PubMed Health⌕ Search

Biomedical subjects

Jozef Bartunek

Publications and source records attributed to Jozef Bartunek.

At least 19 recordsLinked to original sources

Myocardial positive pre-ejection velocity accurately detects presence of viable myocardium, predicts recovery of left ventricular function and bears a prognostic value after surgical revascularization.

AIMS: To assess the accuracy of tissue Doppler imaging-derived myocardial positive pre-ejection velocity (+Vic) in detecting myocardial viability defined by dobutamine stress echocardiography (DSE), fluorine-18 fluorodeoxyglucose positron emission tomography (PET), and contrast-enhanced magnetic resonance imaging (MRI), and in predicting recovery of left ventricular (LV) function after coronary artery bypass grafting (CABG) in patients with chronic ischaemic LV dysfunction. METHODS AND RESULTS: +Vic in dysfunctional segments was recorded in 54 patients treated medically and 65 patients undergoing CABG [age 67 +/- 9 year; LV ejection fraction (EF) 30 +/- 6%]. A good agreement was observed between +Vic and detection of viable myocardium at DSE, PET, and MRI (kappa = 0.76). The presence of +Vic in greater than or equal to five dysfunctional segments had the highest sensitivity (93%) and specificity (60%) to identify patients (n = 28) with > or =10% increase in LV EF between baseline and 6-month echocardiogram. During follow-up (median 333 days, interquartile range 209-490 days), 13 cardiac events (6 deaths, 7 hospitalizations) occurred in 24 patients with small extent of viable myocardium (< 5 + Vic), whereas only four hospitalizations in 39 patients with > or =5 + Vic (54% vs. 10%; P < 0.001). CONCLUSION: The extent of +Vic in dysfunctional segments accurately predicts extent of viable myocardium and bears a clinical prognostic value in patients with ischaemic LV dysfunction considered for CABG.

Aged↗

Bone-marrow-derived cells for cardiac stem cell therapy: safe or still under scrutiny?

Cardiac stem cell therapy with bone-marrow-derived stem cells is a promising approach to facilitate myocardial regeneration after acute myocardial infarction or in congestive heart failure. The clinical data currently available seem to indicate that this approach is safe and is not associated with an increase in the number of adverse clinical events; nevertheless, the level of safety confidence is limited because of the small number of patients who have been treated and the absence of long-term clinical follow-up data. In order to establish the clinical safety of cardiac stem cell therapy, it will be necessary to collect additional data from both previous and ongoing clinical trials in subsets of patients relative to their background risk. Several conceptual safety concerns should also be addressed. These concerns relate to a number of operational mechanisms and include biological effects on differentiation, remote homing of transplanted stem cells, progression of atherosclerosis, and arrhythmias. The proactive scrutiny of these phenomena could eventually facilitate the translation of the promise of cardiac regeneration into a safe and effective therapy.

Bone Marrow Transplantation↗

GLU-27 variant of beta2-adrenergic receptor polymorphisms is an independent risk factor for coronary atherosclerotic disease.

OBJECTIVE: Arg16Gly and Gln27Glu polymorphism of beta(2)-adrenergic receptors (beta 2AR) have been associated with several risk factors for coronary atherosclerotic disease (CAD). Nevertheless, conflicting data have been reported concerning their influence on CAD and cardiovascular clinical events. AIM: To investigate whether (a) beta 2AR polymorphisms are associated with CAD; and (b) the potential impact, if any, of these polymorphisms on cardiovascular clinical events in patients presenting with angina-like pain or silent ischemia. METHODS AND RESULTS: We screened 786 consecutive patients referred to cardiac catheterization because of angina-like pain or silent ischemia for Arg16Gly, Gln27Glu, Thr164Ile beta 2AR polymorphisms. Patients were divided in 2 groups according to the presence or absence of CAD at the angiography. Hundred subjects from blood donor center served as controls. Clinical endpoints were evaluated at baseline and up to 6 years follow-up. Glu-27 homozygous genotype and Glu-27 allele (Glu-27, allele frequency: 47% CAD versus 39% NO CAD, p<0.05) were more frequent in patients with CAD. At multivariate analysis, patients carrying Glu-27 allele showed a significantly higher risk of developing CAD (OR: 1.78, 95% CI: 1.21-2.63, p=0.004). At clinical follow-up, a higher incidence of coronary revascularization was noted in Glu-27 homozygotes as compared with Gln-27 homozygote patients. CONCLUSIONS: In patients at high risk for CAD and/or angina-like pain, Glu-27 allele of beta2 adrenergic receptor polymorphism is an independent risk factor for CAD and appears to be associated with higher incidence of myocardial revascularization.

