Genome-wide association study of nocturnal blood pressure dipping in hypertensive patients.

BACKGROUND: Reduced nocturnal fall (non-dipping) of blood pressure (BP) is a predictor of cardiovascular target organ damage. No genome-wide association studies (GWAS) on BP dipping have been previously reported. METHODS: To study genetic variation affecting BP dipping, we conducted a GWAS in Genetics of Drug Responsiveness in Essential Hypertension (GENRES) cohort (n = 204) using the mean night-to-day BP ratio from up to four ambulatory BP recordings conducted on placebo. Associations with P < 1 × 10- 5 were further tested in two independent cohorts: Haemodynamics in Primary and Secondary Hypertension (DYNAMIC) (n = 183) and Dietary, Lifestyle and Genetic determinants of Obesity and Metabolic Syndrome (DILGOM) (n = 180). We also tested the genome-wide significant single nucleotide polymorphism (SNP) for association with left ventricular hypertrophy in GENRES. RESULTS: In GENRES GWAS, rs4905794 near BCL11B achieved genome-wide significance (ß = - 4.8%, P = 9.6 × 10- 9 for systolic and ß = - 4.3%, P = 2.2 × 10- 6 for diastolic night-to-day BP ratio). Seven additional SNPs in five loci had P values < 1 × 10- 5. The association of rs4905794 did not significantly replicate, even though in DYNAMIC the effect was in the same direction (ß = - 0.8%, P = 0.4 for systolic and ß = - 1.6%, P = 0.13 for diastolic night-to-day BP ratio). In GENRES, the associations remained significant even during administration of four different antihypertensive drugs. In separate analysis in GENRES, rs4905794 was associated with echocardiographic left ventricular mass (ß = - 7.6 g/m2, P = 0.02). CONCLUSIONS: rs4905794 near BCL11B showed evidence for association with nocturnal BP dipping. It also associated with left ventricular mass in GENRES. Combined with earlier data, our results provide support to the idea that BCL11B could play a role in cardiovascular pathophysiology.

Postoperative Cardiac Ischemia Detection by Continuous 12-Lead Electrocardiographic Monitoring in Vascular Surgery Patients: A Prospective, Observational Study.

OBJECTIVES: Elderly patients undergoing vascular surgery are at major risk for perioperative cardiac complications. The authors investigated continuous electrocardiographic Holter monitoring in a postoperative setting to determine the degree of postoperative ischemic load and its possible associations with perioperative myocardial infarction. DESIGN: A prospective, observational study. SETTING: One university hospital. PARTICIPANTS: The study comprised 51 patients aged 65 years or older undergoing peripheral arterial surgery. INTERVENTIONS: Continuous electrocardiographic monitoring with a Holter device was started postoperatively and continued for 72 hours or until discharge. Postural changes were recorded using a 3-axis accelerometer. Standard 12-lead electrocardiography, high-sensitive troponin T measurements, and an inquiry of ischemic symptoms were performed 4 times perioperatively. MEASUREMENTS AND MAIN RESULTS: The primary outcomes were ischemic load (area under the function of ischemic ST-segment deviation and ischemic time) and perioperative myocardial infarction. During 3,262.7 patient-hours of monitoring, 17 patients (33.3%) experienced 608 transient ischemic events, all denoted by ST-segment depression. Of these 17 patients, 5 experienced perioperative myocardial infarction. The mean ischemic load in all patients was 913.2±2,797.3 µV×minute. Ischemic load predicted perioperative myocardial infarction, with an area under receiver operating characteristics curve (95% confidence interval) of 0.87 (0.75-0.99). Ischemic changes occurred most frequently during hours 24 to 60 of monitoring. Ischemia was asymptomatic in 14 of 17 patients (82.4%). CONCLUSION: Postoperative myocardial ischemia was common in peripheral vascular surgery patients and may progress to perioperative myocardial infarction. Ischemic load was a good predictor of perioperative myocardial infarction. Ambulatory electrocardiographic monitoring solutions for continuous postoperative ischemia detection are warranted in the surgical ward.

Postpericardiotomy syndrome.

