Achieving blood pressure goals globally: five core actions for health-care professionals. A worldwide call to action.

The prevalence of hypertension continues to rise across the world, and most patients who receive medical intervention are not adequately treated to goal. A Working Group including representatives of nine international health-care organizations was convened to review the barriers to more effective blood pressure control and propose actions to address them. The group concluded that tackling the global challenge of hypertension will require partnerships among multiple constituencies, including patients, health-care professionals, industry, media, health-care educators, health planners and governments. Additionally, health-care professionals will need to act locally with renewed impetus to improve blood pressure goal rates. The Working Group identified five core actions, which should be rigorously implemented by practitioners and targeted by health systems throughout the world: (1) detect and prevent high blood pressure; (2) assess total cardiovascular risk; (3) form an active partnership with the patient; (4) treat hypertension to goal and (5) create a supportive environment. These actions should be pursued with vigour in accordance with current clinical guidelines, with the details of implementation adapted to the economic and cultural setting.

Heart failure in diabetes mellitus: causal and treatment considerations.

The metabolic abnormalities associated with diabetes mellitus result in macrovascular and microvascular complications in multiple organ systems; it is the cardiovascular impact that accounts for the greatest morbidity and mortality associated with this disease. Heart failure, both with reduced and preserved systolic function, is a major complication, arising from the frequent associations with coronary atherosclerosis, hypertension, and a specific heart muscle dysfunction (cardiomyopathy) that occurs independently of coronary artery disease. Hyperglycemia, insulin resistance, and hypertension, together with activation of both circulating and tissue renin-angiotensin-aldosterone systems, contribute to structural fibrosis and autonomic neuropathy. Thus it becomes imperative to identify cardiac abnormalities early in the course of both type 1 and type 2 diabetes in order to allow early and aggressive intervention to control glucose and blood pressure and to normalize blood lipid profiles. Patients with diabetes should be treated to secondary prevention targets, including blood pressure less than 130/80 mm Hg and LDL less than 100 mg/dL. Angiotensin converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, certain calcium channel blockers, statins, and aspirin have all been demonstrated to significantly reduce cardiovascular morbidity and mortality in patients with diabetes.

Beyond the usual strategies for blood pressure reduction: therapeutic considerations and combination therapies.

Rapidly accumulating clinical data have repeatedly demonstrated not only the critical importance of even small increases in blood pressure as a pathophysiologic factor in the development of cardiovascular disease, particularly in individuals with diabetes mellitus, but also the therapeutic necessity of more aggressive blood pressure reduction and the achievement of progressively lower blood pressure targets in reducing cardiovascular event rates. JNC VI has defined optimal blood pressure as or=140/80 mm Hg. Target blood pressures are now 1 gm/24 hours. Achieving such target pressures is increasingly difficult, particularly in diabetic patients with chronic renal disease, who require complex multidrug antihypertensive regimens. This review attempts to provide some suggestions for constructing such antihypertensive regimens, and provides considerations for the appropriate use of diuretics and the most effective drug combinations. Factors potentially contributing to drug resistant hypertension include such problems as failure to maximize drug dosing, suboptimal diuretic use, noncompliance, and possible confounding effects of such concomitant medications as nonsteroidal and anti-inflammatory drugs or decongestants. The issues underlying drug-resistant hypertension are listed, together with strategies for overcoming this problem.

Left ventricular apex to descending aorta valved conduit: description of transthoracic and transesophageal echocardiographic findings in four cases.

Patients with critical aortic stenosis and a "porcelain" aorta are at an increased risk for complications with aortic cross-clamping during valve replacement. To our knowledge, this is the first report of both transthoracic and transesophageal echocardiographic findings of the left ventricle to the descending aorta (LVDA) valved conduit. We present results of four patients in whom this procedure was performed for critical aortic stenosis, who also had a porcelain aorta. "Normal" echo and Doppler findings, along with those of development of a regurgitant valve within the conduit, are presented.

Patent foramen ovale: a review of associated conditions and the impact of physiological size.