Aged↗

Pretreatment of adult bone marrow mesenchymal stem cells with cardiomyogenic growth factors and repair of the chronically infarcted myocardium.

The in vivo cardiac differentiation and functional effects of unmodified adult bone marrow mesenchymal stem cells (MSCs) after myocardial infarction (MI) is controversial. We postulated that ex vivo pretreatment of autologous MSCs using cardiomyogenic growth factors will lead to cardiomyogenic specification and will result in superior biological and functional effects on cardiac regeneration of chronically infarcted myocardium. We used a chronic dog MI model generated by ligation of the coronary artery (n = 30). Autologous dog bone marrow MSCs were isolated, culture expanded, and specified into a cardiac lineage by adding growth factors, including basic FGF, IGF-1, and bone morphogenetic protein-2. Dogs underwent cell injection >8 wk after the infarction and were randomized into two groups. Group A dogs (n = 20) received MSCs specified with growth factors (147 +/- 96 x 10(6)), and group B (n = 10) received unmodified MSCs (168 +/- 24 x 10(6)). After the growth factor treatment, MSCs stained positive for the early muscle and cardiac markers desmin, antimyocyte enhancer factor-2, and Nkx2-5. In group A dogs, prespecified MSCs colocalized with troponin I and cardiac myosin. At 12 wk, group A dogs showed a significantly larger increase in regional wall thickening of the infarcted territory (from 22 +/- 8 to 32 +/- 6% in group A; P < 0.05 vs. baseline and group B, and from 19 +/- 7 to 21 +/- 7% in group B, respectively) and a decrease in the wall motion score index (from 1.60 +/- 0.05 to 1.35 +/- 0.03 in group A; P < 0.05 vs. baseline and group B, and from 1.58 +/- 0.07 vs. 1.56 +/- 0.08 in group B, respectively). The biological ex vivo cardiomyogenic specification of adult MSCs before their transplantation is feasible and appears to improve their in vivo cardiac differentiation as well as the functional recovery in a dog model of the chronically infarcted myocardium.

Adult Stem Cells↗

Assessment of renal artery stenosis severity by pressure gradient measurements.

OBJECTIVES: The purpose of this study was to define "significant" renal artery stenosis (i.e., a stenosis able to induce arterial hypertension). BACKGROUND: The degree of renal artery stenosis that justifies an attempt at revascularization is unknown. METHODS: In 15 patients, transstenotic pressure measurements were obtained before and after unilateral stenting. After stenting, graded stenoses were created in the stented segment by progressive inflation of a balloon catheter. Stenosis severity was expressed as the ratio of distal pressure (P(d)) corrected for aortic pressure (P(a)). Balloon inflation pressure was adjusted to create 6 degrees of stenosis (P(d)/P(a) from 1.0 to 0.5, each step during 10 min). Plasma renin concentration was measured at the end of each step in the aorta and in both renal veins. RESULTS: For a P(d)/P(a) ratio >0.90, no significant change in plasma renin concentration was observed. However, when P(d)/P(a) became <0.90, a significant increase in renin was observed in the renal vein of the stenotic kidney, finally reaching a maximal increase of 346 +/- 145% for P(d)/P(a) of 0.50 (p = 0.006). These values returned to baseline when the stenosis was relieved. In addition, plasma renin concentration increased significantly in the vein from the non-stenotic kidney (p = 0.02). CONCLUSIONS: In renal artery stenoses, a P(d)/P(a) ratio of 0.90 can be considered a threshold value below which the stenosis is likely responsible for an up-regulation of renin production and, thus, for renovascular hypertension. These findings might contribute to better patient selection for renal angioplasty.

Aged↗

The consensus of the task force of the European Society of Cardiology concerning the clinical investigation of the use of autologous adult stem cells for repair of the heart.

A task force has been established by the European Society of Cardiology to investigate the role of progenitor/stem cell therapy in the treatment of cardiovascular disease. This article is the consensus of this group, of what clinical studies are needed in this field, and the challenges to be addressed in the translation of progenitor/stem cell biology to repair of the heart.