Postpericardiotomy syndrome (PPS) is a common complication following cardiac surgery. In most cases it develops 2 to 3 weeks after the operation. An inflammatory reaction develops in the pericardium or pleural space with fever, chest pain and dyspnea as typical symptoms. The disease process is usually self-limiting. At present, the etiology is unknown, but an immunological mechanism is suspected as the cause of the disease. The incidence of PPS is essentially dependent on diagnostic criteria, patient group and type of operation. Treatment is carried out with anti-inflammatory analgesics, combined with colchicine in more severe cases.

[Perioperative cardiac infarction - an underdiagnosed problem]. / Perioperatiivinen sydäninfarkti - alidiagnosoitu ongelma.

Perioperative cardiac infarction (PMI) associated with surgery and the postoperative period significantly restricts the outcome of operative treatment. PMI is encountered in 0.5 to 1% of surgical patients, but among high-risk patients the incidence exceeds 10%. The disorder is associated with a mortality of 10 to 25%, corresponding to at least 1 000 patient deaths annually, as adjusted to the numbers of operative treatment in Finland, and its care requires at least 20000 extra days of hospitalization.

Tibial Tuberosity Transposition Fixation with a Locking Plate during Medial Patellar Luxation Surgery: An Ex Vivo Mechanical Study.

OBJECTIVES: The purpose of this study was to compare the load at failure, stiffness and mode of failure between three types of tibial tuberosity transposition fixation techniques: (a) pin and figure-8 tension band wire (Pin-TBW), (b) locking plate with pin and a tension band wire (Plate-Pin-TBW) and (c) locking plate with a pin (Plate-Pin). METHODS: Six pairs of raccoon dog cadaveric tibiae were tested in Phase I Pin-TBW versus Plate-Pin-TBW and seven pairs in Phase II Plate-Pin-TBW versus Plate-Pin. One limb of each pair was randomly assigned to one of two groups for each phase. A tensile force was applied to the patellar ligament until construct failure. RESULTS: Pin-TBW (342N ± 54.7N) failed at a lower load than Plate-Pin-TBW (469N ± 77.3N), p = 0.00748, with all Pin-TBW failing by fracture and the majority of Plate-Pin-TBW failing by rupture of patellar ligament. Pin-TBW group Phase I, normalized with Plate-Pin-TBW Phase I, failed at a lower load than Plate-Pin group Phase II, normalized with Plate-Pin-TBW Phase II, p = 0.00467. There was no significant difference in mean load at failure, stiffness or mode at failure between the groups in the Phase II study. CLINICAL SIGNIFICANCE: Although ex vivo mechanical testing does not replicate the postoperative live dog or cat, these results demonstrate lower construct strength of the Pin-TBW construct compared with the Plate-Pin construct in the raccoon dog cadaver model.

Effect of four classes of antihypertensive drugs on cardiac repolarization heterogeneity: A double-blind rotational study.

BACKGROUND: T-wave area dispersion (TW-Ad) is a novel electrocardiographic (ECG) repolarization marker associated with sudden cardiac death. However, limited data is available on the clinical correlates of TW-Ad. In addition, there are no previous studies on cardiovascular drug effects on TW-Ad. In this study, we examined the relation between TW-Ad and left ventricular mass. We also studied the effects of four commonly used antihypertensive drugs on TW-Ad. METHODS: A total of 242 moderately hypertensive males (age, 51±6 years; office systolic/diastolic blood pressure during placebo, 153±14/100±8 mmHg), participating in the GENRES study, were included. Left ventricular mass index was determined by transthoracic echocardiography. Antihypertensive four-week monotherapies (a diuretic, a beta-blocker, a calcium channel blocker, and an angiotensin receptor antagonist) were administered in a randomized rotational fashion. Four-week placebo periods preceded all monotherapies. The average value of measurements (over 1700 ECGs in total) from all available placebo periods served as a reference to which measurements during each drug period were compared. RESULTS: Lower, i.e. risk-associated TW-Ad values correlated with a higher left ventricular mass index (r = -0.14, p = 0.03). Bisoprolol, a beta-blocker, elicited a positive change in TW-Ad (p = 1.9×10-5), but the three other drugs had no significant effect on TW-Ad. CONCLUSIONS: Our results show that TW-Ad is correlated with left ventricular mass and can be modified favorably by the use of bisoprolol, although demonstration of any effects on clinical endpoints requires long-term prospective studies. Altogether, our results suggest that TW-Ad is an ECG repolarization measure of left ventricular arrhythmogenic substrate.