Patent foramen ovale (PFO) is implicated in platypnea-orthodeoxia, stroke and decompression sickness (DCS) in divers and astronauts. However, PFO size in relation to clinical illness is largely unknown since few studies evaluate PFO, either functionally or anatomically. The autopsy incidence of PFO is approximately 27% and 6% for a large defect (0.6 cm to 1.0 cm). A PFO is often associated with atrial septal aneurysm and Chiari network, although these anatomic variations are uncommon. Methodologies for diagnosis and anatomic and functional sizing of a PFO include transthoracic echocardiography (TTE), transesophageal echocardiography (TEE) and transcranial Doppler (TCD), with saline contrast. Saline injection via the right femoral vein appears to have a higher diagnostic yield for PFO than via the right antecubital vein. Saline contrast with TTE using native tissue harmonics or transmitral pulsed wave Doppler have quantitated PFO functional size, while TEE is presently the reference standard. The platypnea-orthodeoxia syndrome is associated with a large resting PFO shunt. Transthoracic echocardiography, TEE and TCD have been used in an attempt to quantitate PFO in patients with cryptogenic stroke. The larger PFOs (approximately > or =4 mm size) or those with significant resting shunts appear to be clinically significant. Approximately two-thirds of divers with unexplained DCS have a PFO that may be responsible and may be related to PFO size. Limited data are available on the incidence of PFO in high altitude aviators with DCS, but there appears to be a relationship. A large decompression stress is associated with extra vehicular activity (EVA) from spacecraft. After four cases of serious DCS in EVA simulations, a resting PFO was detected by contrast TTE in three cases. Patent foramen ovales vary in both anatomical and functional size, and the clinical impact of a particular PFO in various situations (platypnea-orthodeoxia, thromboembolism, DCS in underwater divers, DCS in high-altitude aviators and astronauts) may be different.

The influence of dose of angiotensin I-converting enzyme inhibitor on systolic blood pressure variability in heart failure: a substudy of the Assessment of Treatment with Lisinopril and Survival in heart failure (ATLAS) trial.

UNLABELLED: Heart failure is associated with a decreased variability in circadian systolic blood pressure. ACE inhibitors have been shown to be beneficial in CHF. However, the effect of the magnitude of the dose of ACE inhibitor on blood pressure variability has not been reported. The objective of this sub-study of the ATLAS trial was to determine if there was a difference in effect on systolic blood pressure variability of two doses (35mg, 'high'; and, 5mg, 'low') of the ACE inhibitor, lisinopril, in patients with heart failure (class II-IV; NYHA). Criteria for inclusion were: symptomatic heart failure (class II-IV; NYHA), left ventricular ejection fraction < or = 30%, and 2 months of conventional therapy with diuretics with, or without, digoxin. Twenty-four hour ambulatory blood pressure was recorded prior to randomization and after peak titration (4 weeks) of the study drug for analysis of variability of systolic blood pressure variability. The high dose of lisinopril was associated with greater variability of 24 h systolic blood pressure as noted by inspection of the 24 h recordings or calculation of the blood pressure variability index (P < 0.05). The greater variability in SBP was not associated with a difference in mean 24 h arterial blood pressure. CONCLUSIONS: Variation in circadian systolic blood pressure is useful in reflecting the influence of the magnitude of dose of the ACE inhibitor lisinopril on the pharmacodynamics of patients with heart failure.

Coronary vasodilator responses to bradykinin in euglycemic and diabetic rats.

Diabetes mellitus is associated with endothelial dysfunction that is believed to result in impaired release of vasoconstrictor and vasodilator substances from the endothelium and thereby diminished reactivity of many vascular beds. This study was designed to characterize bradykinin (BK)-induced coronary vasodilation in normal and diabetic rats. Bradykinin-stimulated vasodilation of the rat coronary vasculature is mediated by a cytochrome P450-1A (CYP-1A)- inhibitable metabolite that activates KCa, but not KATP, channels on the coronary vascular smooth muscle. Although BK stimulates the release of nitric oxide from the vascular endothelium, the released nitric oxide and its ability to stimulate guanylate cyclase only modulates the duration of, rather than the magnitude of, BK-induced coronary vasodilation. Twelve weeks of streptozotocin-induced diabetes did not affect the coronary vascular responses to BK or the components that mediate BK-induced vasodilation (ie, K-channel activation, nitric oxide-guanylate cyclase). The data support the conclusions that the coronary vasodilator response of the rat to BK is CYP-1A and KCa-channel mediated, that coreleased nitric oxide only modulates the duration of BK-induced vasodilation, and that these mechanisms are unaffected by moderate diabetes.

Factors affecting circadian variability.