Adult Stem Cells↗

Cardiac resynchronization therapy delays heart transplantation in patients with end-stage heart failure and mechanical dyssynchrony.

BACKGROUND: Cardiac dyssynchrony is frequent in advanced heart failure, and cardiac resynchronization therapy (CRT) may offer an alternative to heart transplantation. We aimed to investigate the impact of CRT on freedom from Tx and death in transplant candidates with end-stage heart failure. METHODS: Over a period of 2 years, 46 consecutive patients with refractory congestive heart failure due to dilated cardiomyopathy were referred for heart transplant evaluation. Patients with cardiac dyssynchrony > 107 milliseconds according to tissue Doppler imaging (TDI) or QRS duration > 150 milliseconds were treated with CRT (CRT group, n = 24), whereas patients without dyssynchrony were not treated (non-CRT group, n = 22). RESULTS: At baseline, both groups showed similar hemodynamic and functional parameters, including ejection fraction (19 +/- 10% vs 21 +/- 12%, not statistically significant [NS]) and Vo2max (11.9 +/- 2.0 vs 12.0 +/- 1.8 ml/kg/min, NS). After a follow-up of 488 +/- 346 days, cumulative survival with freedom from transplantation and death was higher in CRT vs non-CRT patients (92% vs 39%; p < 0.001). CRT patients showed a decrease in New York Heart Association (NYHA) class from 3.2 +/- 1.1 to 2.2 +/- 0.9 (p = 0.003) and an increase in Vo2max from 11.9 +/- 2.0 to 13.1 +/- 1.8 ml/kg/min (p = 0.02), and 71% (17 of 24) of these patients were successfully removed from the waiting list. CONCLUSIONS: In heart transplant candidates with significant dyssynchrony, CRT delays heart transplantation and improves NYHA class and exercise capacity. For these patients, CRT should be considered before heart transplantation.

Aged↗

Assessment of renal flow and flow reserve in humans.

OBJECTIVES: The purpose of this work was to establish the normal range of maximal renal hyperemic response in humans and to identify the ideal renal vasodilatory stimuli. BACKGROUND: Stenotic renovascular atherosclerosis is increasingly treated by percutaneous transluminal renal intervention but with an unpredictable outcome. This may be due to hemodynamically non-significant stenosis or the presence of irreversible damage to the glomerular circulation. We propose that the renovascular hyperemic response may help identify appropriate patients. METHODS: In 28 normotensive patients, quantitative angiographic measurements of the renal artery were obtained, and renal artery pressure and flow velocity were continuously recorded after various hyperemic agents. RESULTS: In a first group of 11 patients, a significant increase in renal artery average peak velocity (APV) was observed after intrarenal (IR) bolus injection of 600 microg isosorbide dinitrate (41 +/- 19%), 30 mg papaverine (50 +/- 34%), 50 microg dopamine (94 +/- 54%), 0.8 microg x kg(-1) fenoldopam (80 +/- 25%), and during IR infusion of 1 microg x kg(-1) x min(-1) fenoldopam (86 +/- 28%). A second group of 17 patients received intravenous infusion of dopamine (3, 5, 10, 20, 30, and 40 microg x kg(-1) x min(-1)). The 3 and 5 microg x kg(-1) x min(-1) of dopamine modestly reduced renal resistance index (RI) (-13 +/- 15% and -25 +/- 20%, respectively). At higher dosages, no further decline in RI was observed. No significant change in vessel diameter was observed before and after the administration of the pharmacological stimuli suggesting that changes in APV corresponded with changes in absolute renal blood flow. CONCLUSIONS: The normal renal flow reserve averages approximately 2 in humans with normal renal function. An IR bolus injection of 50 microg x kg(-1) of dopamine is the most convenient means to elicit maximal renal hyperemia.

Adult↗

Prospective evaluation of the oxygen uptake efficiency slope as a submaximal predictor of peak oxygen uptake in aged patients with ischemic heart disease.

