Citations

Although resistant hypertension affects a minority of all hypertensives, this group continues to experience disproportionately high cardiovascular event rates despite newer antihypertensive agents. Hypertension represents an imbalance of hemodynamic forces within the circulation, usually characterized by elevated systemic vascular resistance. We studied the utility of serial hemodynamic parameters in the selection and titration of antihypertensive medication in resistant hypertensive patients using highly reproducible noninvasive measurements by thoracic bioimpedance. Resistant hypertension patients (n=104) were randomized to drug selection based either on serial hemodynamic (HD) measurements and a predefined algorithm or on drug selection directed by a hypertension specialist (SC) in a 3-month intensive treatment program. Blood pressure was lowered by intensified drug therapy in both treatment groups (169±3/87±2 to 139±2/72±1 mm Hg HD versus 173±3/91±2 to 147±2/79±1 mm Hg SC, P <0.01 for systolic and diastolic BP), using similar numbers and intensity of antihypertensive medications. Blood pressures were reduced further for those treated according to hemodynamic measurements, resulting in improved control rates (56% HD versus 33% SC controlled to ≤140/90 mm Hg, P <0.05) and incremental reduction in systemic vascular resistance measurements. Although the number of patients taking diuretics did not differ between groups, final diuretic dosage was higher in the hemodynamic cohort. Our results demonstrate superior blood pressure control using a treatment algorithm and serial hemodynamic measurements compared with clinical judgment alone in a randomized prospective study. Our measurements of thoracic fluid volume support occult volume expansion as a mediator of antihypertensive drug resistance and use of impedance measurements to guide advancing diuretic dose and adjustment of multidrug antihypertensive treatment.

Background — The Multicenter Unsustained Tachycardia Trial (MUSTT) was designed to evaluate an antiarrhythmic treatment strategy, including drugs and implantable defibrillators (ICDs), guided by electrophysiological (EP) testing. We performed several statistical analyses to assess the contribution of defibrillators to the observed treatment benefit. Methods and Results — First, the effects of defibrillators were indirectly examined by comparing the randomized treatment arms (EP-guided therapy versus no antiarrhythmic therapy) within subgroups that varied according to ICD usage. Use of ICDs increased during the trial; hence, the randomized treatments were compared according to date of enrollment. There were also site-specific differences in ICD use; hence, the randomized arms were compared within groups of sites defined by level of ICD use. There was a distinct “dose response” in relation to ICD use. Where ICD use was high, EP-guided therapy produced significant reductions in arrhythmic death or cardiac arrest ( P <0.004). Where ICD use was low, there was no benefit of EP-guided therapy. Finally, outcomes of EP-guided therapy patients who received an ICD were directly compared with outcomes of other patients using the Cox proportional hazards model with receipt of an ICD as a time-dependent covariate. Adjusted for other prognostic factors, patients who received an ICD had risk reductions of >70% in arrhythmic death or cardiac arrest and >50% in total mortality ( P <0.001 for both end points). Conclusions — The benefit of EP-guided antiarrhythmic therapy observed in MUSTT was due to improved outcomes among patients who received an ICD but not among patients who received antiarrhythmic drugs.

Background — Autosomal dominant hypertrophic cardiomyopathy (HCM) is caused by inherited defects of sarcomeric proteins. We tested the hypothesis that homozygosity for a sarcomeric protein defect can cause recessive HCM. Methods and Results — We studied a family with early-onset cardiomyopathy in 3 siblings, characterized by mid-cavitary hypertrophy and restrictive physiology. Genotyping of DNA markers spanning 8 genes for autosomal dominant HCM revealed inheritance of an identical paternal and maternal haplotype at the essential light chain of myosin locus by the affected children. Sequencing showed that these individuals were homozygous for a Glu143Lys substitution of a highly conserved amino acid that was absent in 150 controls. Family members with one Glu143Lys allele had normal echocardiograms and ECGs, even in late adulthood, whereas those with two mutant alleles developed severe cardiomyopathy in childhood. These findings, coupled with previous studies of myosin light chain structure and function in the heart, suggest a loss-of-function disease mechanism. Conclusions — Distinct mutations affecting the same sarcomeric protein can cause either dominant or recessive cardiomyopathy. Electrostatic charge reversal of a highly conserved amino acid may be benign in the heterozygous state as the result of compensatory mechanisms that preserve cardiac structure and function. By contrast, homozygous carriers of a sarcomeric protein defect may have a malignant course. Recognizing recessive inheritance in children with cardiomyopathy is essential for appropriate family counseling.

