bluuebunny/crossref_metadata_2025_split huggingface dataset:
REDUCTION OF HEART RATE VIA P2X4 RECEPTOR ACTIVATION AS A PROMISING TREATMENT STRATEGY IN PULMONARY ARTERIAL HYPERTENSION
Authors: Ribeiro Cristiana , Neiva Rafael , Silva Diogo , Correia-De-Sá Paulo , Fontes-Sousa Ana Patricia 
Published: June 2022

Objective:
Mounting evidence suggest that the ATP-sensitive ionotropic P2X4 receptor (P2X4R) improves cardiac performance and optimizes myocardial energy demand by reducing chronotropy. Here, we set to investigate whether the digitalis-like effect of the P2X4R in the sinus node was preserved in rats with right heart failure due to pulmonary arterial hypertension (PAH).

Design and method:
Male Wistar rats received a single subcutaneous injection of either monocrotaline (MCT; PAH group) or vehicle (CTRL group). Right heart failure associated to PAH normally occurs in Wistar rats 21 to 25 days after MCT administration. Myographic recordings were performed in spontaneously beating atria (chronotropic effect) isolated from both animal groups.

Results:
Baseline spontaneous atrial rate was 250 ± 5 (n = 26) bpm in CTRL and 237 ± 7 bpm (n = 23) in PAH group (p > 0.05). ATP (0.01–1 mM) concentration-dependently reduced the spontaneous atrial rate of both animal groups. The negative chronotropic effect of ATP (100 M) was smaller in PAH rats (-9 ± 2%; n = 14 vs. -22 ± 4%; n = 25, p < 0.05), but this divergence was attenuated upon increasing the concentration of ATP to 1 mM (CTRL: -54 ± 5%; n = 15 vs. MCT: -50 ± 7%; n = 8; p > 0.05). The P2X4R antagonist, 5-BDBD (10 M), attenuated the negative chronotropic action of ATP (100 M) in CTRL (from -19 ± 5% to -13 ± 3%; n = 5, p > 0.05) and PAH (from -8 ± 3% to 1 ± 8%; n = 4, p > 0.05) rats. The positive allosteric modulator of P2X4R, ivermectin (30 M), potentiated the negative chronotropic effect of ATP (100 M) in CTRL (from -31 ± 5% to -56 ± 14%; n = 5, p > 0.05) and PAH (from -12 ± 6% to -24 ± 9%; n = 4, p < 0.05). The non-selective P2XR agonist, CTP (1 mM), which contrary to ATP does not breakdown into adenosine, also decreased atrial chronotropy in CTRL (-24.31 ± 6.73%; n = 6) and PAH (-11.82 ± 1.98%; n = 6) rats.

Conclusions:
Data suggest that the negative chronotropic effect of P2X4R activation is preserved in atria of rats with heart failure associated to PAH, thus strengthening the hypothesis that heart rate reductions using this ATP-sensitive receptor may increase cardiac performance in patients with PAH-induced heart failure.
CARDIAC PROTECTION THERAPY CAN PREVENT THE ELEVATION OF CENTRAL BLOOD PRESSURE IN ADULT PATIENTS WITH CONGENITAL HEART DISEASE
Authors: Murakami Tomoaki , Horibata Yoko , Tateno Shigeru , Kawasoe Yasutaka , Niwa Koichiro 
Published: June 2022

Objective:
There is no evidence of beneficial effect of cardiac protection (CP) therapy for heart failure, that is medication of renin-angiotensin system antagonists and beta blockers, in patients with congenital heart disease (CHD). However, these drugs have blood pressure (BP) lowering effect and may prevent future hypertension in CHD patients, who are high risk for hypertension. Therefore, we examine the BP lowering effect of CP in adults with CHD.

Design and method:
We enrolled 131 consecutive subjects aged > 20 years who visited the Department of Adult Congenital Heart Disease, Chiba Cardiovascular Center. The exclusion criteria were as follows: (1) a history of atrial fibrillation or frequent supra or ventricular premature beats, (2) history of cardiac operation in the past 6 months, (3) medication for hypertension, and (4) NYHA II-IV. We divided the remaining 60 patients into cardiac protection (+) and (-) and compared their brachial and central systolic BP (SBP). We defined a patient whose brachial SBP was higher than 1SD of age and sex matched control (Japanese general population) as high SBP. Moreover, we defined a patient whose central SBP was higher than 1SD of control as high central SBP.