BACKGROUND: The purpose of this study was to evaluate the oxygen uptake efficiency slope (OUES) as a predictor of peak oxygen consumption (VO2) in aged patients with coronary artery disease (CAD) and to compare its predictive value to that of ventilatory anaerobic threshold (VAT). METHODS: A total of 160 aged (>60 years) patients with stable CAD performed a maximal cardiopulmonary exercise test. The equations were computed by using data of 85 randomly selected patients and were validated in the remaining 75 patients. Bland-Altman (BA) analysis was used to assess the agreement between measured and predicted peak VO2. RESULTS: In the first 85 patients, peak VO2 correlated best with VAT and OUES per kilogram (P < .001). The linear regression to predict peak VO2 for OUES per kilogram was peak VO2 = 4.591 + 0.64 x OUES/kg (SEE = 2.61 mL kg(-1) min(-1)). The BA 95% limits of agreement were -29% and +30% of the predicted value. For VAT, the linear regression to predict peak VO2 was peak VO2 = 2.995 + 1.251 x VAT (SEE = 2.26 mL kg(-1) min(-1)). The BA 95% limits of agreement were -23% and +33% of the predicted value. Cross-tabulation analysis in 3 subgroups with different exercise capacities showed significant relationship between predicted and measured peak VO2 (all P < .001). OUES per kilogram showed the best measure of agreement with measured peak VO2, resulting in high sensitivity and specificity scores. CONCLUSION: OUES is not able to acceptably predict peak VO2 in aged patients with CAD but is at least as performant as VAT in categorizing patients into subgroups with different exercise capacities. Therefore, the objectively measurable OUES is the preferred submaximal predictor of functional capacity in the assessment of aged patients with CAD.

Acridines↗

Timing of intracoronary bone-marrow-derived stem cell transplantation after ST-elevation myocardial infarction.

It is still unclear whether the timing of intracoronary stem cell therapy affects the therapeutic response in patients with reperfused myocardial infarction. The natural course of healing the infarction and the presence of putative homing signals within the damaged myocardium appear to favor cell engraftment during the transendothelial passage in the early days after reperfusion. However, the adverse inflammatory environment, with its high oxidative stress, might be deleterious if cells are administered too early after reperfusion. In addition, current studies use mostly unfractionated cells and it remains to be addressed whether specific cell types, and their enrichment, would be better suited to augmenting the recovery at later time points. Here we highlight several aspects of the timing of intracoronary stem cell therapy and focus on time-related questions that are relevant to the design of future experimental and basic studies.

Animals↗

Hyperdynamic myocardial response to beta-adrenergic stimulation in patients with chest pain and normal coronary arteries.

OBJECTIVES: The goal of this study was to test the hypothesis that an abnormal response to beta-adrenergic stimulation may play a role in the pathophysiology of chest pain in patients with normal coronary arteries. BACKGROUND: The mechanism of angina-like (AL) chest pain in patients with angiographically normal coronary arteries remains controversial. METHODS: Fifty-eight patients with AL pain and a normal coronary angiogram underwent dobutamine echocardiography (DE) to evaluate regional wall motion and intraventricular flow velocities (IFV). Control patients consisted of 22 matched patients free of angina and coronary artery disease. Abnormal IFV were defined as dagger-shaped Doppler spectrum > or =3 m/s. RESULTS: Dobutamine-induced regional wall motion abnormalities did not develop in any of the patients. An IFV > or = 3 m/s was found in 28 patients (48%) with AL pain but in only 4 (18%) control patients (p < 0.05). In the subgroup of patients with AL pain and IFV > or =3 m/s, plasma renin concentration (PRC) was higher as compared with those with IFV <3 m/s (18 +/- 17 pg/ml vs. 9 +/- 6 pg/ml, p < 0.05). There were no differences in plasma ADR, NADR, or angiotensin-converting enzyme levels. Fourteen patients with angina and IFV > or =3 underwent control DE and blood sampling after 6 weeks treatment with 10 mg of bisoprolol. In these patients, a decrease in IFV (from 3.4 +/- 0.35 m/s to 2.46 +/- 0.64 m/s, p < 0.001) and a decrease in angina score (from 5.4 +/- 1.5 to 0.6 +/- 1.4, p < 0.001) were observed at follow-up. CONCLUSIONS: The present data suggest that an exaggerated myocardial response to beta-adrenergic stimulation plays a role in the mechanisms of chest pain in some patients with normal coronary arteries.

Adrenergic beta-Agonists↗

Frequency of abdominal aortic aneurysm in patients >60 years of age with coronary artery disease.

