Hypertension-Mediated Organ Damage and Long-term Cardiovascular Outcomes in Asian Hypertensive Patients without Prior Cardiovascular Disease.

BACKGROUND: Hypertension-mediated organ damage (HMOD), comprising structural and functional changes in arteries or end organs, is a marker of cardiovascular (CV) disease. However, there are limited data on evaluation of risk of CV disease regarding HMOD, especially in Asians. We sought to investigate the association between CV events and HMOD, and we tried to determine the most important diagnostic marker among the component of HMOD for prevention of mortality and CV events in treated Korean hypertensive patients. METHODS: From January 2008 to December 2010, a total of 35,000 hypertensive Vietnamese War veterans who consecutively visited our hospital for medical check-up were reviewed, and 6,158 patients without established CV disease were enrolled. The patients were divided into two groups as follows: HMOD group (n = 766) and non-HMOD group (n = 5,392). The primary outcome was all-cause death. RESULTS: Median age was 63.3 years (interquartile range [IQR], 61.4-65.4), and median follow-up was 6.6 years (IQR, 5.9-7.2). Patients with old age, diabetes, and chronic kidney disease were more prevalent in the HMOD group than in the non-HMOD group (all P < 0.05). The lipid profiles were not significantly different between the two groups. Nephropathy was the most prevalent (54.7%) organ damage in the HMOD group. The 6-year incidence of all-cause death was higher in the HMOD group than in the non-HMOD group (22.5% vs. 9.0%; adjusted hazard ratio [HR], 1.42; 95% confidence interval [CI], 1.01-2.00; P = 0.04). The incidence of cardiac death, ischemic heart disease, and ischemic and hemorrhagic stroke were also significantly higher in the HMOD group than in the non-HMOD group (P < 0.05, respectively). In multivariate analysis, proteinuria (adjusted HR, 2.21; 95% CI, 1.52-3.20; P < 0.001) was the most powerful independent risk factor to predict all-cause death among components of HMOD. As the degree of proteinuria increased, the rate of all-cause death also increased (long-rank P < 0.001). CONCLUSION: HMOD was associated with increased risk of mortality and CV events. Proteinuria was the most powerful independent risk factor for all-cause death, and the degree of proteinuria and mortality rate were proportional. Our data suggest that monitoring of the proteinuria is important to predict long-term CV events in hypertensive patients.

Ascorbate starvation alters endoplasmic reticulum-resident enzymes in cardiac fibroblasts, priming them for increased procollagen secretion.

Since ascorbate is unnecessary for cell growth and survival, cardiac fibroblasts are routinely cultured without it. However, ascorbate is necessary for optimal collagen synthesis, so we hypothesized that its presence would influence cell phenotype. Cardiac fibroblasts cultured without ascorbate had increased intracellular levels of procollagens, with procollagen α1(III) showing the largest accumulation. Endoplasmic reticulum (ER)-resident proteins that are known to bind single-stranded procollagens were also elevated. These included the catalytic prolyl 4-hydroxylase subunits, lysyl hydroxylases, and hydroxylysyl galactosyltransferases, with prolyl 4-hydroxylase α1 and α2 (P4HA1 and P4HA2) demonstrating the largest increases. There were no differences in the levels of protein disulfide isomerase (P4HB/PDI) or the triple-helical procollagen chaperone, HSP47, with or without ascorbate. Results were similar with mouse and rat cardiac fibroblasts, suggesting a conserved response. Ascorbate-replete cells that were subsequently deprived of the vitamin lost the ability to secrete intact procollagen α1(I) within ~3days, approximately when intracellular procollagen α1(III) and P4HA1 levels began to rise. Upon ascorbate re-addition, starved fibroblasts initially secreted high levels of procollagen that gradually declined over ~4days, a pattern that was not universal as extra domain A (EDA)-fibronectin secretion was unchanged. Despite the necessity of the P4HA enzymes for triple-helical procollagen formation, they were not responsible for early increased secretion. However, in the absence of ascorbate, P4HA2 overexpression increased intracellular turnover of procollagens, suggesting that it may help clear accumulating procollagens from the ER. Cardiac fibroblasts change in the absence of ascorbate to cope with increased intracellular levels of procollagens. These changes occur slowly and can render the cells phenotypically altered for several days after ascorbate re-addition. These findings have direct implications for the study of cardiac fibroblasts in culture, and may help our understanding of the response of these cells to fluctuating nutrient levels in ischemic myocardium.

