Acute kidney injury after MitraClip implantation in patients with severe mitral regurgitation.

INTRODUCTION: Percutaneous mitral valve repair (PMVR), such as MitraClip, is performed on high-risk patients and involves hemodynamic alternations that may cause acute kidney injury (AKI). We aimed to evaluate the incidence of AKI, predictors for developing AKI and the correlation with mortality after MitraClip. METHODS: We performed a retrospective analysis of collected data from patients who underwent PMVR in two tertiary medical centers in Israel to identify factors associated with AKI. RESULTS: The study population included 163 patients. The median age was 77 years; 60.7% of patients were male. The median eGFR significantly decreased post-procedure from 49 (35-72) to 47.8 (31-65.5) ml/min/1.73 m2 (p < .001). Forty-seven patients (29%) developed AKI. None of the patients who developed AKI required hemodialysis. Predictors of AKI included: baseline eGFR ≤30 ml/min/1.73 m2 , severity of residual MR, TMPG>5 mmHg, diuretic use, and re-do procedures. Among the patients who developed AKI there was an improvement in kidney function during follow-up, and creatinine levels significantly decreased from a peak mean creatinine of 179.5 (143-252) mmol/l to 136 (92-174) mmol/l (p < .001). However, 19% (9 out of 47) of patients experienced partial recovery and their creatinine level, when compared to their baseline, remained elevated. One-year survival showed a trend for increased mortality among patients who developed AKI (86.2% vs. 80.9%, p = .4), and patients who developed AKI that persisted had increased 1-year mortality compared with patients that had recovered their kidney function (86.8% vs. 55.6%, p = .01). CONCLUSION: The incidence of AKI after MitraClip is high. AKI is reversible in most patients; however, the persistence of kidney injury is associated with increased 1-year mortality.

The Prominin-1-Derived Peptide Improves Cardiac Function Following Ischemia.

Myocardial infarction (MI) remains the leading cause of death in the western world. Despite advancements in interventional revascularization technologies, many patients are not candidates for them due to comorbidities or lack of local resources. Non-invasive approaches to accelerate revascularization within ischemic tissues through angiogenesis by providing Vascular Endothelial Growth Factor (VEGF) in protein or gene form has been effective in animal models but not in humans likely due to its short half-life and systemic toxicity. Here, we tested the hypothesis that PR1P, a small VEGF binding peptide that we developed, which stabilizes and upregulates endogenous VEGF, could be used to improve outcome from MI in rodents. To test this hypothesis, we induced MI in mice and rats via left coronary artery ligation and then treated animals with every other day intraperitoneal PR1P or scrambled peptide for 14 days. Hemodynamic monitoring and echocardiography in mice and echocardiography in rats at 14 days showed PR1P significantly improved multiple functional markers of heart function, including stroke volume and cardiac output. Furthermore, molecular biology and histological analyses of tissue samples showed that systemic PR1P targeted, stabilized and upregulated endogenous VEGF within ischemic myocardium. We conclude that PR1P is a potential non-invasive candidate therapeutic for MI.

[RENAL DENERVATION IN REFRACTORY HYPERTENSION].

INTRODUCTION: Resistant hypertension is a commonplace condition among patients referred to specialty hypertension clinics, which is associated with increased morbidity and mortality. Refractory hypertension however is a rare extreme subtype of resistant hypertension in which blood pressure is uncontrolled despite treatment with five antihypertensive drug classes including a diuretic and a mineralocorticoid receptor antagonist, and is associated with even worse prognosis. We herein describe a 40-year-old woman with severe refractory hypertension and target organ damage for who percutaneous renal sympathetic denervation successfully reduced blood pressure to normal levels and alleviated chronic headaches. Renal denervation should be considered in patients with refractory hypertension, especially when sympathetic over-activity is suspected.

Appropriateness of direct oral anticoagulant dosing and its relation to drug levels in atrial fibrillation patients.

