Iacopo Bertolozzi

Weather-Related Changes in 24-Hour Blood Pressure Profile. Effects of Age and Implications for Hypertension Management

A downward titration of antihypertensive drug regimens in summertime is often performed on the basis of seasonal variations of clinic blood pressure (BP). However, little is known about the actual interaction between outdoor air temperature and the effects of antihypertensive treatment on ambulatory BP. The combined effects of aging, treatment, and daily mean temperature on clinic and ambulatory BP were investigated in 6404 subjects referred to our units between October 1999 and December 2003. Office and mean 24-hour systolic BP, as well as morning pressure surge, were significantly lower in hot (>90th percentiles of air temperature; 136±19, 130±14, and 33.3±16.1 mm Hg; P<0.05 for all), and higher in cold (<10th percentiles) days (141±12, 133±11, and 37.3±9.5 mm Hg; at least P<0.05 for all) when compared with intermediate days (138±18, 132±14, and 35.3±15.4 mm Hg). At regression analysis, 24-hour and daytime systolic pressure were inversely related to temperature (P<0.01 for all). Conversely, nighttime systolic pressure was positively related to temperature (P<0.02), with hot days being associated with higher nighttime pressure. Air temperature was identified as an independent predictor of nighttime systolic pressure increase in the group of elderly treated hypertensive subjects only. No significant relationship was found between air temperature and heart rate. Our results show for the first time that hot weather is associated with an increase in systolic pressure at night in treated elderly hypertensive subjects. This may be because of a nocturnal BP escape from the effects of a lighter summertime drug regimen and may have important implications for seasonal modulation of antihypertensive treatment.

Selective Upregulation of Cardiac Endothelin System in Patients With Ischemic but Not Idiopathic Dilated Cardiomyopathy: Endothelin-1 System in the Human Failing Heart

Only scarce information is available on the activity and modifications of the cardiac endothelin (ET)-1 system in heart failure due to ischemic (ICM) or idiopathic dilated (DCM) cardiomyopathy. The activity of the ET-1 system was investigated by measuring cardiac ET-1 and big ET-1 formation and quantifying cardiac mRNA for prepro-ET-1 (ppET-1), ET-converting enzyme-1, and ET(A) and ET(B) receptors both in myocardium and in isolated myocytes using Northern blot, reverse transcription-polymerase chain reaction, and in situ hybridization in 22 patients with DCM and 20 with ICM who underwent cardiac transplantation and in 7 potential heart transplant donors (nonfailing hearts). Notwithstanding a similar increase of plasma ET-1 in the 2 groups, cardiac ET formation, mRNA levels for ppET-1, and ET(A) and ET(B) receptors were higher on both the myocardium and isolated myocytes from ICM than on those from DCM hearts (P<0.001 for all). ppET-1 and ET-converting enzyme-1 mRNAs were expressed on myocytes and endothelial and interstitial cells in ICM, whereas in DCM and nonfailing hearts they were mainly expressed on nonmyocyte cells. In both ICM and DCM, the ET(A) mRNA signal was expressed on both myocytes and nonmyocyte cells, whereas ET(B) mRNA was almost exclusively localized on nonmyocyte cells. ET(A)- and ET(B)-specific receptor binding was increased on both myocytes and cardiac membranes, showing a positive correlation with left ventricular ejection fraction in ICM (r=0.78 and 0.70) but not in DCM patients. The present results show that human ventricular myocytes express all of the components of the ET-1 system, which is selectively upregulated in ICM patients and appears to be functionally important in the maintenance of cardiac function.

Different Growth Factor Activation in the Right and Left Ventricles in Experimental Volume Overload