Several unfavorable cardiovascular events show a well-defined pattern in their occurrence throughout the day. Myocardial infarction and ischemia, sudden cardiac death and stroke occur with greater frequency in the morning hours after awakening. Multiple biologic functions such as blood pressure, heart rate, sympathetic neurotransmission, vascular tone, platelet aggregability, and coagulation parameters also show a diurnal variation and appear to contribute to adverse cardiac outcomes. Recent studies have emphasized the importance of 24 h control in decreasing cardiovascular risk. The renin-angiotensin system (RAS), through the important effector peptide, angiotensin II (Ang II), has potent effects on blood pressure, salt and water homeostasis, and target-organ damage. Inhibiting the RAS consequently becomes an important therapeutic avenue for treating hypertension and target-organ damage. Ang II receptor antagonists selectively compete with the binding of Ang II to the Ang II type 1 receptor and, by inhibiting the multiple activities mediated by Ang II at this receptor, may confer cardiovascular benefits additional to that of blood pressure control. Ang II receptor antagonists with an intrinsically long duration of action that produce smooth, sustained antihypertensive activity over the dosing period provide a similar 24 h benefit of Ang II inhibition.

Effect of mibefradil, a T-type calcium channel blocker, on morbidity and mortality in moderate to severe congestive heart failure: the MACH-1 study. Mortality Assessment in Congestive Heart Failure Trial.

BACKGROUND: Calcium antagonists have proved disappointing in long-term congestive heart failure (CHF) studies. Mibefradil, a new calcium antagonist that selectively blocks T-type calcium channels, has been shown to be an effective antihypertensive, antianginal, and anti-ischemic agent, and because of its different mechanism of action, it may be beneficial as adjunct therapy in CHF patients. METHODS AND RESULTS: This multicenter, randomized, double-blind study compared mibefradil with placebo as adjunct to usual therapy in 2590 CHF patients (NYHA class II to IV; left ventricular fraction <35%). The initial 50-mg daily dose of mibefradil was uptitrated to 100 mg after 1 month and continued up to 3 years. Patients were monitored at 1 week; 1, 2, and 3 months; and every 3 months thereafter. All-cause mortality, cardiovascular mortality, and cardiovascular morbidity/mortality were analyzed by use of the log-rank test (alpha=0.05). Substudies included exercise tolerance, plasma hormone and cytokines, echocardiography, and quality of life. Total mortality was similar between mibefradil- and placebo-treated patients (P=0.151). The 14% increased risk of mortality with mibefradil in the first 3 months was not statistically significant (P=0.093). Treatment groups had similar cardiovascular mortality (P=0.246), cardiovascular morbidity/mortality (P=0.783), and reasons for death or hospitalization. Patients comedicated with mibefradil and antiarrhythmics (class I or III), including amiodarone, had a significantly increased risk of death. Substudies demonstrated no significant differences between treatments. CONCLUSIONS: When used as adjunct therapy, mibefradil did not affect the usual outcome of CHF. The potential interaction with antiarrhythmic drugs, especially amiodarone, and drugs associated with torsade de pointes may have contributed to poor outcomes early in the study.

Echocardiographic texture analysis using the wavelet transform: differentiation of early heart muscle disease.

Echocardiographic quantitation of myocardial texture for diagnosis of early cardiomyopathy (CMP) remains problematic. Conventional statistical methods are limited, contributed by a small image region-of-interest (ROI) and difficulty in discrimination from noise. This study was performed to evaluate the 2-D Haar wavelet decomposition method as a tool to identify textural changes in a rat model of early CMP, focusing on changes that occur before development of M-mode structural abnormalities. Early diabetic CMP, ethanol CMP and diabetic-ethanol CMP rat models were evaluated. Echocardiography was performed on two groups of rats. Group I (5 week cohort, n = 4 per subgroup) included controls, rats on 12% ethanol, a diabetic subgroup, and diabetic rats on 4% ethanol. Group II (10 week cohort, n = 5 per subgroup) included the same categories as group I with an additional subgroup taking 4% ethanol was also studied. M-mode left ventricular measurements were comparable in all subgroups of group I. However, diabetic rats in group II had an increased left ventricular dimension (LVD) compared to all others and an increased septal dimension (IVSD) and posterior wall dimension (PWD) were noted in the 4% and 12% ethanol groups. End-diastolic digital images of all rats in the parasternal short axis view, at the papillary muscle level, were downloaded to a computer. A 16 x 16 (ROI) was selected from the anterior interventricular septum. Although standard statistical methods could not differentiate any of the groups, calculation of textural energy and normalized textural energy with the 2-D Haar wavelet decomposition method found at 5 weeks increased normalized texture energy in diabetics compared to all others. At 10 weeks increased texture energy was noted in diabetics. Diabetic-ethanol rats at both 5 and 10 weeks revealed a blunted textural energy compared to diabetic rats. In a rat model of diabetic cardiomyopathy, the 2-D wavelet decomposition method identified textural energy changes before development of echocardiographic structural changes. Ethanol-associated blunting of textural changes in diabetic rats was also noted. This method for quantitation of ventricular texture may be relevant for diagnosis of early cardiomyopathy.