Discoidin domain receptor 2 germline gene deletion leads to altered heart structure and function in the mouse.

Discoidin domain receptor 2 (DDR2) is a fibrillar collagen receptor that is expressed in mesenchymal cells throughout the body. In the heart, DDR2 is selectively expressed on cardiac fibroblasts. We generated a germline DDR2 knockout mouse and used this mouse to examine the role of DDR2 deletion on heart structure and function. Echocardiographic measurements from null mice were consistent with those from a smaller heart, with reduced left ventricular chamber dimensions and little change in wall thickness. Fractional shortening appeared normal. Left ventricular pressure measurements revealed mild inotropic and lusitropic abnormalities that were accentuated by dobutamine infusion. Both body and heart weights from 10-wk-old male mice were ~20% smaller in null mice. The reduced heart size was not simply due to reduced body weight, since cardiomyocyte lengths were atypically shorter in null mice. Although normalized cardiac collagen mass (assayed by hydroxyproline content) was not different in null mice, the collagen area fraction was statistically higher, suggesting a reduced collagen density from altered collagen deposition and cross-linking. Cultured cardiac fibroblasts from null mice deposited collagen at a slower rate than wild-type littermates, possibly due to the expression of lower prolyl 4-hydroxylase α-isoform 1 enzyme levels. We conclude that genetic deletion of the DDR2 collagen receptor alters cardiac fibroblast function. The resulting perturbations in collagen deposition can influence the structure and function of mature cardiomyocytes.

Adherence to triple-component antihypertensive regimens is higher with single-pill than equivalent two-pill regimens: A randomized controlled trial.

Using a single-pill combination (SPC) for hypertension (HTN) treatment resulted in better adherence and persistence than a free-equivalent combination in previous observational studies. The aim of this study is to confirm superior adherence with a triple-component SPC compared with an equivalent two-pill regimen in a randomized controlled trial (RCT) using a medication event monitoring system (MEMS). This is a multicenter, open-label, RCT. Subjects were persons with HTN whose clinic blood pressure was not adequately controlled (systolic >140 mmHg or diastolic >90 mmHg) with a dual combination. Eligible patients were randomized to either the triple-component SPC (olmesartan/amlodipine/hydrochlorothiazide 20/5/12.5 mg) group or the equivalent two-pill (olmesartan/hydrochlorothiazide 20/12.5 mg + amlodipine 5 mg) group and maintained for 12 weeks. Primary outcomes were the difference in percentage of doses taken (PDT) and percentage of days with the prescribed dose taken correctly (PDTc) between the single- and two-pill therapy groups, calculated from MEMS data. From 8 hospitals, 145 patients with HTN were randomized. The single-pill group had significantly higher PDT and PDTc than the two-pill group: median (25-75 percentile) PDT 95.1 (86.7-100.0) versus 92.1 (73.0-97.3); and PDTc 91.0 (79.4-96.5) versus 88.6 (69.2-96.3%), P = 0.04 for both by the Wilcoxon rank sum test. The single-pill combination of the triple-component antihypertensive regimen showed better adherence than the equivalent two-pill therapy. Reducing pill burden by means of a single-pill combination is an effective strategy for enhancing adherence to multiple-agent antihypertensive therapy. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? Previous studies suggested that the use of a single-pill combination (SPC) in hypertension (HTN) treatment produced better adherence and persistence than a free-equivalent combination. However, supportive data are confined to dual-component SPC and came from observational studies using medication possession ratio as an outcome. WHAT QUESTION DID THIS STUDY ADDRESS? The objective of this study is to investigate whether a triple-component SPC improved medication adherence over an equivalent two-pill combination therapy in a randomized controlled trial using medication event monitoring systems. WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? Medication adherence in the SPC group was superior to that of two-pill group, confirming previous findings from observational studies. HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE? This finding strongly supports the current HTN treatment guideline to prefer SPC with a higher level of evidence.

