Ammann, Peter

Fehr, Thomas

Wüthrich, Rudolf P.

Zimmermann, Dieter R.

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Nephrol Dial Transplant (2004) 19: 1646–1649DOI: 10.1093/ndt/gfh134Teaching Point(Section Editor: K. Ku¨hn)Supported by an educational grant fromA young renal transplant recipient with unexplained resting sinustachycardia, hypertension and b-blocker resistanceThomas Fehr1, Dieter R. Zimmermann2, Rudolf P. Wu¨thrich1 and Peter Ammann31Division of Nephrology and 3Division of Cardiology, Department of Internal Medicine, Kantonsspital,St. Gallen and 2Laboratory for Molecular Biology, Department of Pathology, University Hospital,Zurich, SwitzerlandKeywords: b1 adrenergic receptor polymorphism;b-blocker; hypertension; resistance; tachycardiaCaseWe report on a 32-year-old patient with reﬂuxnephropathy diagnosed at the age of 11 years. Overthe following 18 years, he developed end-stage renaldisease (ESRD) and was started on haemodialysis in2001. He had to be treated for severe hypertension withvarious medications including diuretics, b-blockers,a-blockers, calcium antagonists and angiotensin recep-tor blockers in various combinations. After 1 year ofhaemodialysis, the patient received a cadaveric renaltransplant that immediately functioned well. Immuno-suppression was installed according to the localstandard protocol with basiliximab, cyclosporin A,mycophenolate mofetil and corticosteroids. The patientsuffered from one episode of biopsy-proven acutetubulointerstitial rejection in the ﬁrst week aftertransplantation, which was treated with three pulsesof intravenous methylprednisolone. The subsequentcourse was uneventful, and corticosteroids could bestopped after 9 months.The patient’s family history revealed hypertensionin his father and mother. The father suffered from amyocardial infarction at the age of 60, when hyperten-sion was detected and treated. The mother hasacknowledged mild to moderate hypertension for >10years, but she was never treated and no furthercardiovascular evaluation was performed.Pulse and blood pressure profilesAlready during haemodialysis this young and well-trained male patient suffered from moderate to severehypertension. This problem persisted after trans-plantation and was always associated with high normalto high resting heart rate (80–115/min). Therefore,post-transplant antihypertensive treatment was basedprimarily on b-blockers. The course of resting bloodpressure and heart rate under escalating doses ofatenolol is shown in Figure 1. Since atenolol had noeffect on both parameters even at 200mg/day, itsubsequently was replaced by carvedilol. This drug’scombined a- and b-blocking effect led to an immediateamelioration of blood pressure. However, although thedose was maximally escalated, the patient’s heart rateremained 100/min (Figure 1).Therefore, secondary causes of tachycardia weresought. Haemoglobin, thyrotropic hormone, fastingcortisol and glucose were within normal ranges.Cardiological examination revealed sinus tachycardiaon resting electrocardiogram (ECG) and left ventric-ular hypertrophy in echocardiography, but no otherabnormalities.Based on pathophysiological considerations, thecombination of tachycardia, hypertension and a clinicalresistance to high dose b-blocker therapy pointed to again of function of the b1 adrenergic receptor. Thishypothesis was evaluated in two respects: (i) a geneticanalysis of the two most frequent polymorphisms of theb1 adrenergic receptor was performed (see below); and(ii) clinically: diltiazem, a class II Ca channel blockerwith inhibitory effects on atrioventricular conductionindependent of b1 adrenergic receptors, was added tothe otherwise unchanged drug therapy (Figure 1). Thisefﬁciently lowered the patient’s resting heart rate asmeasured by 24 h ECG analysis before and afterintroduction of diltiazem (mean pulse drop of 20/min).Correspondence and offprint requests to: Thomas Fehr, MD,Transplantation Biology Research Center, Massachusetts GeneralHospital, MGH East CNY 149 5th ﬂoor, 13th street, Boston MA02129, USA. Email: thomas.fehr@tbrc.mgh.harvard.edu 2004 European Renal Association–European Dialysis and Transplant AssociationMolecular analysis of two 1 adrenergic receptorpolymorphismsIn 1999, two important b1 adrenergic receptor poly-morphisms were identiﬁed: one at amino acid position49 (Ser49Gly) and one at position 389 (Arg389Gly) [1].Whereas homozygosity for the serine allele at position49 is associated with higher resting heart rate [2],homozygosity for arginine at position 389 is linked toelevated blood pressure and elevated heart rate [3].Therefore, we analysed these two polymorphisms inour patient and his parents according to the originaldescription in 1999 [1] with modiﬁed primers. Brieﬂy,genomic DNA was extracted from EDTA blood. Thepolymorphic loci were ampliﬁed by polymerase chainreaction (PCR) with the following primers: for theSer49Gly locus, upstream 50-GTCGCCGCCCGCCTCGTT-30 and downstream 50-CCATGCCCGCTGTCCACTGCT-30; and for the Arg389Gly locus, upstream50-GGCCTTCAACCCCATCATCTA-30 and down-stream 50-CCGGTCTCCGTGGGTCGCGT-30 [2].The conditions for the