Direct oral anticoagulants (DOACs) are commonly administered at a level that is lower than that recommended by dose reduction criteria. This raises concern regarding the adequacy of anticoagulation achieved. To evaluate the relationship between inappropriate dosing and DOAC levels. Medical records of atrial fibrillation patients who underwent DOAC level testing during 2013-2017 were reviewed. The primary outcomes were drug levels under and above the expected steady-state range, and in the lowest and highest quartiles. Of 143 patients who underwent DOAC measurements, only 87 (60.8%) received the appropriate dose. Levels under the expected range and in the lowest quartile were found in 11.9% and 15.0% of patients treated with appropriate dosing compared to 21% and 41.5% of patients treated with inappropriately low dose. DOAC levels were above the expected range and in the highest quartile in 23.8% and 32.5% of patients treated with the appropriate dose compared to 7.1% and 9.4% treated with inappropriately low dose. In multivariate analysis, the administration of an appropriate DOAC dose was associated with a lower rate of DOAC in the lowest level (adjusted odds ratio [95% CI] 0.30 (0.12, 0.76), P = 0.011). On the other hand, appropriate dose was associated with drug levels in the highest quartile (odds ratio [95% CI] 3.77 (0.12, 0.76), P = 0.011). Treatment with inappropriately low DOAC dosing compared to appropriate dose is associated with lower DOAC levels. However, among those treated with appropriate dosing, a higher proportion had high DOAC levels above the expected range.

Degenerative mitral regurgitation predicts worse outcomes in patients undergoing transcatheter aortic valve replacement.

OBJECTIVES: To evaluate the role mitral regurgitation (MR) etiology and severity play in outcomes for patients undergoing transcatheter aortic valve replacement (TAVR). BACKGROUND: Multiple prior studies have investigated the influence of MR severity on outcomes for patients undergoing TAVR. Less has been published regarding the effects of MR etiology on outcomes, including its impact on heart failure hospitalization. METHODS: Two hundred and seventy patients undergoing TAVR at 2 hospitals were enrolled. Each patient had a baseline and follow-up (within 30 days of TAVR) echocardiogram that was analyzed. MR was graded as none, mild, moderate, or severe, as well as functional or degenerative. We compared patient outcomes, including death and heart failure hospitalization, among none-mild MR, moderate-severe functional MR, and moderate-severe degenerative MR groups. RESULTS: Two hundred and seventy patients underwent TAVR, reducing mean aortic valve gradients from 45 ± 15 mm Hg to 9 ± 4 mm Hg. On multivariable analysis, only patients with moderate-severe degenerative MR had decreased survival free of death or CHF hospitalization compared to those with none-mild MR (P = .011). Subanalysis showed patients with moderate-severe degenerative MR were more likely to be hospitalized for heart failure at 2 years compared to those with moderate-severe functional MR (P = .02). Patients with moderate-severe degenerative MR were also less likely to have improvement in MR severity at follow up (P = .01). CONCLUSIONS: Special consideration should be given to patients with moderate-severe degenerative MR undergoing TAVR. As transcatheter approaches for mitral valve repair and replacement continue to evolve, moderate-severe degenerative MR patients may benefit from consideration of double valve intervention.

[LONG TERM FOLLOW-UP OF TRANSCATHETER SELF EXPANDABLE AORTIC VALVE IMPLANTATION].