Long-term Survival in Korean Elderly Patients with Symptomatic Severe Aortic Stenosis Who Refused Aortic Valve Replacement.

BACKGROUND AND OBJECTIVES: Aortic valve replacement (AVR) is the treatment of choice in severe symptomatic aortic stenosis (AS) patients. However, a substantial number of elderly patients refuse AVR and treated medically. We investigated their long-term prognosis. METHODS: From January 2005 to December 2016, we analyzed elderly patients with severe symptomatic AS who refused to have AVR. RESULTS: After screening of total 534 patients, we analyzed total 180 severe symptomatic AS patients (78±7 years old, 96 males). Hypertension was the most common cardiovascular risk factor (72%) and the most common symptom was dyspnea (66%). Calculated aortic stenosis area was 0.73±0.20 cm² and mean left ventricular ejection fraction (LVEF) was 57.8±12.2%. Total 102 patients died during follow-up period (39.1±31.0 months). One-, 3-, and 5-year all-cause mortality rate was 21.1±3.0%, 43.1±3.8%, and 56.5±4.2%, respectively. Of them, 87 died from cardiac causes, and 1-, 3-, and 5-year cardiac mortality rate was 18.0±2.9%, 38.2±3.8%, and 50.7±4.3%, respectively. Their all-cause mortality and cardiac mortality were significantly higher than those of controls. Univariate analysis showed that age, anemia, LVEF, and Log N-terminal pro B-type natriuretic peptide (NT-proBNP) were significant parameters in all-cause mortality (p<0.001, p=0.001, p=0.039, and p=0.047, respectively) and in cardiac mortality (p<0.001, p<0.001, p=0.046, and p=0.026, respectively). Multivariate analysis showed that age and anemia were significant prognostic factors for cardiac and all-cause mortality. CONCLUSIONS: In elderly severe symptomatic AS patients who treated medically, their 1-, 3- and 5-year all-cause mortality rate was 21.1±3.0%, 43.1±3.8%, and 56.5±4.2%, respectively. Age and anemia were significant prognostic factors for cardiac and all-cause mortality.

Efficacy and Tolerability of Combination Therapy Versus Monotherapy with Candesartan and/or Amlodipine for Dose Finding in Essential Hypertension: A Phase II Multicenter, Randomized, Double-blind Clinical Trial.

PURPOSE: Intensive blood pressure (BP) lowering is important for the treatment of hypertension; however, it has been a challenge to achieve target BP in many patients. The purpose of this study was to explore the optimal dosage of a fixed-dose combination of candesartan cilexetil (CAN) and amlodipine besylate (AML), by examining the tolerability and efficacy of CAN/AML combination therapy compared with those of monotherapy with either drug in patients with essential hypertension. METHODS: This Phase II multicenter, randomized, double-blind clinical trial enrolled patients aged 19 years or older with essential hypertension, defined as a mean sitting diastolic BP (msDBP) between 95 and 115 mm Hg, and a mean sitting systolic BP (msSBP) of <200 mm Hg after a 2-week placebo run-in period. A total of 635 patients were screened, of whom 439 were randomized to receive treatment; 425 patients were included in the full analysis set (combination therapy, 212; monotherapy, 213). Participants were randomly assigned to receive 1 of 8 treatments: CAN (8 or 16 mg), AML (5 or 10 mg), CAN/AML (8 mg/5 mg, 8 mg/10 mg, 16 mg/5 mg, or 16 mg/10 mg), once daily for 8 weeks. FINDINGS: After 8 weeks of treatment, changes in msDBP were significantly greater in the groups receiving CAN/AML combination therapies compared with monotherapies at matched doses, with the exception of CAN 8 mg/AML 10 mg versus AML 10 mg. The response to treatment and the achievement of target BP (both msSBP and msDBP) at week 8 were significantly greater overall in the groups that received combination therapy versus monotherapy. All medications were relatively well tolerated in each group. IMPLICATIONS: Eight-week administration of CAN/AML (8 mg/5 mg, 16 mg/5 mg, and 16 mg/10 mg) resulted in a significantly greater BP reduction than that with CAN or AML monotherapy, and was determined to be well tolerated. ClinicalTrials.gov identifier: NCT02944734.