PCRs were as follows: initialdenaturation at 94C for 5min, 40 cycles with 1min at94C, 1min at 68C (Ser49Gly) or 63C (Arg389Gly)and 2min at 72C with ﬁnal extension for 10min.The PCR products were then directly sequenced, andthe results are shown in Figure 2. The ﬁgure showselectropherograms from an automated sequenceanalyser, where each of the four bases (A, T, C and G)is represented by an individual colour. In Figure 2A,nucleic acid position 145 is shaded. The electrophero-gram shows a single green peak for A in all threeindividuals, meaning that they are all homozygous forA at this position. The triplet AGC codes for the aminoacid serine at position 49 (Ser49Gly locus). In Figure2B, the nucleic acid position 1165 is shaded. In ourindex patient and his mother, we observed a single peakfor C, meaning that they are homozygous for C at thisposition. However, the father shows a double peakfor C (blue, lower peak) and G (black, higher peak).This means that he is heterozygous at this position. Thetriplet CGA codes for the amino acid arginine atposition 389 (Arg389Gly locus), whereas for the fatherthe triplet GGA codes for glycine on one and CGA forarginine on the other allele.Thus, our patient and his mother were both homo-zygous for serine at position 49 and for arginine atposition 389, therefore harbouring the highest riskconstellation for tachycardia and hypertension atthese two loci. In contrast, the patient’s father washeterozygous for arginine at position 389, but alsohomozygous for serine at 49.DiscussionCardiovascular diseases are the most frequent cause ofhospitalizations and death in industrialized countries.Several modiﬁable risk factors such as hypertension,Fig. 1. Heart rate (HR) and systolic blood pressure (SBP) course. Heart rate (circles) and systolic blood pressure (diamonds) are indicated forthe ﬁrst year after renal transplantation. Medications with an effect on blood pressure and/or heart rate (name and total daily dose) arementioned in separate boxes: atenolol is a b1-selective b-blocker, carvedilol a combined b- and a-blocker, amlodipin a class I calcium channelblocker and diltiazem a class II calcium channel blocker with inhibitory effects on atrioventricular conduction.b1 receptor polymorphism, tachycardia and hypertension 1647hyperlipidaemia, diabetes mellitus and smoking havebeen identiﬁed. Familial history of coronary heartdisease or stroke is another important risk factor,which until now could not be modiﬁed. In the era ofmolecular medicine, several genetic causes of cardio-vascular diseases have been recognized. Some of theminﬂuence the mentioned cardiovascular risk factors,e.g. mutations of the low-density lipoprotein receptor,genetic variants of diabetes mellitus (maturity onsetdiabetes of the young type 1–6) and angiotensin-converting enzyme (ACE) polymorphisms predisposingto hypertension [4]. Others lead directly to structural(e.g. genetic forms of hypertrophic and dilated cardi-omyopathy with myosin or troponin mutations) orarrhythmogenic heart disease (e.g. familial forms oflong-QT syndrome with ion channel mutations) [5].In recent years, reports on adrenergic receptor poly-morphisms (a1, b1, b2, b3) and their inﬂuence onblood pressure, heart rate and prognosis of cardio-vascular disease have been published. The human b1adrenergic receptor was cloned in 1987 [6], but thesigniﬁcance of polymorphisms in this gene for thecourse of cardiovascular disease was recognized only10 years later. The two main polymorphisms of theb1 adrenergic receptor (Ser49Gly and Arg389Gly)are associated with elevated heart rate and/orhypertension [2,3].We describe a young patient with unexplained restingtachycardia and hypertension, in which pathophysio-logical considerations together with speciﬁc pharma-cological treatment interventions have led to geneticanalysis and detection of homozygosity for two b1adrenergic receptor polymorphisms. These polymor-phisms are associated with a higher risk for hyperten-sion and tachycardia [2,3] and may explain thepatient’s resistance to b-blocker therapy. The clinicalﬁndings exactly ﬁt in vitro studies on the cellular level,where a gain of function could be demonstrated for thearginine vs glycine allele at position 389 (enhancedagonist-induced adenylyl cyclase activity [7]) and alsofor the serine vs glycine allele at position 49 (reducedagonist-promoted receptor downregulation [8]).Among a long list of antihypertensive drug classes, b-blockers and thiazide diuretics represent the standardtreatment for patients with simple primary hyperten-sion [9]. Concomitant diseases and side effects are themajor determinants for the choice of other drug classes.However, with the detection of ACE polymorphisms,which are frequent among African Americans andlead to a partial resistance to ACE inhibitor therapy[4], the importance of genetic factors for the indi-vidual response to cardiovascular drug treatments hasbecome evident. In our patient, we found a comparablesituation with resistance to b-blocker therapy due toFig. 