Effects of ethanol on neutrophil recruitment and lung host defense in nitric oxide synthase I and nitric oxide synthase II knockout mice.

BACKGROUND: Ethanol (ETOH) inhibits Escherichia coli endotoxin [lipopolysaccharide (LPS)]-mediated induction of nitric oxide (NO) synthase (NOS) transcription and translation in macrophages and neutrophils [polymorphonuclear (PMN) cells] within the lung. ETOH also inhibits PMN recruitment into the lung and enhances NOS I-mediated production of NO. The contribution of the individual NOS isozymes to ETOH-mediated suppression of the host defense response to lung infection has not been defined. METHODS: We evaluated the role of constitutive NOS I and NOS II in ETOH-mediated inhibition of PMN recruitment into the lung and ETOH-mediated suppression of lung clearance of inhaled Klebsiella pneumonia (K. pneumoniae) in female, homozygous transgenic mice deficient in the genes for NOS I (nNOS-KO) or NOS II (iNOS-KO) and their wild-type controls (WT). RESULTS: Four hours after intratracheal administration of LPS or aerosol inhalation of K. pneumoniae, the lung content of PMNs obtained by bronchoalveolar lavage from WT mice was significantly reduced when compared with that obtained from the lungs of nNOS-KO and iNOS-KO mice. Pretreatment of WT mice with the NOS II inhibitor L-N6-iminoethyllysine (L-NIL; 10 mg/kg, i.p.) or with the NOS I inhibitor 7-nitroindazole (7-NI) (10, 25, or 40 mg/kg, i.p.) 30 min before LPS administration enhanced the lung content of PMNs recoverable by bronchoalveolar lavage. However, pretreatment of iNOS-KO with L-NIL did not affect lung recruitment of PMNs. Moreover, administration of 25 or 40 mg/kg, i.p. of 7-NI to nNOS-KO mice resulted in death of all the animals within 10 min. Pretreatment of nNOS-KO with 7-NI (10 mg/kg) did not affect LPS-stimulated PMN recruitment. Pretreatment of mice with ETOH (4.5 g/kg, i.p.) produced a greater inhibition of LPS-stimulated lung recruitment of PMNs in iNOS-KO mice than in WT mice. In contrast, pretreatment of nNOS-KO with ETOH produced little inhibition of LPS-stimulated lung recruitment of PMNs when compared with that measured in WT mice. Finally, 4 hr after aerosol inhalation of K. pneumoniae, lung clearance of this bacteria was enhanced in iNOS-KO when compared with WT and inhibited in nNOS-KO when compared with WT mice. ETOH-mediated suppression of lung clearance of K. pneumoniae was unaffected in nNOS-KO mice and enhanced in the iNOS-KO mice, when compared with that obtained in WT mice. ETOH-stimulated the production of NOS I-derived nitrate and nitrite production by rat brain and lung and inhibited LPS-induced NOS II mRNA, protein, and production of nitrate and nitrite anion. Finally, inhibition of NOS I and NOS I deletion inhibited the in vivo metabolism of ETOH. CONCLUSIONS: We conclude that constitutive NOS I is involved in protection of the lung from stressor-induced lung injury. NOS I within the PMNs may limit PMN recruitment into the lung. Speculatively, NOS II-derived NO may also limit PMN-induced lung damage at the expense of a slower clearance of the bacterial burden.

Pharmacoeconomic issues in antihypertensive therapy.

Today's healthcare environment is one of perpetual change, increasing costs, and scarce resources. Healthcare professionals, insurers, and consumers are constantly challenged with balancing healthcare costs and quality of life. With so many antihypertensive agents to choose from, therapies that provide benefits beyond the decreasing of blood pressure, will become the preferred therapies. However, these agents must also demonstrate a desirable side-effect profile; agents that are effective but not complied with will neither reduce costs nor improve quality of life. Angiotensin II receptor antagonists have the most favorable adverse event profile of the antihypertensive agents. These drugs may become the preferred agents of physicians who factor indirect costs--less morbidity and greater productivity--into their selection of an antihypertensive therapy.

Angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonists in the treatment of heart failure caused by left ventricular systolic dysfunction.

