular calcium homeostasis

Retinoid-related molecules (RRMs) are derivatives of retinoic acid and promising antileukemic agents with a mechanism of action different from that of other common chemotherapeutics. Here, we describe a novel chemical series designed against the RRM prototype, CD437. This includes molecules with apoptotic effects in acute promyelocytic leukemia and other myelogenous leukemia cell lines, as well as ST2065, an RRM with antagonistic properties. The most interesting apoptotic agent is ST1926, a compound more powerful than CD437 in vitro and orally active in vivo on severe combined immunodeficiency (SCID) mice that received transplants of NB4 cells. ST1926 has the same mechanism of action of CD437, as indicated by the ability to trans-activate retinoic acid receptor gamma, to induce the phosphorylation of p38 and JNK, and to down-regulate the expression of many genes negatively modulated by CD437. ST1926 causes an immediate increase in the cytosolic levels of calcium that are directly related to the apoptotic potential of the RRMs considered. The intracellular calcium elevation is predominantly the result of an inhibition of the mitochondrial calcium uptake. The phenomenon is blocked by the ST2065 antagonist, the intracellular calcium chelator BAPTA (1,2 bis (2-aminophenoxy) ethane-N, N, N',N'-tetraacetic acid tetrakis (acetoxymethyl ester), and by high concentrations of calcium blockers of the dihydropyridine type, compounds that suppress ST1926-induced apoptosis.     

Sustained sympathoinhibitory effects of cardiac resynchronization therapy in severe heart failure

Evidence is available that in heart failure, cardiac resynchronization therapy by biventricular pacing improves myocardial function and exercise capacity. Whether this is accompanied by a sustained inhibition of heart failure-dependent sympathoexcitation is uncertain. In 11 heart failure patients (mean+/-SEM age, 68.4+/-1.5 years) in New York Heart Association (NYHA) class III and IV under medical treatment with an intraventricular conduction delay (QRS duration > or =130 ms), with a markedly depressed left ventricular ejection fraction, and undergoing implantation of a biventricular pacemaker, we measured beat-to-beat blood pressure and muscle sympathetic nerve traffic. Measurements, which also included echocardiographic and clinical variables, were performed before and approximately 10 weeks after successful resynchronization therapy. Ten age- and NYHA class-matched heart failure patients who were under medical treatment for the same time period served as controls. Long-term resynchronization therapy improved cardiac function and caused a significant increase in systolic blood pressure coupled with an improvement in maximal oxygen consumption and exercise capacity. These effects were coupled with a significant and marked reduction in sympathetic nerve traffic when expressed both as burst frequency over time (44.1+/-3.6 vs 30.7+/-3.0 bs/min, -30.5%, P<0.02) and as burst frequency corrected for heart rate (68.3+/-5.9 vs 47.3+/-4.3 bs/100 beats, -32.1%, P<0.02). No significant change in the aforementioned parameters was seen in the control group. These data provide the first direct evidence that in severe heart failure, resynchronization therapy exerts a marked and sustained sympathoinhibition. Because in heart failure sympathetic overactivity adversely affects prognosis, this may have important clinical implications.     

Lymphoproliferative disease of granular lymphocytes in a patient with concomitant hepatitis B virus infection of CD4 lymphocytes

In this report we studied a 35-year-old male who developed an abnormal expansion of granular lymphocytes (GL) which spontaneously regressed over a period of 2 years. The immunological and molecular characterizations of expanded cells showed the CD3⁺,CD8⁺,HNK-1⁺ phenotype, a polyclonal organization of the T-cell receptor -chain gene and normal natural killer activity. At the time of presentation, spot and blot hybridization techniques revealed the presence of viral hepatitis B virus (HBV) DNA sequences only in highly enriched CD4⁺ T cells, while proliferating GL were negative. With this as a background, we addressed the question of whether in our case the polyclonal GL proliferation represented an immunoreactive response against CD4⁺ infected cells. In particular, we tested the possibility that expanded GL could be cytotoxic against autologous infected CD4⁺ cells. At the time of the first determination, when several of the CD4⁺ cells harbored HBV, GL showed a minimal degree of cytotoxicity against⁵¹Cr-labeled CD4⁺ cells; 2 years later, when GL became capable of lysing these targets, the appearance of the specific cytotoxicity was concomitant with the disappearance of the HBV-infected CD4⁺ cells and with the recovery of granular lymphocytosis. Taken together, our data suggest that in this case GL proliferation could represent an immunoreactive process against CD4⁺ cells.     