Results:
Fifteen patients were medicated CP drugs (carvedilol 7, bisoprolol 1, enalapril 11, candesartan 2) (CP+). The mean age was 34.1 ± 13.2 years in CP- and 30.3 ± 11.4 in CP+. The brachial systolic/diastolic BP was 124.4 ± 19.7/74.6 ± 14.0 mmHg in CP- 116.7 ± 12.5/66.2 ± 12.1 mmHg in CP+. There were 14 high SBP patients in CP- and one patient in CP+ (p = 0.0535). The central SBP was 126.8 ± 21.0 mmHg in CP- and 113.2 ± 16.0 mmHg in CP+. There were 16 high central CBP patients in CP- and one patient in CP+ (p = 0.0043).

Conclusions:
The number of high central SBP in patients with CP+ was smaller than CP-. It may be obvious because the drugs used for CP have BP lowering effect. It is well known that hypertension is popular in patients with CHD. CP drugs for heart failure may prevent future cardiovascular disease in patients with CHD.
VALIDATION OF A NONINVASIVE METHOD TO ESTIMATE SUBENDOCARDIAL OXYGEN SUPPLY AND DEMAND BALANCE
Authors: Grillo Andrea , Parati Gianfranco , Salvi Lucia , Scalise Filippo , Tan Isabella , Sorropago Antonio , Sorropago Giovanni , De Censi Lorenzo , Rovina Matteo , Fabris Bruno , Moretti Francesco , Avolio Alberto , Salvi Paolo 
Published: June 2022

Objective:
Evaluation of balance between subendocardial oxygen supply and demand is useful in order to assess the risk of myocardial ischemia. The subendocardial viability ratio (SEVR, also known as Buckberg index) evaluated by invasive recordings of left ventricular and aortic pressure curves represents a valid method to estimate the degree of myocardial perfusion relative to left ventricular workload. However, routine clinical use of this parameter requires a noninvasive estimation and the demonstration of its reliability.

Design and method:
Arterial applanation tonometry allows a noninvasive estimation of SEVR as the ratio of the areas directly beneath the central aortic pressure curves obtained during diastole (myocardial oxygen supply) and during systole (myocardial oxygen demand). However, this traditional method does not account for the intraventricular diastolic pressure and proper allocation to systole and diastole of left ventricular isometric contraction and relaxation, respectively, resulting in an overestimation of the SEVR values. These issues are considered in a novel method for SEVR assessment tested in this study. SEVR values were estimated with carotid tonometry by traditional and new method and compared with those evaluated invasively in 51 undergoing an cardiac catheterization for coronary angiography.

Results:
The traditional method provided significantly higher SEVR values than the reference invasive SEVR: average of differences ± SD = 44 ± 11%. The noninvasive new method showed a much better agreement with the invasive determination of SEVR: average of differences ± SD = 0 ± 8%. The new method for SEVR estimation showed a good repeatability between consecutive assessments (coefficient of variation 7.8%).

Conclusions:
A noninvasive estimation of SEVR by carotid applanation tonometry is feasible. All the main factors determining myocardial supply and demand flow should be considered in order to provide a valid estimate, in particular intraventricular diastolic pressure, left ventricular isometric contraction and relaxation.
LEFT ATRIAL RESERVOIR FUNCTION DECLINES IN HYPERTENSIVE SUBJECTS WITH DYSLIPIDEMIA
Authors: Ezhova Nadezhda , Bazdyreva Elena , Shavarova Elena , Khomova Irina , Kobalava Zhanna 
Published: June 2022

Objective:
Abnormal metabolism of triglycerides and very low density lipoproteins was is involved in structural and electrical atrial remodeling as it was shown in several preclinical studies but data on such relationship with left atrium (LA) function is lacking. As far as we know, the link between LA function and dyslipidemia was never studied in hypertensive patients. We intended to compare LA reservoir function in young hypertensive subjects with or without dyslipidemia.