INTRODUCTION: Aortic stenosis is the most common significant valvular disease in the western world. These patients are treated operatively unless they are at high operative risk or inoperable. During the last decade an alternative approach has evolved - transcatheter aortic valve implantation (TAVI). This method was shown to be at least as effective and safe as the operative one. However, very little data exists on long term follow-up (5 years and above), especially regarding valve durability and patient survival. OBJECTIVES: To present a long term follow-up on patients who underwent transcutaneous self-expandable aortic valve implantation in our department between the years 2008-2011. METHODS: In September 2008 the first CoreValve implantation was performed in Israel at Hadassah Medical Center. All records of patients who were transplanted between 9.2008 and 10.2011 were reviewed. The function of the valve early after the procedure was compared to its function at the end of the follow-up period. RESULTS: A total of 38 patients (out of 71) survived at least 54 months, of them, 19 have an echocardiography examination at the end of the follow-up period. In all patients the implanted valve was found to function well at the end of the follow-up period, without significant stenosis or paravalvular leak. In fact, in approximately half of these patients, the degree of paravalvular leak decreased during the follow-up period. DISCUSSION: On long term (5 years) follow-up of patients who were implanted with the self-expandable aortic valve (CoreValve), no deterioration of the valve was observed. In fact, in approximately half of the patients, a decrease in the severity of the paravalvular leak was demonstrated.

Pericardial covered stent for coronary perforations.

OBJECTIVES: To evaluate initial and long term results of coronary perforation treatment with pericardial covered stent. BACKGROUND: Iatrogenic coronary perforation is a rare life threatening complication of percutaneous coronary interventions (PCI) occurring in 0.1-0.8% of cases. Covered stents are the mainstay of therapy for coronary perforation. However, polytetrafluoroethylene covered stents are bulky with limited flexibility and thus may not be easy to deliver in difficult anatomy. Therefore, they are reserved to perforations in proximal or mid straight segments where their delivery is relatively easy. The pericardial covered stent is a highly deliverable fully covered stent that may be used to treat coronary perforations. Only a single case has been reported of the use of this stent in its previous version for the treatment of coronary perforation. METHODS: The electronic databases of four tertiary medical centers were retrospectively reviewed for cases of coronary perforations in which PCS was used. During a five years period, between 2008 and 2013, 18,364 patients underwent PCI in these centers. Nine cases of perforations for which balloon dilatation was not sufficient and pericardial covered stent was used were recorded. RESULTS: All nine cases were successfully treated with pericardial covered stent. Six of the patients underwent repeated angiography at 2-15 months, and in two of them instent restenosis that warranted repeated angioplasty was observed. One of them was catheterized for NSTEMI 3 months after the covered stent implantation, and stent thrombosis was demonstrated. CONCLUSIONS: Pericardial covered stents offer a safe and effective therapy for coronary perforation when balloon inflation and reversal of anticoagulation are insufficient.

Role of thromboxane receptor in C-reactive protein-induced thrombosis.

OBJECTIVE: Thromboxane A(2) and prostacyclin are thromboregulatory prostaglandins. The inflammatory C-reactive protein (CRP) promotes thrombosis after vascular injury, presumably via potentiation of thromboxane activity. Using a genetic approach, we investigated the role of thromboxane receptor (TP) pathway in CRP-induced thrombosis. METHODS AND RESULTS: Four genetically engineered mice strains were used: C57BL/6 wild-type, human CRP transgenic (CRPtg), thromboxane receptor-deficient (Tp(-/-)), and CRPtgTp(-/-) mice. CRP and TP expression were correlated, and suppression of CRP expression using small interfering RNA/CRP led to reduction in TP expression. Platelet-endothelial adherence was increased in CRPtg and suppressed in CRPtgTP(-/-)and CRPtg cells that were suppressed with TP small interfering RNA. TP deficiency in both platelets and endothelial cells was synergistic in affecting platelet-endothelial interactions. Time until arterial occlusion, measured after photochemical injury, was significantly shorter in CRPtg and prolonged in CRPtgTp(-/-) compared with controls (n=10-15, 35±3.4, 136±13.8, and 67±8.9 minutes, respectively; P<0.05). CONCLUSIONS: TP pathway is of major importance in CRP-induced thrombosis. The expression of TP is increased in CRPtg endothelial cells, and its blockade significantly suppresses the prothrombotic effect of CRP.

Coronary Embolism After Transcatheter Aortic Valve Replacement-Case Series and Review of Literature.