Mitral Valve Damage After an Aortic Balloon Valvuloplasty in an Infant

The case of a 2-year-old infant admitted to our Institution with a diagnosis of severe aortic valve stenosis is presented. After a balloon valvuloplasty with no results in terms of gradient reduction, an echocardiogram showed a moderate mitral regurgitation. The patient underwent surgical repair of both the aortic and mitral valves. Inspection of the mitral valve showed a 5-mm hole in the posterior leaflet at the P2 scallop. Probably, the dilation tore a secondary cord, pulling away a piece of the leaflet. A quadrangular resection was performed with good results.     

Long-term risk of diabetes, hypertension and left ventricular hypertrophy associated with the metabolic syndrome in a general population

OBJECTIVES: Metabolic syndrome is accompanied by an increased risk of developing diabetes mellitus. Limited or no evidence exists on whether and to what extent metabolic syndrome increases the risk of developing office hypertension, daily-life hypertension and left ventricular hypertrophy. METHODS: In 1412 individuals representative of the population of Monza, plasma glucose, office, home and ambulatory blood pressure, and echocardiographic left ventricular mass index were measured between 1990 and 1992 and 10 years later. New onset diabetes mellitus, new onset office, home and ambulatory hypertension as well as new onset left ventricular hypertrophy were assessed in individuals with and without metabolic syndrome (Adult Treatment Panel criteria) at the first examination. RESULTS: New onset diabetes mellitus, hypertension and left ventricular hypertrophy were all much more frequent in individuals with metabolic syndrome than in those without. In patients with metabolic syndrome, the adjusted risk of new onset diabetes mellitus was five to six times greater (P < 0.001), that of new onset office, home or ambulatory hypertension 3.5, 2.9 and 3.2 times greater (P < 0.001), respectively, and that of new onset left ventricular hypertrophy 2.6 times greater (P < 0.001). The most important predictors of new onset diabetes mellitus, hypertension and left ventricular hypertrophy were the baseline blood glucose, blood pressure and left ventricular mass index, respectively, with an independent contribution, in each condition, from other metabolic syndrome components. The metabolic syndrome as such did not have an additional predictive value. CONCLUSION: In the general population, metabolic syndrome is associated with a marked increase in the risk not only of new onset diabetes mellitus but also of new onset office and daily-life hypertension, and left ventricular hypertrophy. This may account for the increased rate of cardiovascular morbidity and mortality exhibited with this condition in long-term studies.     

Cardiovascular risk and adrenergic overdrive in the metabolic syndrome

AimsThis paper will review the role of the sympathetic nervous system in the pathogenesis of the metabolic syndrome as well as its importance as target of non-pharmacologic and pharmacologic treatment.Data synthesisSeveral indices of adrenergic drive, such as plasma norepinephrine, norepinephrine spillover from adrenergic nerve terminals and efferent postganglionic muscle sympathetic nerve traffic, have all shown an increase in the different conditions clustering in metabolic syndrome, such as obesity, hypertension and insulin resistance state. This increase: 1) appears to be potentiated in the metabolic syndrome; and 2) contributes to a large extent at the cardiovascular structural and functional alterations typical of the disease. Based on this evidence, non-pharmacologic life-style interventions as well as drug treatment procedures used in the therapeutic approach to the metabolic syndrome should be aimed at exerting not only favourable haemodynamic and metabolic effects but also pronounced sympathoinhibition.ConclusionThe data reviewed in this paper strongly support the relevance of the sympathetic nervous system in the pathogenesis of the metabolic syndrome and the importance of the sympathomodulation as a specific aim of therapeutic intervention.