Rare loss-of-function mutations of PTGIR are enriched in fibromuscular dysplasia.

AIMS: Fibromuscular dysplasia (FMD) and spontaneous coronary artery dissection (SCAD) are related, non-atherosclerotic arterial diseases mainly affecting middle-aged women. Little is known about their physiopathological mechanisms. We aimed to identify rare genetic causes to elucidate molecular mechanisms implicated in FMD and SCAD. METHODS AND RESULTS: We analysed 29 exomes that included familial and sporadic FMD. We identified one rare loss-of-function variant (LoF) (frequencygnomAD = 0.000075) shared by two FMD sisters in the prostaglandin I2 receptor gene (PTGIR), a key player in vascular remodelling. Follow-up was conducted by targeted or Sanger sequencing (1071 FMD and 363 SCAD patients) or lookups in exome (264 FMD) or genome sequences (480 SCAD), all independent and unrelated. It revealed four additional LoF allele carriers, in addition to several rare missense variants, among FMD patients, and two LoF allele carriers among SCAD patients, including one carrying a rare splicing mutation (c.768 + 1C>G). We used burden test to test for enrichment in patients compared to gnomAD controls, which detected a putative enrichment in FMD (PTRAPD = 8 × 10-4), but not a significant enrichment (PTRAPD = 0.12) in SCAD. The biological effects of variants on human prostaclycin receptor (hIP) signalling and protein expression were characterized using transient overexpression in human cells. We confirmed the LoFs (Q163X and P17RfsX6) and one missense (L67P), identified in one FMD and one SCAD patient, to severely impair hIP function in vitro. CONCLUSIONS: Our study shows that rare genetic mutations in PTGIR are enriched among FMD patients and found in SCAD patients, suggesting a role for prostacyclin signalling in non-atherosclerotic stenosis and dissection.

Sarcoidosis presenting as severe renin-dependent hypertension due to kidney vascular injury.

Renal sarcoidosis embraces a wide variety of clinical patterns. Renal vascular involvement has seldom been reported and usually in the setting of systemic vasculitis. We report the case of a 22-year-old patient in whom inaugural manifestation of renal sarcoidosis consisted of severe hypertension associated with bilateral perfusion defects and tumour-like nodules. In the setting of renal sarcoidosis, our case suggests that renin-dependant hypertension may arise from renal ischaemia as a result of extrinsic compression of kidney blood vessels due to severe granulomatous inflammation.

Acute catecholamine cardiomyopathy in patients with phaeochromocytoma or functional paraganglioma.

OBJECTIVE: Phaeochromocytomas and paragangliomas (PPGL) can cause acute catecholamine cardiomyopathy (ACC). We assessed the prevalence of ACC and compared the presentation of cases with and without ACC in a large series of PPGL. DESIGN: Single centre retrospective study. SETTING: Hypertension Unit, University Hospital, Paris. PATIENTS: 140 consecutive patients with PPGL, referred from January 2003 to September 2012. MAIN OUTCOME MEASURES: Left ventricular ejection fraction (LVEF), perioperative mortality. RESULTS: Fifteen patients (11%) had suffered an ACC, occurring in 14 cases before the diagnosis of PPGL. Precipitating factors were identified in 11 cases. Twelve patients presented with acute pulmonary oedema, including 10 with cardiogenic shock, requiring life support in eight cases. Seven patients (five with pulmonary oedema) presented with acute chest pain and cardiac dysfunction. Electrocardiographic abnormalities were present in 14 cases: ST segment elevation or pathological Q waves, ST segment depression, and/or diffuse T wave inversion. Six patients displayed classical (apical ballooning) or inverted (basal/mid ventricular stunning) takotsubo-like cardiomyopathy. Coronary arteries were always normal on angiography. In patients with ACC, median LVEF rose from 30% (IQR 23-33%) during ACC to 71% (50-72%) before surgery (n=11, p<0.001). Median LVEF before PPGL surgery was 65% (51-72%) and 65% (60-70%) in patients with and without a history of ACC, respectively (not significant). CONCLUSIONS: PPGL may present as ACC in 11% of cases, excluding patients dying from undiagnosed tumours. Left ventricular dysfunction is usually reversible before surgery. PPGL should be suspected in patients with acute heart failure without evidence of valvular or coronary artery disease.

Outcomes in cardiac surgery in 500 consecutive Jehovah's Witness patients: 21 year experience.