Combination Therapy of Rosuvastatin and Ezetimibe in Patients with High Cardiovascular Risk.

PURPOSE: The aim of this study was to evaluate the efficacy and tolerability of rosuvastatin/ezetimibe combination therapy in Korean patients with high cardiovascular risk. METHODS: This was a 12-week, randomized, double-blind, placebo-controlled, multicenter study. A total of 337 patients were screened. After a 4-week run-in period, 245 of these patients with high or moderately high risk as defined by the National Cholesterol Education Program Adult Treatment Panel III guidelines were randomly assigned. Patients received 1 of 6 regimens for 8 weeks as follows: (1) rosuvastatin 5 mg, (2) rosuvastatin 5 mg/ezetimibe 10 mg, (3) rosuvastatin 10 mg, (4) rosuvastatin 10 mg/ezetimibe 10 mg, (5) rosuvastatin 20 mg, or (6) rosuvastatin 20 mg/ezetimibe 10 mg. The primary outcome variable was percentage change in the level of LDL-C at week 8 of drug treatment. Secondary outcome variables included percentage changes of other lipid variables and achievement rates of LDL-C targets. Tolerability analyses were also performed. FINDINGS: The percentage change of LDL-C ranged from -45% to -56% (mean, -51%) in the monotherapy groups and from -58% to -63% (mean, -60%) in the combination therapy groups. The percentage change was greater in the pooled combination therapy group than in the counterpart (P < 0.001 for the pooled groups); this difference was more obvious for regimens with a lower statin dose. The percentage reductions of total cholesterol and triglycerides were greater in the combination groups than in the monotherapy groups. The LDL-C target achievement rates were 64% to 87% (mean, 73%) in the monotherapy groups and 87% to 95% (mean, 91%) in the combination groups (P = 0.01 for the pooled groups). The rates were significantly greater in patients receiving the combination therapy than in the monotherapy at lower doses of rosuvastatin. The proportions of patients with various adverse events were not significantly different between the groups. IMPLICATIONS: Rosuvastatin/ezetimibe combination therapy has better efficacy and target achievement rates than rosuvastatin monotherapy in patients with high cardiovascular risk.

Utility of graded exercise tolerance tests for prediction of cardiovascular mortality in old age: The Rancho Bernardo Study.

BACKGROUND: Exercise electrocardiography in asymptomatic adults has been criticized because of relatively poor accuracy predicting future heart disease risk, but studies may have been too short. We investigated if integrated analysis of graded exercise tolerance tests (GXT) predicted long-term coronary heart disease (CHD) and all-cause mortalities among community-dwelling older adults. METHODS AND RESULTS: From 1972 to 1974, 1789 adult residents of a predominantly Caucasian, middle- to upper-middle-class southern California community participated in a clinical evaluation that included a GXT; 52.4% (N=939) of those who had baseline GXT were followed up to 2010-up to 36years-for vital status, CHD and all-cause mortality. Multiply adjusted hazard ratios of an abnormal graded GXT were 1.65 (95% CI 0.78-3.49) and 1.56 (95% CI 1.15-2.11) for CHD and all-cause mortality, respectively. An integrated analysis hazard ratio was calculated based on the following GXT findings: significant ST change, inability to achieve target heart rate [THR], abnormal heart rate recovery [HRR], and chronotropic incompetency [ChI]. Compared to those with 0 or 1 abnormality, participants with 2 or more positive findings had significantly higher CHD (HR 2.18) and all-cause (HR 1.92) mortalities. Participants with 3 or more positive findings showed even higher hazard ratios-CHD (HR 6.16) and all-cause (HR 2.49) mortalities. When adjusted for any of 3 Framingham risk models, the integrated electrocardiographic model correlated well with CHD and all-cause mortalities. CONCLUSIONS: An integrated analysis of electrocardiographic and non-electrocardiographic measures of GXT is useful in predicting long-term CHD and all-cause mortalities in an asymptomatic middle-aged population.