Using B-mode ultrasound, we studied the prevalence of abdominal aortic aneurysm (AAA; diameter > or =3 cm) and its predictive risk factors in 109 consecutive patients who were >60 years of age and had coronary artery disease (CAD). A group of 60 age-matched patients who did not have CAD served as controls. The prevalence of AAA was higher in the CAD group than in the control group (14%, 16 of 109, vs 3%, 2 of 60, p <0.05). By multivariate analysis, only smoking was strongly associated with AAA (odds ratio 4.86, 95% confidence interval 1.55 to 15.25). In contrast, presence of diabetes mellitus was negatively associated with AAA in univariate analysis (odds ratio 0.11, 95% confidence interval 0.01 to 0.83) and a strong trend of inverse association remained in multivariate analysis (odds ratio 0.12, 95% confidence interval 0.01 to 1.03). Thus, systematic screening can detect AAA in 1 of 7 patients who are >60 years of age and have CAD. AAA shares some, but not all, risk factors of atherosclerosis.

Age Factors↗

Intracoronary injection of CD133-positive enriched bone marrow progenitor cells promotes cardiac recovery after recent myocardial infarction: feasibility and safety.

BACKGROUND: Bone marrow CD133-positive (CD133+) cells possess high hematopoietic and angiogenic capacity. We tested the feasibility, safety, and functional effects of the use of enriched CD133+ progenitor cells after intracoronary administration in patients with recent myocardial infarction. METHODS AND RESULTS: Among 35 patients with acute myocardial infarction treated with stenting, 19 underwent intracoronary administration of CD133+ progenitor cells (12.6+/-2.2 x 10(6) cells) 11.6+/-1.4 days later (group 1) and 16 did not (group 2). At 4 months, left ventricular ejection fraction increased significantly in group 1 (from 45.0+/-2.6% to 52.1+/-3.5%, P<0.05), but only tended to increase in case-matched group 2 patients (from 44.3+/-3.1% to 48.6+/-3.6%, P=NS). Likewise, left ventricular regional chordae shortening increased in group 1 (from 11.5+/-1.0% to 16.1+/-1.3%, P<0.05) but remained unchanged in group 2 patients (from 11.1+/-1.1% to 12.7+/-1.3%, P=NS). This was paralleled by reduction in the perfusion defect in group 1 (from 28.0+/-4.1% to 22.5+/-4.1%, P<0.05) and no change in group 2 (from 25.0+/-3.0% to 22.6+/-4.1%, P=NS). In group 1, two patients developed in-stent reocclusion, 7 developed in-stent restenosis, and 2 developed significant de novo lesion of the infarct-related artery. In group 2, four patients showed in-stent restenosis. In group 1 patients without reocclusion, glucose uptake shown by positron emission tomography with 18fluorodeoxyglucose in the infarct-related territory increased from 51.2+/-2.6% to 57.5+/-3.5% (P<0.05). No stem cell-related arrhythmias were noted, either clinically or during programmed stimulation studies at 4 months. CONCLUSIONS: In patients with recent myocardial infarction, intracoronary administration of enriched CD133+ cells is feasible but was associated with increased incidence of coronary events. Nevertheless, it seems to be associated with improved left ventricular performance paralleled with increased myocardial perfusion and viability.

AC133 Antigen↗

Hybrid revascularization strategy: a pilot study on the association of robotically enhanced minimally invasive direct coronary artery bypass surgery and fractional-flow-reserve-guided percutaneous coronary intervention.