Abstract—Mechanical factors play a key role in activation of cardiac growth factor response in hemodynamic overload, and both cooperate in myocardial remodeling. The present study was performed to investigate whether a different growth factor response is activated in the right and left ventricles in aortocaval fistula and its effects on regional myocardial adaptation. Relations between regional growth factor expression (angiotensin II, insulin-like growth factor-I, and endothelin-1), myocyte shape changes, and collagen deposition were investigated at mRNA and peptide levels in adult pigs after the creation of an aortocaval fistula distal to the renal arteries (n=15) and in sham-operated animals (n=15). The role of angiotensin II was investigated by the administration of angiotensin-converting enzyme inhibitor or angiotensin II receptor antagonist. In the left ventricle, pure volume overload was accompanied by persistent increase of insulin-like growth factor-I mRNA expression, peptide concentration (2.2-fold versus sham at 3 months, P <0.05), and significant increase of myocyte length (+29% at 3 months, P <0.05). Conversely, the mixed pressure-volume overload faced by the right ventricle resulted in significant regional overexpression of all growth factors investigated (angiotensin II, insulin-like growth factor-I, and endothelin-1), with corresponding increase of myocyte diameter and length and collagen deposition (+117% at 3 months). Collagen accumulation in the right ventricle as well as the increase in right ventricular end-diastolic pressure at the 3-month observation were inhibited by angiotensin II antagonism. The left and right ventricles respond differently to aortocaval fistula, and local growth factor expression is closely related to the regional myocardial adaptation.

Characterization of endothelin-1 receptor subtypes in isolated human cardiomyocytes.

On cardiac membranes and isolated cardiomyocytes from the human heart, cell-type distribution and functional activities of endothelin-1 (ET-1) receptor subtypes were investigated by using binding methods and messenger RNA (mRNA) in situ hybridization. The ET-receptor antagonist BMS-182874 selectively and competitively inhibits ET(A) receptors both on isolated myocytes and ventricular membranes with approximately 1,300 times greater affinity for ET(A) than ET(B) subtypes. The [125I]-ET-1 specific binding revealed 42.851+/-2,546 receptors/myocyte with a prevalent proportion of ET(A)-receptor subtypes on both myocytes (84+/-2%) and ventricular membranes (66+/-3%). In situ hybridization studies revealed that mRNA for ET(A) receptors was expressed on both myocytes and nonmyocyte cells, whereas mRNA for ET(B) receptors was almost exclusively expressed on fibroblasts and endothelial cells. Specific binding of [125I]-ET-1 to both myocytes and ventricular membranes in the presence of specific ET(A) (BMS-182874) and ET(B) (BQ-788)-receptor antagonists showed a displacement of [125I]-ET-1 by unlabeled ET-1, which were significantly faster from ET(B) than from ET(A). This suggests a clearance function of ventricular ET(B) receptors.

Impairment of cardiopulmonary receptor sensitivity in the early phase of heart failure

Objectives: To characterise the efficiency of the cardiopulmonary baroreflex system in the early phase of heart failure and its relation to limitation of physical activity. Design: Forearm blood flow (venous occlusion plethysmography), vascular resistance, and central venous pressure (CVP), estimated from an antecubital vein, were measured in the supine position at baseline and 15 minutes after application of lower body negative pressure at −7 and −14 mm Hg (receptor downloading) or leg raising (receptor loading). Subjects: Heart failure patients without limitation (NYHA class I; n  =  18) or with slight limitation of physical activity (NYHA class II; n  =  13), and 11 healthy controls. Results: The efficiency of the cardiopulmonary baroreflex function, expressed by the slope of the relation between CVP changes and the corresponding changes of calculated forearm vascular resistance (gain), was reduced both in NYHA class I patients (mean (SD) −1.99 (0.83) v −2.78 (0.66) in controls; p < 0.05) and NYHA class II patients (−1.29 (0.5); p<0.001 v controls). However, change in peripheral vascular resistance during preload increase was similar in controls (−3.3 (0.9) units) and in NYHA class I patients (−3.3 (2.1) units; NS v controls), and was significantly reduced only in NYHA class II patients (−1.6 (1.3) units, p < 0.03 v controls). The gain in the cardiopulmonary reflex was related to the distance walked during the six minute corridor test. Conclusions: A reduced tonic efficacy of the cardiopulmonary reflex system is already detectable in the early phase of heart failure, the impairment in acute response to preload increase being detectable only in symptomatic patients.