Usefulness of the integrated scoring model of treadmill tests to predict myocardial ischemia and silent myocardial ischemia in community-dwelling adults (from the Rancho Bernardo study).

To investigate the association between analyses of submaximal treadmill exercise test (TMT) and long-term myocardial ischemia (Mis) and silent Mis in community-dwelling older adults, 898 Rancho Bernardo Study participants (mean age 55 years) without coronary heart disease underwent TMT and were followed up to 27 years. The main outcome measures are incidence of Mis and silent Mis. During follow-up, 97 Mis and 103 silent Mis events occurred. We measured ST change, inability to achieve target heart rate, abnormal heart rate recovery (HRR), and chronotropic incompetence (ChI). Each parameter was a significant predictor for Mis and silent Mis. An integrated scoring model was based on these 4 parameters and defined as sum of numbers of abnormal parameters. After multiple adjustments, an integrated scoring model independently predicted Mis and silent Mis. The incidence rates of abnormalities of parameters are 36.5% for 1 abnormality, 9.1% for 2 abnormalities, and 2.0% for 3 or 4 abnormalities. Compared with those with normal results, participants with 1 or 2 abnormalities had significantly increased risk for Mis (hazard ratio [HR] 1.79 or 2.34, respectively) and silent Mis (HR 1.80 or 2.64, respectively). Participants with 3 or more positive findings showed an even greater risk for Mis (HR 7.96 [3.02 to 21.00]) and silent Mis (HR 3.22 [0.76 to 13.60]). In conclusion, ST change, ChI, abnormal HRR, inability to achieve target heart rate, and integrated scoring model of TMT were independent predictors of long-term Mis and silent Mis in an asymptomatic middle-aged population. Management of ChI or abnormal HRR in an asymptomatic population may prevent future ischemic heart disease and thus improve the quality of life.

Vascular endothelial growth factor-induced angiogenic gene therapy in patients with peripheral artery disease.

This phase 1 clinical trial tested the safety of intramuscular gene transfer by using naked plasmid DNA encoding the gene for VEGF, and analyzed the potential therapeutic benefits in patients with severe peripheral arterial disease (PAD). This study was an open-labeled, dose- escalating, single-center trial on nine male patients with severe debilitating PAD who had not responded to conventional therapy. Seven had Buerger's disease and two had arteriosclerosis obliterans. Plasmid DNA (pCK) containing human VEGF165 was given by eight intramuscular injections in and around the area in need of new blood vessels. The study evaluated three escalating total doses (2, 4, and 8 mug of pCK- VEGF165), with half of each total dose given four weeks apart. The follow-up duration was nine months. The gene injections were well tolerated without significant side effects or laboratory abnormalities related to gene transfer. Three patients showed transient edema in their extremities. Ischemic pain of the affected limb was relieved or improved markedly in six of seven patients. Ischemic ulcers healed or improved in four of six patients. The mean ankle-brachial index (ABI) improved significantly. Six of nine patients showed an increase in collateral vessels around the injection sites demonstrated by digital subtraction angiography. However, there was no relationship between the degree of ABI improvement and the dose given. Mean plasma levels of VEGF did not increase significantly. In conclusion, intramuscular injections of pCK- VEGF165 can be performed safely to induce therapeutic angiogenesis in patients with severe PAD.