Human essential hypertension: no significant association of polygenic risk scores with antihypertensive drug responses.

Polygenic risk scores (PRSs) for essential hypertension, calculated from > 900 genomic loci, were recently found to explain a significant fraction of hypertension heritability and complications. To investigate whether variation of hypertension PRS also captures variation of antihypertensive drug responsiveness, we calculated two different PRSs for both systolic and diastolic blood pressure: one based on the top 793 independent hypertension-associated single nucleotide polymorphisms and another based on over 1 million genome-wide variants. Using our pharmacogenomic GENRES study comprising four different antihypertensive monotherapies (n ~ 200 for all drugs), we identified a weak, but (after Bonferroni correction) statistically nonsignificant association of higher genome-wide PRSs with weaker response to a diuretic. In addition, we noticed a correlation between high genome-wide PRS and electrocardiographic left ventricular hypertrophy. Finally, using data of the Finnish arm of the LIFE study (n = 346), we found that PRSs for systolic blood pressure were slightly higher in patients with drug-resistant hypertension than in those with drug-controlled hypertension (p = 0.03, not significant after Bonferroni correction). In conclusion, our results indicate that patients with elevated hypertension PRSs may be predisposed to difficult-to-control hypertension and complications thereof. No general association between a high PRS and less efficient drug responsiveness was noticed.

Relationship of electrocardiographic repolarization measures to echocardiographic left ventricular mass in men with hypertension.

OBJECTIVE: Arterial hypertension often leads to an increase in left ventricular mass (LVM). Marked left ventricular hypertrophy (LVH) is associated with potentially arrhythmogenic ventricular repolarization abnormalities, which may contribute to the increased risk of sudden cardiac death in this disorder. We studied whether electrocardiographic repolarization changes are already detectable in mild LVM increase associated with hypertension. METHODS: In 220 men (mean age 51+/-6 years) attending the GENRES hypertension study, we measured QT intervals (QTend and QTpeak), T-wave peak to T-wave end (TPE) intervals, and novel T-wave morphology parameters (principal component analysis ratio, T-wave morphology dispersion, total cosine R-to-T, and T-wave residuum) from a digital standard 12-lead electrocardiogram, and related them to echocardiographically determined LVM. RESULTS: In this group of moderately hypertensive men, the mean LVM index (LVMI; LVM divided by body surface area) was 99+/-19 g/m2, with only 18% of the subjects showing evidence of echocardiographic LVH (LVMI>116 g/m2). LVMI correlated significantly with QT intervals (r=0.16-0.21, P=0.018-0.002), TPE intervals (r=0.23-0.27, P<0.001), and T-wave morphology parameters (r=0.22-0.39, P<0.001). Except for the QTpeak interval, the relationship between LVMI and electrocardiographic repolarization parameters was independent in multivariate analyses. CONCLUSION: Altered electrocardiographic ventricular repolarization, indicating reduced repolarization reserve and possibly increased repolarization heterogeneity, is already present in hypertensive men with only mild LVM increase. At a population level, this may carry important risk implications for the large group of hypertensive patients.

Predictors of antihypertensive drug responses: initial data from a placebo-controlled, randomized, cross-over study with four antihypertensive drugs (The GENRES Study).