Periprocedural systemic embolism is a well-documented complication of transcatheter aortic valve replacement (TAVR). Although the most focus was given to cerebral embolism (which remains unpredictable, difficult to prevent, and a source of increased morbidity and mortality after TAVR), coronary embolism remains less investigated and potentially overlooked. This study provides a case series of 3 patients diagnosed with coronary embolism after TAVR in our institution over a 2-year period (3 of 297 cases, 1%) and a systematic literature review (4 studies; 19 case reports). Overall, coronary embolism associated with TAVR is frequently characterized by proximal vessel occlusion causing ST-elevation myocardial infarction and hemodynamic instability with lower mortality in the acute phase as compared with late coronary embolism. However, it often presents with distal vessel occlusion and minor symptoms that may be overlooked in the periprocedural period. In conclusion, we suggest that TAVR-associated coronary embolism has a much higher prevalence than previously documented. Further studies are warranted to properly assess the prevalence and impact of this phenomenon.

Thoracic Aorta Perforation Treated Conservatively After TAVR in a Patient With Extremely Tortuous Aorta.

Aortic perforation is a rare complication of transcatheter aortic valve replacement associated with grim outcomes. Tortuous and calcified aortas increase the risk of aortic trauma and perforation. We report a case in which, despite massive thoracic bleeding, avoidance of thoracic aortic surgery resulted in clinical recovery. (Level of Difficulty: Intermediate.).

Endothelial C-reactive protein increases platelet adhesion under flow conditions.

While data regarding the pathogenetic role of C-reactive protein (CRP) in atherothrombosis are accumulating, it is still controversial whether local CRP secretion is of any pathobiological significance. The present study examined whether endothelial-derived CRP modulates autocrine prothrombotic activity. Endothelial cells were isolated from hearts of mice transgenic to human CRP and grown in primary cultures. Human CRP expression was confirmed in these cells compared with no expression in cultures derived from wild-type congenes. Adhesion of human platelets to endothelial cells was studied in the "cone and plate" flow system. Platelet adhesion to cells expressing CRP was significantly increased compared with that in controls (n = 6, P < 0.01). The proadhesive effect of CRP was significantly suppressed in mouse heart endothelial cells and in human umbilical vein endothelial cells following treatment with small interfering RNA for human CRP. Adhesion was modulated by an increase in P-selectin. P-selectin expression correlated with a proadhesive phenotype, and blocking P-selectin with neutralizing antibody significantly decreased the adhesion of platelets to CRP-expressing cells (40.4 ± 10.5 to 9.4 ± 6.9 platelets/high-power field, n = 5 to 6, P < 0.01). In conclusion, human CRP that is locally produced in endothelial cells increases platelet adhesion to endothelial cells under normal shear flow conditions. These findings indicate that CRP exerts a local effect on endothelial cells via P-selectin expression, which promotes platelet adhesion and subsequent thrombus formation.

Incidence and Predictors of Target Lesion Failure in Patients With Lesions in Small Vessels Undergoing PCI With Contemporary Drug-Eluting Stents: Insights From the BIONICS Study.

Treatment of lesions in small coronary vessels is associated with an increased risk of adverse cardiovascular events after percutaneous coronary intervention (PCI).We aimed to evaluate the outcomes of patients undergoing small-vessel PCI in the BIONICS trial and to identify predictors of stent failure. 1910 patients were randomized to treatment with the EluNIR™ ridaforolimus-eluting stent (RES) or Resolute™ zotarolimus-eluting stent (ZES). Small vessels were defined as reference vessel diameters (RVD) ≤2.5 mm. A Cox proportional hazards model was used to identify predictors of target lesion failure (TLF) through 2 years. Patients undergoing small vessel disease PCI had a higher frequency of diabetes, prior myocardial infarction (MI), and prior PCI. 2 year TLF was higher among patients with small vessels (9.7% vs. 5.9%, HR 1.7 [95% CI 1.22-2.37], p < 0.01), driven by increased rates of target vessel-MI and target lesion revascularization (TLR). Stent thrombosis at 2 years was higher among patients with small vessel disease (1.4% vs. 0.3%, HR 5.25 [95% CI 1.47-18.8], p < 0.01). 2 year TLF rates were similar in the RES and ZES patient groups (Pinteraction 0.86). In conclusion, patients undergoing PCI in small vessels have significantly worse outcomes despite the use of contemporary stents.