Thioredoxin, adiponectin and clinical course of acute fulminant myocarditis.

BACKGROUND: In an animal model of viral myocarditis, plasma levels of thioredoxin and adiponectin have been reported to be associated with the severity of inflammation and recovery of ventricular dysfunction, respectively. However, there have been few reports about the clinical significance of these cytokine levels in human myocarditis. OBJECTIVES: To examine the hypothesis that cytokine levels correlate with clinical courses of patients with acute fulminant myocarditis (FM). METHODS: A total of 33 consecutive patients with biopsy-proven acute myocarditis were evaluated. Twenty patients were ascribed to an FM group and the other 13 patients were grouped as a non-fulminant group (NFM). Plasma cytokine levels at the time of admission and after 2 weeks were evaluated and correlated with the duration of mechanical circulatory support application. RESULTS: Plasma thioredoxin level at admission was raised in the FM group (3.08±2.15 ng/ml) compared with the NFM group (1.63±0.45 ng/ml, p=0.011) and reduced after an initial unstable period. However there was no significant difference in plasma adiponectin level between the two groups. In a multivariable regression model, increased plasma thioredoxin level (OR=5.79, 95% CI 1.67 to 20.1, p=0.006) and reduced plasma adiponectin level (OR=0.16, 95% CI 0.055 to 0.49, p=0.001) were associated with longer duration of mechanical circulatory support application in the patients with FM, which in turn was significantly related to death or cardiac transplantation. CONCLUSION: In patients with acute myocarditis, the plasma thioredoxin level was increased in the more severe form, and a reduced level of adiponectin was closely correlated with worse short-term outcome in patients with FM.

Left ventricular metastasis from renal cell carcinoma causing left ventricular outflow tract obstruction.

Most cases of cardiac metastasis from renal cell carcinoma (RCC) involve the vena cava or right atrium. Left ventricular metastases from RCC without involving the vena cava or right atrium are extremely rare. Herein we report a case of RCC with left ventricular metastasis causing left ventricular outflow obstruction (LVOT).

Non-ischemic cardiomyopathy attributed to adult myotonic dystrophy.

In patients with myotonic dystrophy (MD), impairment of the conduction system is a common and progressive finding. However, only a few cases of MD with cardiomyopathy have been reported. Herein we report a case of MD with progressive non-ischemic cardiomyopathy and severe electrocardiographic abnormalities.

Isolated double-chambered right ventricle presenting in adulthood.

We report the case of a 55-year-old woman who was admitted for exertional chest pain with dyspnea. The patient was diagnosed with an isolated double-chambered right ventricle (DCRV) without associated congenital anomalies. Most cases of DCRV are diagnosed at a young age and commonly associated with VSD; isolated DCRV in adults is extremely rare.

Improvement after thalidomide and dexamethasone treatment for advanced cardiac amyloidosis: a case report.

A case of advanced cardiac amyloidosis was treated with thalidomide. The patient showed early and significant improvement of diastolic cardiac function, as well as symptoms.

Spontaneous closure of iatrogenic coronary artery fistula to left ventricle after septal myectomy for hypertrophic obstructive cardiomyopathy.

Cases of iatrogenic coronary artery fistulas draining into the left ventricle after surgical myectomy for hypertrophic obstructive cardiomyopathy have been published as sporadic reports. However, its management scheme and prognosis are not clear because of the low incidence. A 46-yr-old woman was hospitalized for evaluation of chest pain and shortness of breath for 3 months. Transthoracic echocardiographic examination showed typical hypertrophic obstructive cardiomyopathy with a peak pressure gradient of 71 mmHg across the left ventricular outflow tract. The patient underwent surgical septal myectomy. Postoperative color Doppler imaging revealed a diastolic blood flow from the interventricular septal myocardium to the left ventricular cavity, i.e. iatrogenic coronary artery fistula to the left ventricle. Ten days later, the fistula closed spontaneously which was diagnosed by transthoracic echocardiography and confirmed by coronary angiography.