Design and method:
We included 87 young subjects (median of age 23 [21; 25] years, mean BMI 25,2 ± 4,5 kg/m2, median 24 hours systolic blood pressure (BP) and diastolic BP (134 [128; 145] and 79 [74,0; 87,0] mm Hg, respectively) with HTN diagnosed with 24-hours ambulatory blood pressure monitoring according to ESH guidelines criteria (2018). None of the patients was taking hypolipidemic drugs at the baseline. Patients were divided in groups according to national criteria for dyslipidemia (fasting total cholesterol > 4,9 mmol/L or low density lipoproteins (LDL) > 3,0 mmol/L or high density lipoproteins (HDL) < 1,0 mmol/L in males and < 1,2 mmol/L in females or triglycerides > 1,7 mmol/L) in which we compared left atrial longitudinal strain during reservoir phase (LASr) ratio and left atrial volume index (LAVI).

Results:
58% of patients were diagnosed with dyslipidemia. Left atrial structure and function differed in groups divided according to presence of dyslipidemia: LAVI was higher (24,7 [21,5; 28,3] vs 21,5 [17,9; 26,5] mL/m2, P = 0,045) and LASr was lower (34,9 [30,2; 40,2] vs 40,8 [33,2; 45,5] %, P = 0,017) in patients with dyslipidemia while BP levels were similar. In groups allocated according to isolated criteria for dyslipidemia LASr and LAVI did not differ except patients with or without HDL decrease. Patients with HDL deficiency had lower LASr (33,9 [28,7; 37,8] vs 39,4 [31,8; 43,8] %, P = 0,043) with similar LAVI ranges.

Conclusions:
Left atrial reservoir function is worse in hypertensive patients with dyslipidemia, in particular in those with HDL deficiency.
EFFECTS OF ACUTE NORMOBARIC HYPOXIA-INDUCED PULMONARY HYPERTENSION ON ELECTROCARDIGRAPHIC MEASURES IN POST-MYOCARDIAL INFARCTION PATIENTS
Authors: Kramer Tilmann , Hoenemann Jan , Weis Henning , Jordan Jens , Tank Jens , Rosenkranz Stephan , Baldus Stephan , Limper Ulrich 
Published: June 2022

Objective:
Normobaric hypoxia induces pulmonary hypertension (PH) in healthy individuals and post-myocardial infarction (P-MI) patients. Depending on the size of the myocardial scar and the remaining left ventricular ejection fraction, P-MI patients are potentially more vulnerable to cardiac rhythm disorders than healthy individuals. Albeit of utmost importance for P-MI patients planning high altitude sojourn, data regarding effects of hypoxia on cardiac rhythm remain contradictory.
The objective was to evaluate if normobaric hypoxia-induced PH triggers electrocardiographic changes at rest and under exertion in P-MI patients.

Design and method:
At the German Aerospace Center:envihab facility, 4 non-professional male athletes (57.8 ± 3.3years) in clinically stable condition after left ventricular ST-elevation MI (3 type I and 1 type II MI, all> 1 year since event) and subsequent drug-eluting stent implantation for single-vessel coronary artery disease were exposed to normobaric hypoxia achieved by nitrogen dilution. Starting at 20.9%, oxygen content was gradually decreased to a minimum of 11.5% over a period of 19 days. Within the following 3 days hypoxia was stepwise reduced back to 20.9% oxygen. Standard 12-lead resting electrocardiogram (ECG) and transthoracic echocardiography (TTE) were performed daily. For echocardiographic detection of PH, systolic pulmonary arterial pressure (sPAP) was measured. Exercise ECG was performed under normoxia and under 17.5% oxygen.

Results:
Normobaric hypoxia with a minimum of 11.5% O2 led to elevated sPAP in TTE. Echocardiographic signs of PH were closely linked to significantly increased QTc interval using Bazett’s (from 402 ± 13 to 417 ± 25ms) and Holzmann’s (103 ± 4 to 107 ± 6%) formula compared to normoxia (all p < 0.01). In exercise ECG under hypoxia, an increased number of ventricular and supraventricular extrasystoles could be detected compared to normoxia.