First-in-Human Transcatheter Tricuspid Valve Repair: 30-Day Follow-Up Experience With the Mistral Device.

OBJECTIVES: This study sought to report short-term results of safety, performance, and efficacy of the Mistral device first-in-human study in patients suffering from severe functional tricuspid insufficiency. BACKGROUND: Patients who suffer from severe tricuspid regurgitation (TR) and who are at high surgical risk have no standard care therapy. Therefore, minimally invasive and safer methods are sought. The Mistral device is an investigational spiral-shaped device intended for percutaneous transcatheter repair. The Mistral device approximates the tricuspid leaflets by grasping together the chordae tendineae of the tricuspid valve. METHODS: Seven patients (4 women; mean age 73.14 ± 7.4 years) with severe (n = 5) and massive (n = 2) symptomatic TR and high surgical risk underwent Mistral tricuspid repair under transesophageal echocardiography guidance. RESULTS: Mistral was successfully implanted in all cases with a single device deployed in 6 patients, with 2 devices deployed in 1 patient. No procedural or 30-day adverse events occurred. TR was reduced by at least 1 grade in all patients. Effective regurgitant orifice area was reduced from median 0.52 cm2 (interquartile range [IQR]: 0.40 to 0.60 cm2) at baseline to 0.15 cm2 (IQR: 0.14 to 0.21 cm2) at 30 days post-procedure (p < 0.01), vena contracta width was reduced from 0.95 cm (IQR: 0.81 to 1.16 cm) to 0.62 cm (IQR: 0.52 to 0.67 cm) (p < 0.05), and regurgitant volume decreased from 49.4 ml/beat (IQR: 45.2 to 57.7 ml/beat) to 19.7 ml/beat (IQR: 12.4 to 23.9 ml/beat) (p < 0.01). Right ventricular fractional area change improved from 27.0% (IQR: 21.3% to 33.5%) at baseline to 38.5% (IQR: 29.0% to 47.1%) at 30-day follow-up (p < 0.05). Significant improvements in New York Heart Association functional class, Kansas City Cardiomyopathy Questionnaire score, and 6-min walk test were observed at 30 days. CONCLUSIONS: Tricuspid valve repair with the Mistral device appears safe and leads to 30-day reduction of tricuspid insufficiency and improvement of right ventricular function and exercise capacity.

Pulmonary artery pressures and outcomes after MitraClip.

AIMS: We evaluated the impact of MitraClip on systolic pulmonary artery pressure (sPAP) and the effects of baseline sPAP on outcomes. METHODS AND RESULTS: In a cohort of patients who underwent MitraClip implantation, three groups were defined according to pre-procedure sPAP levels. Clinical and echocardiographic data were compared. The study included 177 patients: 59 had severe pulmonary hypertension (PHT), 96 had mild to moderate PHT, and 22 had no PHT. In patients with pre-existing severe PHT, sPAP was reduced from 70.8 ± 9.2 to 56.8 ± 13.7 mmHg (P < 0.001), sPAP remained unchanged in patients with mild to moderate PHT but was significantly increased from 30.8 ± 4.3 to 38.6 ± 8.3 mmHg in the no-PHT group (P < 0.001). Improvement of sPAP was observed in 77% of severe PHT group, while worsening of sPAP was more common among patients with no-PHT [57% compared with 33% among the mild to moderate PHT and 7% in the severe PHT group, respectively, (P < 0.001)]. One year survival was similar among the study groups. CONCLUSIONS: MitraClip decreases PHT among patients with severe PHT. A concerning finding is that most patients with no-PHT increase their sPAP.