Background — Although severe chronic kidney disease (CKD) is an independent predictor of mortality among patients with coronary artery disease, the impact of mild CKD on morbidity and mortality has not been fully defined. Methods and Results — Morbidity and mortality for the 3608 patients with multivessel coronary artery disease enrolled in the Bypass Angioplasty Revascularization Investigation randomized trial and registry were compared on the basis of the presence and absence of CKD, defined as a preprocedure serum creatinine level of >1.5 mg/dL. Seventy-six patients had CKD. Patients with renal insufficiency were older and more likely to have a history of diabetes, hypertension, and other comorbidities. Among patients undergoing PTCA, patients with CKD had a greater frequency of in-hospital death and cardiogenic shock ( P <0.05 and 0.01, respectively). There was a trend toward a larger proportion of patients with CKD experiencing angina at 5 years ( P =0.079). Patients with CKD had more cardiac admissions ( P =0.003 and <0.0001 for patients undergoing PTCA and CABG, respectively) and a shorter time to subsequent CABG after initial revascularization than patients without CKD ( P =0.01). CKD was associated with a higher risk of death at 7 years, both of all causes (relative risk 2.2, P <0.001) and of cardiac causes (relative risk 2.8, P <0.001). Conclusions — CKD is associated with an increased risk of recurrent hospitalization, subsequent CABG, and mortality. This increased risk of death is independent of and additive to the risk associated with diabetes.

Background — Data are absent that compare midterm angiographic outcome between patients with and without diabetes after initial percutaneous transluminal coronary angioplasty (PTCA) and coronary artery bypass graft surgery (CABG). Importantly, diabetes mellitus may differentially influence long-term survival after PTCA or CABG. Methods and Results — Patients with multivessel coronary disease who were previously enrolled in the Bypass Angiopathy Revascularization Investigation to compare initial PTCA versus CABG (n=1829) and who had a reduction in jeopardized myocardium after initial revascularization and at least 1 angiogram during 5-year follow-up were analyzed (n=897). This included 369 CABG-treated patients (16% with diabetes) and 528 PTCA-treated patients (18% with diabetes). The influence of diabetes on angiographic increase in percentage of jeopardized myocardium after initial revascularization with either PTCA or CABG was investigated. Among PTCA patients, the mean percentage increase in total jeopardized myocardium was significantly greater in those with diabetes than in those without at 1-year protocol-directed angiography (42% versus 24%, P =0.05) and on the first clinically performed (unscheduled) angiogram within 30 months (63% versus 50%, P =0.01) but not at 5-year protocol-directed angiography (34% versus 26%, P =0.33). This excess midterm risk associated with diabetes persisted after statistical adjustment. In contrast, among CABG patients, diabetes was not associated with percentage increase in jeopardized myocardium at any angiographic follow-up interval. Conclusions — Presence of diabetes differentially influences worsening of jeopardized myocardium after initial PTCA compared with CABG. This differential effect occurs irrespective of whether follow-up angiography is undertaken for clinical or nonclinical purposes.

Background — Regional myocardial function assessment is essential in the management of coronary artery disease (CAD). Tissue Doppler imaging (TDI) by depicting local myocardial motion can potentially quantify regional myocardial function. Strain rate imaging (SRI) that depicts regional deformation is less susceptible to cardiac translation and tethering and may be superior to TDI for regional function analysis. We examined regional myocardial function using TDI and SRI in a unique clinical model of a small, discrete myocardial infarction. Method and Results — Ten patients with severely symptomatic septal hypertrophy underwent basal septal ablation via intracoronary alcohol injection and had TDI and SRI pre- and postablation. Invasive hemodynamics showed no appreciable change in global function. Peak systolic strain rate was significantly lower postablation versus preablation (−0.5 versus −1.2 s −1 , P <0.001) and when comparing infarct and noninfarct areas (−0.5 versus −1.5 s −1 , P <0.001). In contrast, peak systolic tissue velocities were similar pre- and postablation (3.9 versus 2.9 cm/s, P =0.16) and between infarct and noninfarct areas (2.9 versus 2.2 cm/s, P =0.13). SRI analysis demonstrated reduced systolic function in the peri-infarct zone and preserved systolic function in the remote nonischemic zone. Conclusion — In the clinical setting of a small, discrete infarct unaccompanied by changes in global function, SRI accurately depicted changes in regional function. These data suggest that SRI may be the optimal method for objective, quantitative assessment of regional myocardial dysfunction.