2. Sequencing results of b1 receptor polymorphism analysis for the index patient and his father and mother. Genomic DNA of the twomain polymorphic loci of the human b1 receptor (Ser49Gly and Arg389Gly) was ampliﬁed by PCR. Products were sequenced according tostandard procedures (see text). (A) Ser49Gly polymorphism: the index patient, his father and his mother were homozygous for serine atposition 49. The important nucleic acid position 145 is shaded. A single peak for A is seen in all three individuals. AGC at this position codesfor serine at position 49. (B) Arg389Gly polymorphism: the index patient and his mother were homozygous for arginine at position 389,whereas the father was heterozygous for arginine and glycine at this position. The important nucleic acid position 1165 is shaded. A singlepeak for C is seen in the index patient and his mother, whereas a double peak for C and G is observed in the father (S stands for C or G in thesequence analysis, which results in arginine or glycine for the encoded amino acid).1648 T. Fehr et al.b1 adrenergic receptor polymorphisms. The clinicalimportance of adrenergic receptor polymorphisms hasonly been recognized very recently by clinical studiesthat demonstrated their association with the incidence[10] and mortality [11] of congestive heart failure, andtheir predictive value for exercise capacity in patientswith heart failure [12].In conclusion, gain of function of the b1 adrenergicreceptor seems to be detrimental for the heart muscle,which was experimentally proven by the developmentof heart failure in b1 adrenergic receptor transgenicmice [13]. In contrast, its inhibition by b-blockertherapy has highly beneﬁcial effects in patients withheart failure [14]. Given the large number of patientswith arterial hypertension and unexplained systolicheart failure, screening for adrenergic receptor poly-morphism might have increasing clinical importance inthe near future.Teaching pointAdrenergic receptor polymorphisms are an increasinglyrecognized cause of unexplained tachycardia, hyperten-sion and congestive heart failure. These polymorphismsadd to a growing list of genetic factors that determinean individual’s response to antihypertensive pharma-cotherapy. It will be a major task in the future tointegrate this information in order to maximally tailordrug therapy to each individual’s genetic proﬁle. Anoptimal effect–side effect relationship should thenresult, and our patient may serve as an early examplefor this attempt.Conﬂict of interest statement. None declared.References1. Maqbool A, Hall AS, Ball SG, Balmforth AJ. Commonpolymorphisms of beta1-adrenoceptor: identiﬁcation and rapidscreening assay. Lancet 1999; 353: 8972. Ranade K, Jorgenson E, Sheu WH et al. A polymorphism inthe beta1 adrenergic receptor is associated with resting heartrate. Am J Hum Genet 2002; 70: 935–9423. Bengtsson K, Melander O, Orho-Melander M et al.Polymorphism in the beta(1)-adrenergic receptor gene andhypertension. Circulation 2001; 104: 187–1904. Kurland L, Melhus H, Karlsson J et al. Angiotensinconverting enzyme gene polymorphism predicts blood pressureresponse to angiotensin II receptor type 1 antagonist treatmentin hypertensive patients. J Hypertens 2001; 19: 1783–17875. Keller DI, Carrier L, Schwartz K. Genetics of familialcardiomyopathies and arrhythmias. Swiss Med Weekly 2002;132: 401–4076. Frielle T, Collins S, Daniel KW et al. Cloning of the cDNA forthe human beta 1-adrenergic receptor. Proc Natl Acad Sci USA1987; 84: 7920–79247. Mason DA, Moore JD, Green SA, Liggett SB. A gain-of-function polymorphism in a G-protein coupling domain ofthe human beta1-adrenergic receptor. J Biol Chem 1999; 274:12670–126748. Levin MC, Marullo S, Muntaner O, Andersson B, MagnussonY. The myocardium-protective Gly-49 variant of the beta1-adrenergic receptor exhibits constitutive activity and increaseddesensitization and down-regulation. J Biol Chem 2002; 277:30429–304359. Chobanian AV, Bakris GL, Black HR et al. The SeventhReport of the Joint National Committee on Prevention,Detection, Evaluation, and Treatment of High BloodPressure: The JNC 7 Report. J Am Med Assoc 2003; 289:2560–257210. Small KM, Wagoner LE, Levin AM, Kardia SL, Liggett SB.Synergistic polymorphisms of beta1- and alpha2C-adrenergicreceptors and the risk of congestive heart failure. N Engl J Med2002; 347: 1135–114211. Borjesson M, Magnusson Y, Hjalmarson A, Andersson B.A novel polymorphism in the gene coding for the beta(1)-adrenergic receptor associated with survival in patients withheart failure. Eur Heart J 2000; 21: 1853–185812. Wagoner LE, Craft LL, Zengel P et al. Polymorphisms ofthe beta1-adrenergic receptor predict exercise capacity in heartfailure. Am Heart J 2002; 144: 840–84613. Engelhardt S, Hein L, Wiesmann F, Lohse MJ. Pro-gressive hypertrophy and heart failure in beta1-adrenergicreceptor transgenic mice. Proc Natl Acad Sci USA 1999; 96:7059–706414. The Cardiac Insufﬁciency Bisoprolol Study II (CIBIS-II): arandomised trial. Lancet 1999; 353: 9–13b1 receptor polymorphism, tachycardia and hypertension 1649

A young renal transplant recipient with unexplained resting sinus tachycardia, hypertension and β-blocker resistance

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