BACKGROUND: Robotically enhanced minimally invasive direct coronary artery bypass (RE-MIDCAB) graft of the left internal mammary artery to the left anterior descending coronary artery (LAD) and/or the first diagonal branch might be the least traumatic surgical revascularization approach available so far. When combined with fractional flow reserve (FFR)-guided percutaneous coronary intervention (PCI) in the non-LAD vessels, this "hybrid" strategy takes advantage of the survival benefit conferred by the internal mammary artery graft to the LAD while providing the patients with a truly minimally invasive, functionally complete revascularization. METHODS AND RESULTS: Twenty patients with multivessel disease were selected to undergo combined PCI and RE-MIDCAB because they had a lesion amenable to PCI in the right and/or the left circumflex coronary artery and a lesion in the LAD and/or the first diagonal branch that was considered less than ideal for PCI. PCI was actually performed only when FFR was <0.80 ("provisional PCI"). In 7 stenoses, FFR was >0.80 and the planned PCI was not performed. Surgery was performed before provisional PCI in 6 cases. An angiogram was obtained in all patients before discharge, and a complete clinical follow-up including a stress test was obtained in all patients after a mean of 12 months. There were no significant intraoperative complications, conversions to cardiopulmonary bypass, or reinterventions for bleeding. At early control angiogram, 2 moderate stenoses just proximal to anastomosis were observed, both with normal run-off. After 12 months there were no objective signs of ischemia at stress testing. After an average follow-up of 19+/-10 months there were no deaths, myocardial infarctions, or repeat revascularizations. CONCLUSIONS: A hybrid strategy combining FFR-guided PCI and RE-MIDCAB seems safe and provides selected patients with a functionally complete revascularization with minimal surgical trauma and excellent clinical outcomes.

Aged↗

Long-term clinical outcome after fractional flow reserve-guided percutaneous coronary intervention in patients with multivessel disease.

OBJECTIVES: In the present study, we analyzed the clinical outcome of patients with multivessel coronary artery disease in whom at least one vessel was treated by percutaneous coronary intervention (PCI) and at least one other vessel was deferred on the basis of fractional flow reserve (FFR) measurements during the same session. BACKGROUND: Myocardial FFR is an established tool for assessing the severity of epicardial stenoses. It has been shown that it is safe to defer an intervention in single vessel disease patients when FFR >0.75. METHODS: One hundred two patients (66 +/- 10 years) with multivessel coronary artery disease were included in the study. In all patients, PCI of at least two vessels was contemplated. Yet in all of them at least one vessel was treated by PCI, whereas at least one other vessel was deferred based on an FFR >0.75. Major adverse cardiac events (MACE) were recorded during an average follow-up of 29 +/- 18 months. RESULTS: In 102 patients, 113 coronary arteries underwent PCI. In these arteries FFR was 0.57 +/- 0.13 and mean diameter stenosis was 68 +/- 14%. One hundred twenty-seven coronary arteries had an FFR >0.75 and PCI was deferred. In these arteries FFR was 0.86 +/- 0.06 and mean diameter stenosis was 47 +/- 12%. No death occurred during the follow-up. A MACE occurred in 9% and 13% of patients after 12 and 36 months, respectively. These MACE were related to 22 (9.2%) arteries. Among them, 8 (6.3%) MACE were related to one of the initially deferred vessels, whereas 14 (12.3%) MACE were related to one of the initially treated coronary artery. CONCLUSIONS: In patients with multivessel disease, PCI of hemodynamically non-significant stenoses can be safely deferred, even if initially planned on the basis of the angiogram.

Aged↗

Pressure-derived measurement of coronary flow reserve.

OBJECTIVES: We aimed to validate the technique of measuring the coronary flow reserve (CFR) with coronary pressure measurements against an established thermodilution technique. BACKGROUND: The CFR has traditionally required measurement of coronary blood flow velocity with the Doppler wire and, more recently, using a thermodilution technique with the coronary pressure wire. However, recent work has suggested that the CFR may be derived from pressure measurements alone (the ratio of the square root of the pressure drop across an epicardial stenosis during hyperemia to that value at rest). This depends on the assumption that friction losses across a coronary stenosis are negligible. METHODS: We compared pressure-derived CFR values with those obtained by the thermodilution technique using the intracoronary pressure wire in 38 stenoses in 34 patients with significant coronary stenoses undergoing percutaneous intervention. We also compared these two techniques of measuring CFR in 25 stenoses (6 vessels) artificially created by inflating small balloons within a stented coronary artery after percutaneous intervention. RESULTS: There is a close linear relationship between pressure-derived and thermodilution CFR in native (r(2) = 0.52; p < 0.001) and artificial stenoses (r(2) = 0.54; p < 0.05), although the pressure-derived technique appears to systematically underestimate CFR values in both situations. This applies to native and artificial stenoses. CONCLUSIONS: Coronary flow reserve cannot be measured merely with pressure alone, and it cannot be safely assumed that friction losses are negligible across a native coronary stenosis. These data suggest that friction loss is an important determinant of the pressure gradient along an atherosclerotic coronary artery.

Aged↗