Background — A hallmark of congestive heart failure (CHF) is the elevation of the cardiac natriuretic peptides (NPs), which have natriuretic, renin-inhibiting, vasodilating, and lusitropic properties. We have reported that chronic subcutaneous (SQ) administration of brain natriuretic peptide (BNP) in experimental CHF improves cardiorenal function. Vasopeptidase inhibitors (VPIs) are single molecules that simultaneously inhibit both neutral endopeptidase 24.1 (NEP) and ACE. We hypothesized that acute VPI administration would potentiate the cardiorenal actions of SQ BNP in experimental CHF. Methods and Results — We determined the cardiorenal and humoral responses to acute VPI alone with omapatrilat (OMA) (1 μmol/kg IV bolus) (n=6), acute low-dose SQ BNP (5 μg/kg) alone (n=5), acute VPI plus low-dose SQ BNP (n=5), and acute high-dose SQ BNP (25 μg/kg) alone in 4 groups of anesthetized dogs with experimental CHF produced by ventricular pacing for 10 days. Plasma BNP was greater with VPI+low-dose SQ BNP compared with VPI alone or low-dose SQ BNP alone and was similar to high-dose SQ BNP alone. Urinary BNP excretion was greatest with VPI+SQ BNP. Urinary sodium excretion was also highest with VPI+SQ BNP, with the greatest increase in glomerular filtration rate. VPI+SQ BNP resulted in a greater increase in cardiac output and reduction in cardiac filling pressures as compared with low-dose SQ BNP, high-dose SQ BNP, or VPI alone. Conclusions — This study reports that acute VPI potentiates the cardiorenal actions of SQ BNP in experimental CHF. This study advances the concept that protein therapy with BNP together with vasopeptide inhibition represents a novel therapeutic strategy in CHF to maximize the beneficial properties of the natriuretic peptide system.

Background — CD4 T lymphocytes accumulate in unstable plaque. The direct and indirect involvement of these T cells in tissue injury and plaque instability is not understood. Methods and Results — Gene profiling identified perforin, CD161, and members of the killer-cell immunoglobulin-like receptors as being differentially expressed in CD4 + CD28 null T cells, a T-cell subset that preferentially infiltrates unstable plaque. Frequencies of CD161 + and perforin-expressing CD4 T cells in peripheral blood were significantly increased in patients with unstable angina (UA). CD161 appeared on CD4 + CD28 null T cells after stimulation, suggesting spontaneous activation of circulating CD4 T cells in UA. Perforin-expressing CD4 + T-cell clones from patients with UA exhibited cytotoxic activity against human umbilical vein endothelial cells (HUVECs) in redirected cytotoxicity assays after T-cell receptor triggering and also after stimulation of major histocompatibility complex class I–recognizing killer-cell immunoglobulin-like receptors. HUVEC cytolysis was dependent on granule exocytosis, as demonstrated by the paralyzing effect of pretreating CD4 + CD28 null T cells with strontium. Incubation of HUVECs with C-reactive protein (CRP) increased HUVEC lysis in a dose-dependent fashion. Conclusions — In patients with UA, CD4 T cells undergo a change in functional profile and acquire cytotoxic capability. Cytotoxic CD4 T cells effectively kill endothelial cells; CRP sensitizes endothelial cells to the cytotoxic process. We propose that T-cell–mediated endothelial cell injury is a novel pathway of tissue damage that contributes to plaque destabilization. The sensitizing effect of CRP suggests synergy between dysregulated T-cell function and acute phase proteins in acute coronary syndromes.