Conclusions:
In clinically stable P-MI patients, exposure to normobaric hypoxia leading to PH significantly prolongs corrected QT interval and potentially triggers cardiac arrhythmias like premature beats under exertion. P-MI patients should undergo echocardiography and exercise electrocardiography in suitable facilities under hypoxic conditions prior to planned high altitude sojourn. Particularly P-MI patients with prolonged QTc interval under normoxia appear susceptible to cardiac arrhythmias due to the additional QTc interval-prolonging effect under hypoxia. Further studies are pending in this context.
DISSOCIATION BETWEEN LEFT ATRIAL AND LEFT VENTRICULAR CHANGES IN HYPERTENSIVE PATIENTS WITH ATRIAL CARDIOMYOPATHY
Authors: Shavarov Andrey , Kobalava Zhanna 
Published: June 2022

Objective:
Arterial hypertension (AH) is most important cardiovascular risk factor, associated with adverse left ventricular (LV) remodeling. In according to concept of atrial cardiomyopathy (ACMP) left atrium (LA) may be a more sensitive to pressure and volume overload than LV. We tried to delineate atrial and ventricular remodeling in hypertensive patients (pts) with and without ACMP.

Design and method:
Conventional and speckle tracking echocardiography was performed on 426 hypertensive patients [mean age 63 yrs, 51% men] with LV ejection fraction > 45%. Global peak LA longitudinal strain (PALS) and strain rate (PALSR) in the reservoir © and contractile © phase were assessed. ACMP was defined as P-wave terminal force in lead V1 > 4000 V × ms and/or LA size > 4,3 sm for women and > 4,7 sm for men.

Results:
Pts with ACMP (n = 214) were significantly younger to compare with non-ACMP pts (n = 212) [60 (51; 69) vs 66 (61; 73) yrs, p < 0,001] and were less likely to have CAD [87 (41%) vs 174 (82%) pts, p < 0,001], type 2 diabetes mellitus [18 (8%) vs 47 (22%) pts, p = 0,001]. Frequency of atrial fibrillation and anamnesis of previous heart failure hospitalization did not differ between comparing groups. Pts with ACMP had significantly higher LA diameter [3,9 (3,6; 4,5) vs 3,8 (3,5; 4,0) sm, p < 0,001], LA volume index [34 (27; 42) vs 28 (22; 34) ml/m2, p < 0,001] and lower PALSr [11,7 (10,4; 14,3) vs 14,7 (11,9; 16,4) %, p = 0,003], PALSc [-12,5 (-14,9; -9,5) vs -13,9 (-15,5; -11,2) %, p = 0,04] as well as PALSRr [1,85 (1,45; 1,95) vs 2,15 (1,78; 2,31) 1/s, p = 0,01] and PALSRc [-1,75 (-2,00; -1,38) vs -1,96 (-2,20; -1,81) 1/s, p = 0,009] than non-ACMP pts. Along with that pts with ACMP had significantly lower LV end-diastolic diameter [4,8 (4,5; 5,2) vs 4,9 (4,5; 5,4) sm, p = 0,006], A [0,60 (0,53; 0,70) vs 0,62 (0,55; 0,77) m/s, p = 0,04], E/É [6,6 (5,3; 9,6) vs 7,2 (6,2; 10,5), p = 0,01] and greater LV ejection fraction [62 (58; 67) vs 58 (51; 62), p < 0,001].

Conclusions:
In hypertensive pts with ACMP more prominent LA changes were accompanied by less obvious LV abnormalities.
THE TRIGLYCERIDE- GLUCOSE INDEX: AN INDEPENDENT FACTOR OF A SUBCLINICAL LEFT VENTRICULAR DYSFUNCTION IN TREATED HYPERTENSIVE PATIENTS
Authors: Ouabdesselam Souhila , Mokhtar Omar Ait , Bendiab Nabila Taleb Soufi , Henaoui Latifa , Benkhedda Salim 
Published: June 2022

Objective:
The triglyceride-glucose (TyG) index is known to be a simple surrogate marker of insulin resistance. The aim of this study was to investigate association between the TyG index and the two- dimensional longitudinal left vetricular global strain in treated hypertensive patients.

Design and method:
A total of 75 treated hypertensive patients were enrolled in this study. Anthropometric and cardiovascular risk factors were measured. The TyG index was calculated as ln[fasting triglycerides (mg/dl) × fasting glucose(mg/dl)/2]. The two- dimensional longitudinal left vetricular global strain where evaluated and express in absolute value. Others echocardiographic parameters where mesured: E/E’, left atrial volume and biological parameters: Total cholesterol, HDL cholesterol, LDL cholesterol and glomerular filtartion. Multivariable linear regression analysis was performed to identify the associations between this parameters.