BACKGROUND: Refusal of heterogenic blood products can be for religious reasons as in Jehovah's Witnesses or otherwise or as requested by an increasing number of patients. Furthermore blood reserves are under continuous demand with increasing costs. Therefore, transfusion avoidance strategies are desirable. We describe a historic comparison and current results of blood saving protocols in Jehovah's Witnesses patients. METHODS: Data on 250 Jehovah's Witness patients operated upon between 1991 and 2003 (group A) were reviewed and compared with a second population of 250 patients treated from 2003 to 2012 (group B). RESULTS: In group A, mean age was 51 years of age compared to 68 years in group B. An iterative procedure was performed in 13% of patients in group B. Thirty days mortality was 3% in group A and 1% in group B despite greater operative risk factors, with more redo, and lower ejection fraction in group B. Several factors contributed to the low morbidity-mortality in group B, namely: preoperative erythropoietin to attain a minimal hemoglobin value of 14 g/dl, warm blood cardioplegia, the implementation of the Cornell University protocol and fast track extubation. CONCLUSIONS: Cardiac surgery without transfusion in high-risk patients such as Jehovah Witnesses can be carried out with results equivalent to those of low risk patients. Recent advances in surgical techniques and blood conservation protocols are main contributing factors.

Salvage therapy with bevacizumab-sunitinib combination after failure of sunitinib alone for metastatic renal cell carcinoma: a case series.

We present a case series of seven patients with metastatic renal cell carcinoma treated with bevacizumab (10 mg/kg) in combination with sunitinib 25-50 mg as salvage therapy after disease progression under sunitinib monotherapy. Two patients had a partial response, four had stable disease, and one patient had disease progression. After a median follow-up of 17.2 mo, median progression-free survival and overall survival were 8.5 and 15.1 mo, respectively. Two patients experienced exacerbation of their preexisting hypertension; there were no grade 4 toxicities. The bevacizumab-sunitinib combination in sunitinib-refractory patients seems active and has a tolerable toxicity profile.

Blood pressure and renal outcomes in patients with kidney infarction and hypertension.

OBJECTIVE: To assess the causes and frequency of kidney infarction associated with hypertension, and the blood pressure and renal function outcomes. METHODS: We analyzed the records of patients with kidney infarction documented by angiography and referred to a hypertension unit. RESULTS: Spontaneous kidney infarction was documented in 55 of 18,287 patients and was associated with renal artery disease in 41 cases. Twenty-five patients had a longstanding history of hypertension at referral, and 30 patients presented with acute hypertension. Patients with acute hypertension were more likely to report a history of lumbar pain and to develop malignant hypertension than patients with longstanding hypertension; they also had higher plasma renin concentrations. Data for long-term follow-up after referral were available for 36 patients, including 15 patients who underwent surgery or renal artery angioplasty. From referral to most recent follow-up, the blood pressure decreased from 176/111 to 143/89 mmHg in patients with longstanding hypertension, and from 183/111 to 127/80 mmHg in those with acute hypertension (P = 0.007/0.041 for between-group differences). Three patients with acute hypertension had normal blood pressure without treatment at follow-up. Patients with long-term follow-up displayed no change in the glomerular filtration rate. CONCLUSION: Kidney infarction is a rare cause of hypertension, usually associated with renal artery lesions. In cases of kidney infarction with acute hypertension, the blood pressure outcome is favorable following intervention and/or medication, and hypertension may resolve spontaneously.

Blunt renal trauma-induced hypertension: prevalence, presentation, and outcome.

BACKGROUND: Blunt renal trauma (RT) may cause hypertension. We assessed the frequency and mechanisms of RT, and blood pressure (BP) outcome after treatment. METHODS: We searched the records of all patients referred to our hypertension unit and included those of previously normotensive patients who developed hypertension within 6 months of RT. RESULTS: Ten of the 17,410 referred patients, with a median age of 26 years, developed hypertension 0 to 3 months after a well-documented RT. Median BP at referral was 170/107 mm Hg. Median glomerular filtration rate was 89 mL/min. Five patients had hematuria. Median kidney length was 107 mm on the damaged side and 114 mm on the opposite side. Renal artery lesions were present in six cases. A pattern of unilateral renin hypersecretion and contralateral suppression was present in five of eight cases with unilateral RT. Six patients underwent surgery. Seven months after referral, median BP was 128/79 mm Hg. The BP was <140/90 mm Hg without medication in one patient who did not undergo surgery and in three patients who did. CONCLUSIONS: Renal trauma is a rare cause of hypertension, mostly in young men. Hypertension is usually renin dependent and associated with parenchymal injury. The RT-induced hypertension may resolve spontaneously and is amenable to surgery.