Stent thrombosis: a poor man's disease?

BACKGROUND: Stent thrombosis is a rare but devastating complication of coronary stent implantation. The incidence and potential predictors were assessed in a "real world" single center. OBJECTIVES: To examine whether socioeconomic status indeed affects the occurrence of stent thrombosis. METHODS: We searched our database for cases of "definite" stent thrombosis (according to the ARC Dublin definitions). Each case was matched by procedure date, age and gender with three cases of stenting that did not result in stent thrombosis. Demographic and clinical parameters were compared and socioeconomic status was determined according to a standardized polling and market survey database. RESULTS: A total of 3401 patients underwent stent implantation in our hospital during the period 2004-2006. Their mean age was 63 +/- 11 years, and 80% were males. Twenty-nine cases (0.85%) of "definite" sub-acute/late stent thrombosis were recorded. Mortality at 30 days was recorded in 1 patient (3.5%). Thrombosis occurred 2 days to 3 years after stent implantation. All patients presented with acute myocardial infarction. Premature clopidogrel discontinuation was reported in 60%. Patients with stent thrombosis had significantly higher rates of AMI at the time of the initial procedure (76 vs. 32%, P < 0.001) and were cigarette smokers (60 vs. 28%, P < 0.001). Drug-eluting stents were used less in the stent thrombosis group. There was no difference in stent diameter or length between the two groups. Socioeconomic status was significantly lower in the stent thrombosis group, 3.4 +/- 2.4 vs. 5.4 +/- 2.6 (mean +/- SD, scale 1-10, P < 0.01). CONCLUSIONS: The incidence rate of stent thrombosis is at least 0.85% in our population. It appears in patients with significantly lower socioeconomic status and with certain clinical predictors. These results warrant stricter follow-up and support the policy of healthcare providers regarding patients at risk for stent thrombosis.

Uraemic hyperparathyroidism causes a reversible inflammatory process of aortic valve calcification in rats.

AIMS: Renal failure is associated with aortic valve calcification (AVC). Our aim was to develop an animal model for exploring the pathophysiology and reversibility of AVC, utilizing rats with diet-induced kidney disease. METHODS AND RESULTS: Sprague-Dawley rats (n = 23) were fed a phosphate-enriched, uraemia-inducing diet for 7 weeks followed by a normal diet for 2 weeks ('diet group'). These rats were compared with normal controls (n = 10) and with uraemic controls fed with phosphate-depleted diet ('low-phosphate group', n = 10). Clinical investigations included serum creatinine, phosphate and parathyroid hormone (PTH) levels, echocardiography, and multislice computed tomography. Pathological examinations of the valves included histological characterization, Von Kossa staining, and antigen and gene expression analyses. Eight diet group rats were further assessed for reversibility of valve calcification following normalization of their kidney function. At 4 weeks, all diet group rats developed renal failure and hyperparathyroidism. At week 9, renal failure resolved with improvement in the hyperparathyroid state. Echocardiography demonstrated valve calcifications only in diet group rats. Tomographic calcium scores were significantly higher in the diet group compared with controls. Von Kossa stain in diet group valves revealed calcium deposits, positive staining for osteopontin, and CD68. Gene expression analyses revealed overexpression of osteoblast genes and nuclear factor kappaB activation. Valve calcification resolved after diet cessation in parallel with normalization of PTH levels. Resolution was associated with down-regulation of inflammation and osteoblastic features. Low-phosphate group rats developed kidney dysfunction similar to that of the diet group but with normal levels of PTH. Calcium scores and histology showed only minimal valve calcification. CONCLUSION: We developed an animal model for AVC. The process is related to disturbed mineral metabolism. It is associated with inflammation and osteoblastic features. Furthermore, the process is reversible upon normalization of the mineral homeostasis. Thus, our model constitutes a convenient platform for studying AVC and potential remedies.