Results:
Multivariable linear regression analysis showed that a higher TyG index was associated with lower global longitudinal LV strain (p = 0,04), higher body mass index (p = 0,000), higher E/E’ (p = 0,009) and lowest glomerular filtration rate (p = 0,001).

Conclusions:
A high TyG index was significantly associated with a low global longitudinal LV strain. The results suggest that the TyG index, as a simple indicator of insulin resistance, may reflect subclinical cardiac dysfunction.
LONGITUDINAL LEFT VENTRICULAR FUNCTION IN HYPERTENSIVE SUBJECTS WITH NORMAL EJECTION FRACTION: NEW INSIGHT BY SPECKLE TRACKING ECHOCARDIOGRAPHY
Authors: Hajri Samia Ernez , Messaoudi Yosra , Ernez Safia , Bouraoui Hatem , Ben Ameur Zied , Saoudi Wassim , Bouhlel Imene , Ben Abdessalem Aymen , Mahdhaoui Abdallah , Jeridi Gouider 
Published: June 2022

Objective:
The aim of the current case-control study was to use speckle tracking imaging to identify subclinical longitudinal left ventricular systolic function abnormalities in hypertensive subjects with normal ejection fraction (EF).

Design and method:
Standard 2D Doppler echocardiography, tissue Doppler imaging, and 2D speckle strain imaging were performed in 50 hypertensive subjects with normal ejection fraction and 50 control subjects.
Peak systolic (S) and diastolic (E’) annular velocities were obtained by tissue Doppler imaging, whereas longitudinal myocardial strain was obtained by speckle tracking.

Results:
The two groups were comparable by age (56,4 ± 8,87 years in the hypertensives versus
55,7 ± 8,24 years in the controls, p = 0,66) and gender distribution (42% males in hypertensives vs 46% in the controls; p = 0,68). Other baseline characteristics, except for blood pressure parameters, which were predictably higher in the hypertensive subjects, were comparable between the two groups.
Among the hypertensive subjects, 28 had diastolic dysfunction.
27 hypertensives (54%) had normal geometry, 7 (14%) had excentric hypertrophy and 11(22%) had concentric hypertrophy.
LV systolic longitudinal function as assessed by systolic myocardial velocity (S) was not significantly reduced in the hypertensive group compared with controls(8,92 ± 1,46 cm/s vs. 9,15 ± 0,79 cm/s; p = 0,33).
However, global longitudinal strain (GLS) was significantly reduced compared with controls (-20,39 % ± 2,65 vs. -22,52% ± 2,3; p = 0,000). Longitudinal strain appears to be correlated with LV mass index (r = 0,293; p = 0,039), age, E/E’ ratio (R = 0,303 (IC = 0, 95 [0,023–0,506]) p = 0,032), left atrium size and duration of hypertension.
No correlation was found between GLS and systolic or diastolic blood pressure.

Conclusions:
Patients with hypertension and normal EF were demonstrated to have reduced LV systolic longitudinal function. Longitudinal strain is more sensitive than tissue Doppler imaging to assess this dysfunction.There is a significant association between age, obesity, LV mass index, impaired diastolic function and reduced LV longitudinal contractility.
Thus, LV systolic strain is early reduced during systemic hypertension and seems to be an index of global LV remodelage.
EFFECT OF AN ELECTRO-STIMULATOR DEVICE ON THE AVERAGE 24-HOUR BLOOD PRESSURE IN PATIENTS WITH MILD AND MODERATE HYPERTENSION
Authors: Youssef Ghada , Mesalm Muhammad H. , Reda Ghada , Bakhoum Sameh , Ghareeb Haytham Soliman , Ghareeb Soliman , El-Mageed Hazem Abd , Talaat Remon 
Published: June 2022

Objective:
Hypertension is considered the third leading killer over the world. Non-pharmacological therapy to prevent and to manage hypertension gained more popularity worldwide. Low frequency transcutaneous electrical nervous stimulation (TENS) was found to be beneficial in decreasing systolic and diastolic blood pressures. The aim of the study was to assess the effectiveness of TENS-based device in reducing blood pressure in hypertensive patients.