Listen to your heart

Case reportIacopo Bertolozzi, Angelo PucciA 61-year-old woman came to the Emergency Departmentof our Hospital for fatigue and breathlessness. She wasdischarged from the surgery ward 2 days before, after asubtotal colectomy for adenocarcinoma had been performed10 days before. While explaining her history, she appearedvery worried because of not hearing since the day before,the usual clicking noise of her mechanical mitral valveprosthesis. The metallic bileaflet-tilting—disk valve (StJude Medical, Inc.) had been implanted 10 years before.Anticoagulant therapy (acenocumarol) was interruptedbefore the colon surgery, and the patient was receiving low-molecular weight heparin (nadroparin 5,700 UI bid).On physical examination, the heart rate was 100 beatsper minute, blood pressure was 90/50 mmHg, and respi-ratory rate was 18 breaths per minute. Auscultation of theheart revealed an absence of a prosthetic closure sound anda grade III holosystolic murmur in the mitral area. Raleswere present at both lung bases. A transthoracic echocar-diogram, immediately performed, revealed severelyrestricted movement of the prosthetic mitral valve leafletswith an increased peak diastolic transmitral pressure gra-dient (Fig. 1a).Unfractioned heparin was commenced immediately. Theidea of arranging a transfer to another hospital for cardiacsurgery was rejected because of the high operative risk andthe presence of co-morbidities. The hemodynamic statusindeed rapidly and dramatically worsened, with the clinicalevidence of cardiogenic shock. Notwithstanding the recentabdominal surgery, systemic thrombolysis was adminis-tered (rt-PA 100 mg over 120 min). The patient’shemodynamic status rapidly improved, and a transthoracicechocardiogram, performed at the end of the rt-PA infu-sion, showed normalization of the transmitral flow pattern(Fig. 1b). The patient was discharged after a 2-week hos-pitalization on anticoagulant treatment.Prosthetic valve thrombosis is an infrequent but poten-tially life-threatening complication with a reportedincidence of 0.5–8% of left-sided valves and up to 20% oftricuspid valves [1–3]. Reoperation, the traditional treat-ment of severe prosthetic thrombosis is associated withsignificant morbidity and mortality particularly in criticalpatients [4, 5]. Evidence is growing that fibrinolysis can beconsidered as the first-line treatment in the absence ofcontraindications [6]. Although recent (less than 2 weeks)major surgical procedures usually exclude the possibility offibrinolysis in myocardial infarction [7], this condition isnot considered a contraindication for treating obstruction ofprosthetic valve in critically ill patients [8] where a totallydifferent balance of risks and benefits exists.CommentPietro Amedeo ModestiThe recent disappearance of the usual clicking noise of thevalve prosthesis referred by the patient immediately led to

Proton Pump Inhibitors and Serum Magnesium Levels in Patients With Torsades de Pointes

Background: Torsades de pointes (TdP) is a life-threatening ventricular tachycardia occurring in long QT-syndrome patients. It usually develops when multiple QT-prolonging factors are concomitantly present, more frequently drugs and electrolyte imbalances. Since proton–pump inhibitors (PPIs)-associated hypomagnesemia is an increasingly recognized adverse event, PPIs were recently included in the list of drugs with conditional risk of TdP, despite only few cases of TdP in PPI users have been reported so far. Objectives: Aim of the present study is to evaluate whether PPI-induced hypomagnesemia actually has a significant clinical impact on the risk of TdP in the general population. Methods: Forty-eight unselected patients who experienced TdP were consecutively enrolled (2008-2017). Shortly after the first TdP episode, in those patients who did not receive magnesium sulfate and/or potassium or calcium replacement therapy, serum electrolytes were measured and their relationship with PPI usage analyzed. Results: Many patients (28/48, 58%) were under current PPI treatment when TdP occurred. Among TdP patients in whom serum electrolyte determinations were obtained before replacement therapy (27/48), those taking PPIs had significantly lower serum magnesium levels than those who did not. Hypomagnesemia occurred in ~40% of patients receiving PPIs (6/14), in all cases after an extended treatment (>2 weeks). In patients taking PPIs the mean QT-prolonging risk factor number was significantly higher than in those who did not, a difference which was mainly driven by lower magnesium levels. Conclusions: In unselected TdP patients, PPI-induced hypomagnesemia was common and significantly contributed to their cumulative arrhythmic risk. By providing clinical support to current recommendations, our data confirm that more awareness is needed when a PPI is prescribed, specifically as regards the risk of life-threatening arrhythmias.