Activation of the renin-angiotensin-aldosterone system (RAAS) in left ventricular systolic dysfunction is a critically important determinant in the pathophysiologic processes that lead to progression of heart failure and sudden death. Angiotensin II, acting at the specific angiotensin receptor (AT1-R), activates a series of intracellular signaling sequences which are ultimately expressed within the cardiovascular system as vasoconstriction and associated vascular hypertrophy and remodeling. Angiotensin converting enzyme (ACE) inhibition leads to increases in the vasodilatory peptides bradykinin and substance P and at least an initial reduction in angiotensin II concentrations. AT1-R blocking drugs prevent access of angiotensin II to the AT1-R and thus prevent cellular activation. ACE inhibitors have clearly been demonstrated through a large number of clinical trials to increase survival in congestive heart failure, primarily by reducing the rate of progression of left ventricular dilatation and decompensation. However, this beneficial effect diminishes over time. Preliminary short-term clinical studies evaluating the efficacy of AT1-R blocking drugs in the treatment of heart failure have suggested that they elicit similar hemodynamic and neuroendocrine effects as do the ACE inhibitors. The combination ACE inhibitors and AT1-R blocking drugs offer the theoretical advantage of increasing bradykinin while blocking the actions of angiotensin II, and thus possibly show a synergistic effect. Again, preliminary studies have yielded encouraging results that are difficult to interpret because neither ACE inhibitor nor the AT1-R blocking drug doses were titrated to tolerance. Pharmacological manipulation of the RAAS has led to better understanding of its role in heart failure and improved clinical outcomes.

Modern evaluation of the hypertensive patient: autonomic tone in cardiovascular disease and the assessment of heart rate variability.

Analysis of heart rate variability (HRV) permits an assessment of sympathetic and parasympathetic activity from EKG recordings. Analysis of HRV may be performed in both the time and frequency domain by the application of mathematical principles of signal processing. HRV demonstrates abnormalities in myocardial infarction, sudden death, heart failure, autonomic neuropathy and hypertension. The technique is useful for assessing prognosis and for evaluating therapeutic interventions.

Human and rat neutrophils constitutively express neural nitric oxide synthase mRNA.

Freshly isolated rat circulating neutrophils (PMN) constitutively expressed neural nitric oxide synthase (nNOS) mRNA and nNOS protein and exhibited spontaneous basal release of low concentrations of nitrate and nitrite anion (RNI). In contrast, rat peripheral monocytes and macrophages were devoid of nNOS mRNA and protein and did not exhibit basal or spontaneous release of RNI. Constitutive neural NOS mRNA was also found in human PMN. However, nNOS protein was not expressed and spontaneous generation of RNI was absent in the human PMN. Spontaneous release of RNI from rat PMN was inhibited by 7-nitroindazole but not by L-N-iminoethyllysine, which further supported the nNOS origin of the spontaneously produced RNI. Intravenous administration of Escherichia coli endotoxin (0.6 mg/kg) did not acutely affect the content of nNOS mRNA or protein but inhibited nNOS-derived production of RNI in PMN and up-regulated iNOS mRNA and iNOS protein in PMN, macrophages, and monocytes. This communication demonstrates the existence of nNOS mRNA in rat and human PMN and nNOS protein in rat PMN. Moreover, the data also show that the nNOS system in rat PMN is functional and is inhibitable by the nNOS inhibitor 7-nitroindazole. These findings offer an explanation for the spontaneous formation of the PMN-derived relaxing factor resembling nitric oxide (NO). Moreover, since basal production of NO can affect expression of adhesion molecules and cell-cell binding, the nNOS system within the rat may play an important role in PMN function in normal and disease states. Finally and speculatively, if constitutively expressed nNOS mRNA is subject to activation and translation into nNOS protein, nNOS may also play a role in the function of human PMN.

The potential mechanism of induction of inducible nitric oxide synthase mRNA in alveolar macrophages by lipopolysaccharide and its suppression by ethanol, in vivo.

This study reviews the putative mechanism of ethanol (ETOH)-mediated downregulation of inducible nitric oxide synthase (iNOS) messenger RNA (mRNA) and protein and upregulation of constitutive NOS activity (ecNOS) in immunocompetent cells and endothelium, in vivo. Current evidence supports the hypothesis that ETOH inhibits the phospholipase D-tyrosine kinase pathway involved in the phosphorylation and activation of NADPH oxidase and myeloperoxidase, which upregulates the formation of reactive oxygen intermediates and mitogen-activated protein kinase cascade, including the extracellular receptor-linked kinase 1 and 2 (erk1 and erk2). This decreases reactive oxygen intermediate formation, tyrosine kinase-induced phosphorylation, and activation of transcription factors that, in turn, decreases the expression of iNOS mRNA. Also, ETOH-mediated attenuation of endotoxin-induced downregulation of nuclear protein kinase C activity appears to decrease the stability of expressed iNOS mRNA. ETOH-mediated inhibition of tyrosine kinase activity may also explain the ability of ETOH to upregulate ecNOS enzymatic activity, because tyrosine kinase activity suppresses ecNOS enzymatic activity.