Design and method:
This was a prospective interventional paired study which examined the effect of low frequency TENS device (Inferum-050) on the 24-hour ambulatory blood pressure in a cohort of 50 patients with mild and moderate hypertension (based on the European Society of Cardiology definition). The device looks like a digital watch and in the baseline visit, patients were taught to use. They were told to wear the device on the ventral aspect of the distal left forearm. turn it on and just sit and relax as the device acts automatically. Patients were instructed to use the device for 6 minutes/session, twice daily, for 14 consecutive days at home. Office and Ambulatory blood pressures were evaluated at baseline and after 14 days of device use.

Results:
The mean age of patients was 51.8 ± 15.0 years and almost half were females (n = 26, 52%). Baseline office measurements showed that 28 patients (56%) had moderate hypertension. There were statistically significant reductions of office systolic (147.9 ± 14.4 vs 159.2 ± 8.6mmHg, p < 0.001), office diastolic (88.5 ± 8 vs 96.7 ± 6.6 mmHg, p < 0.001), 24-hours ambulatory systolic (147.7 ± 14.5 vs 158.4 ± 8.2mmHg, p < 0.001) and 24-hours ambulatory diastolic blood pressures (89.1 ± 8.1 vs 95.1 ± 7.1 mmHg, p < 0.001) in follow up as compared to baseline values. Nineteen patients (38%) complained of symptoms, mostly headache and fatigue, at baseline, and most of them (n = 15, 79%) reported improvement of these symptoms at follow up.

Conclusions:
Inferum ABP-050 device could be used as a non-pharmacologic adjuvant therapy to help further reduction of blood pressure in patients with mild and moderate hypertension. Most of the symptomatic patients reported improvement of their symptoms after device use. However, further studies and larger number of patients are needed to validate these results.
THE EFFECT OF RENAL DENERVATION ON PERIPHERAL AND CEREBRAL VASOREACTIVITY IN PATIENTS WITH RESISTANT HYPERTENSION AND TYPE 2 DIABETES MELLITUS
Authors: Falkovskaya Alla , Mordovin V. , Pekarskiy S. , Manukyan M. , Zyubanova I. , Lichikaki V. , Tsoy E. , Vtorushina A. , Khunkhinova S. , Shalishev I. , Triss S. 
Published: June 2022

Objective:
Vasoreactivity is fundamental mechanisms of the control of tissue perfusion, that distributes supply of blood flow according to metabolic needs and protecting the organs from changes in systemic blood pressure (BP). The presence of vascular risk factors such as hypertension (HTN) and diabetes mellitus (DM) impairs vasoreactivity, leading to an increased risk of stroke and myocardial infarction. The aim of this study was to evaluate the effect of renal denervation (RDN) on peripheral and cerebral vasoreactivity in patients with resistant HTN (RHTN) and type 2 DM at 6 month after procedure.

Design and method:
The assessment of the effect of RDN on peripheral vasoreactivity was performed in 31 patients with RHTN and type 2 DM, participants in single-arm prospective interventional studies (protocol numbers NCT02667912 and NCT01499810 at ClinicalTrials.gov) (mean age 59.1 ± 8.6 years, mean office (systolic/diastolic) BP (SBP/DBP) 167.7 ± 18.5/86.7 ± 16.6 mmHg, HbA1c 7.8 ± 1.8%, 22 (68%) men), of which cerebral vasoreactivity was evaluated in 21 patients with good visualization. All patients underwent ambulatory 24-hour BP. Flow-mediated dilation (FMD) of brachial artery and vasoreactivity of middle cerebral artery (MCA) during both breath-holding and hyperventilation testes were measured by high-resolution ultrasound at baseline and 6 month follow-up.

Results:
RDN led to a decrease in mean 24-hour BP (SBP/DBP) (from 157.5 ± 18.2/76.5 ± 9.7 to 147.8 ± 15.6/71 ± 12.8mmHg, p = 0.049/0.096) without significant changes in number of antihypertensive drugs (from 4.7 ± 0.9 to 4.5 ± 1.2, p = 0.52). There were increase in FMD (from 3.4 ± 5.5 to 7.7 ± 4.2%, p = 0.004), but vasoreactivity of MCA to hyperventilation and breath-holding test was not changed. The degree of improvement of FMD not correlated with the baseline BP and its change after RDN.

Conclusions:
According to our results, RDN in diabetic patients with RHTN improved peripheral vasoreactivity regardless of the degree of BP reduction, but did not significantly change cerebral vasoreactivity at 6 month follow up.