Effects of estradiol and raloxifene on arterial thrombosis in ovariectomized mice.

OBJECTIVE: The effects of estrogen and selective estrogen receptor modulators (eg, raloxifene) on arterial thrombosis are not well defined. This study assessed the manner and mechanism by which estrogen and raloxifene affect homeostatic pathways in ovariectomized mice after acute arterial injury. DESIGN: Female mice (3 weeks old) underwent ovariectomy or sham operation. Five days after surgery, mice were assigned to treatment with estradiol (5.3 nmol/kg), raloxifene (2.7 micromol/kg), or placebo (n = 10-12/group). The biological effects of both treatments were assessed by measurements of bone mass and the degree of uterine atrophy. After 4 months of therapy, carotid artery thrombosis was induced by photochemical injury, and the time to vascular occlusion was measured. RESULTS: Both treatments increased bone mineral density (4.1%-7.85%). Reversal of macroscopic uterine atrophy was observed only in estrogen-treated mice. Ovariectomized mice had a shorter time to occlusion compared with sham-operated mice (70.8 +/- 7.4 vs 103 +/- 11.3 min), suggesting accelerated thrombosis. Both estradiol and raloxifene significantly inhibited intra-arterial thrombosis in ovariectomized mice, prolonging the time to occlusion to 136.33 +/- 13.5 and 141.43 +/- 9.26 min, respectively. Cyclooxygenase-2 levels in the lung tissue were significantly increased by both raloxifene and estradiol with endothelial nitric oxide synthase expression being unaltered. Platelet adhesion (measured by surface coverage under a shear rate of 1,800 s for 2 min) was significantly reduced in ovariectomized animals, being 4.63% +/- 1.47%, 5.78% +/- 1.58%, and 10.04% +/- 1.33% for raloxifene, estradiol, and placebo, respectively. CONCLUSIONS: Ovariectomy amplifies thrombosis. We found that 4 months of treatment with both estradiol and raloxifene attenuates intravascular thrombosis. The antithrombotic effect was accompanied by increased expression of cyclooxygenase-2 and suppression of platelet surface adhesion.

The role of monocyte subpopulations in vascular injury following partial and transient depletion.

The innate immunity system plays a critical role in vascular repair and restenosis development. Liposomes encapsulating bisphosphonates (LipBPs), but not free BPs, suppress neointima formation following vascular injury mediated in part by monocytes. The objective of this study was to elucidate the role of monocyte subpopulations on vascular healing following LipBP treatment. The potency- and dose-dependent treatment effect of clodronate (CLOD) and alendronate (ALN) liposomes on restenosis inhibition, total monocyte depletion, and monocytes subpopulation was studied. Rats subjected to carotid injury were treated by a single IV injection of LipBPs at the time of injury. Low- and high-dose LipALN treatment (3 and 10 mg/kg, respectively) resulted in a dose-dependent effect on restenosis development after 30 days. Both doses of LipALN resulted in a dose-dependent inhibition of restenosis, but only high dose of LipALN depleted monocytes (-60.1 ± 4.4%, 48 h post injury). Although LipCLOD treatment (at an equivalent potency to 3 mg/kg alendronate) significantly reduced monocyte levels (72.1 ± 6%), no restenosis inhibition was observed. The major finding of this study is the correlation found between monocyte subclasses and restenosis inhibition. Non-classical monocyte (NCM) levels were found higher in LipALN-treated rats, but lower in LipCLOD-treated rats, 24 h after injury and treatment. We suggest that the inhibition of circulating monocyte subpopulations is the predominant mechanism by which LipBPs prevent restenosis. The effect of LipBP treatment on the monocyte subpopulation correlates with the dose and potency of LipBPs.