BACKGROUND: Only a minority of hypertensive individuals is adequately controlled for their hypertension, partially because reliable predictors for efficient antihypertensive drug therapy are lacking. METHODS: In a prospective, randomized, double-blind, cross-over, placebo-controlled study (The GENRES Study), 208 moderately hypertensive Finnish men (aged 35 to 60 years) were treated for 4 weeks with antihypertensive drugs from four different classes: amlodipine (5 mg), bisoprolol (5 mg), hydrochlorothiazide (25 mg), or losartan (50 mg) daily. Each individual received each of the four monotherapies in a randomized order. Four-week placebo periods were included before and between drug treatment periods. Antihypertensive responses were assessed with 24-h ambulatory and office measurements and analyzed according to age, body mass index, triceps skin fold thickness, waist-to-hip ratio, duration of hypertension, number of previous antihypertensive drugs, number of affected parents, and blood pressure (BP) levels, and profiles during placebo periods. RESULTS: The median BP responses in 24-h ambulatory recordings (systolic/diastolic) were 11/8 mm Hg for bisoprolol, 9/6 mm Hg for losartan, 7/5 mm Hg for amlodipine, and 5/2 mm Hg for hydrochlorothiazide. The highest pairwise within-subject correlations in BP responses were seen for the combinations of bisoprolol-losartan and amlodipine-hydrochlorothiazide. The BP responses to bisoprolol and losartan did not vary according to the variables. Amlodipine and hydrochlorothiazide responses were positively correlated with age, placebo BP level, and lower night-time dipping on placebo. CONCLUSIONS: Baseline clinical and BP parameters may be used to predict the efficacy of antihypertensive therapies. The GENRES Study material should provide an excellent platform for future pharmacogenetic analyses of antihypertensive drug responsiveness.

Plasma progesterone concentration depends on sampling site in pigs.

The objective of this study was to examine a possible difference in progesterone concentrations between the systemic venous blood and the caudal vena cava in early pregnant gilts. Nineteen crossbred pregnant gilts were offered three different regimens of feeding to examine influence of feeding on the secretion pattern of progesterone. The groups were high (H-H), low (L-L) and low-high (L-H) receiving 3.6, 1.8 and 1.8/3.6 kg/day, respectively. Catheters were placed in a jugular vein and the caudal vena cava (to sample ovarian secretion) on day 19 of pregnancy. Two consecutive samples taken at 30-min intervals were collected four times a day for 5 days (days 20-24). In addition, three gilts were simultaneously sampled from both catheters at 30-min intervals for 12 h on day 22. Progesterone concentration was significantly lower in the jugular vein compared with the caudal vena cava in all three feeding groups (P<0.001). An indication of episodic pattern of progesterone production occurred in plasma collected from the caudal vena cava, but not from the jugular vein. Dietary intake did not cause a profound effect on plasma progesterone concentrations during days 20-24 of gestation. It seemed that ovarian progesterone was released into the vena cava in an episodic pattern and there were implications that these episodes were temporally associated with LH pulses.

Resection and patch repair of a large saccular coronary artery aneurysm at the left main bifurcation.

Coronary artery aneurysm is a rare condition with primarily conservative treatment. Here, we present a case of saccular left main coronary aneurysm with a successful patch repair and discuss the indications for operative treatment.

Short-term electrophysiological effects of losartan, bisoprolol, amlodipine, and hydrochlorothiazide in hypertensive men.

BACKGROUND AND AIM: Hypertension-induced left ventricular structural remodelling associates with repolarization abnormalities. We investigated if antihypertensive drugs can modulate ventricular repolarization. METHODS: A total of 183 hypertensive men received for 4 weeks drugs (losartan 50 mg, bisoprolol 5 mg, amlodipine 5 mg, hydrochlorothiazide (HCTZ) 25 mg) in a randomized order, separated by 4-week placebo periods. Electrocardiograms (ECG) were recorded at the end of placebo and drug periods. Measurements of repolarization duration (QT intervals), repolarization heterogeneity (T-wave peak to T-wave end (TPE) intervals), and T-wave morphology (T-wave principal component analysis (PCA) ratio, T-wave morphology dispersion (TMD), and total cosine R-to-T (TCRT)) during each drug were compared to placebo measurements. RESULTS: Losartan and bisoprolol shortened maximum and mean rate-adjusted QT intervals as well as mean TPE interval, decreased TMD, and increased TCRT. Losartan also shortened precordial maximum TPE interval and decreased PCA ratio. Amlodipine had no repolarization effects, whereas HCTZ prolonged precordial maximum TPE interval and mean TPE interval. CONCLUSION: Losartan and bisoprolol have beneficial short-term ECG repolarization effects. Amlodipine seems to have no repolarization effects. HCTZ seems to prolong the ECG TPE interval, potentially reflecting increased repolarization heterogeneity. These findings show that antihypertensive drugs may relatively rapidly and treatment-specifically modulate ECG markers of ventricular repolarization.